Targeting KITENIN signaling in cancer progression and therapeutic resistance: mechanistic insights and future directions

S M Abdus Salam; Eshrat Jahan; Jeong A Bae; Eun-Jung Ahn; Sung Jin Kim; Kyung-Hwa Lee; Kyung-Sub Moon; Kyung Keun Kim

doi:10.1186/s12935-026-04320-4

. 2026 May 19;26:257. doi: 10.1186/s12935-026-04320-4

Targeting KITENIN signaling in cancer progression and therapeutic resistance: mechanistic insights and future directions

S M Abdus Salam ^1,^2,^#, Eshrat Jahan ^1,^2,^#, Jeong A Bae ³, Eun-Jung Ahn ^1,², Sung Jin Kim ^3,⁴, Kyung-Hwa Lee ^2,^5,^✉, Kyung-Sub Moon ^1,^✉, Kyung Keun Kim ^3,^4,^✉

PMCID: PMC13360528 PMID: 42157238

Abstract

KITENIN (KAI1 C-terminal interacting tetraspanin) has emerged as a critical oncogenic mediator involved in tumor initiation, progression, metastasis, and therapeutic resistance. Initially identified through its interaction with the metastasis suppressor KAI1/CD82, KITENIN activates c-Jun N-terminal kinase (JNK) signaling and AP-1–dependent transcription, thereby driving epithelial–mesenchymal transition (EMT), cytoskeletal remodeling, and invasive behavior. Aberrant KITENIN expression has been reported in diverse solid tumors, including colorectal, gastric, hepatocellular carcinomas, and glioblastoma, where it correlates with aggressive phenotypes and poor prognosis. Preclinical studies show that genetic knockdown or pharmacological inhibition of KITENIN reduces metastatic potential and restores sensitivity to chemotherapy, underscoring its therapeutic relevance. Beyond metastasis, KITENIN contributes to cancer stemness, immune evasion, and resistance to conventional treatments, positioning it as a multifaceted regulator of tumor biology. Recent efforts to therapeutically target KITENIN include small molecules, natural compounds, and peptide-based inhibitors, though clinical translation remains in early stages. This review outlines the structural and mechanistic underpinnings of KITENIN-driven oncogenesis, evaluates its prognostic significance, and consolidates emerging evidence on KITENIN-targeted approaches. By highlighting current gaps and future directions, we propose that targeting the KITENIN axis holds promise for suppressing metastasis and improving outcomes in precision oncology.

Keywords: Cancer invasion, Cancer metastasis, KITENIN, Novel therapeutics, Therapeutic resistance

Introduction

Cancer remains a major global health burden, ranking as the second leading cause of mortality after cardiovascular disease. A predominant contributor to this high mortality is distant metastasis, which accounts for the vast majority of cancer-related deaths [1]. Although chemotherapy, targeted therapy, and more recently immunotherapy have improved patient survival, these benefits are often transient or limited to select subgroups, largely due to metastatic relapse and acquired resistance [2]. Aggressive malignancies, such as those of the brain and nervous system, epitomize this clinical challenge [3].

The development of cancer is driven by the progressive accumulation of genetic alterations that disturb cellular homeostasis, ultimately leading to oncogene activation and loss of tumor suppressor function [4]. Within this context, metastasis suppressor genes have attracted attention as they specifically inhibit metastatic dissemination without preventing primary tumor formation. The therapeutic limitations of current regimens ultimately reflect their inability to fully prevent or eradicate metastatic disease, underscoring the clinical importance of understanding these suppressors [5].

Among them, KAI1 (CD82) was the first metastasis suppressor identified in prostate cancer and later implicated in pancreatic, non-small cell lung, and breast cancer [6–9]. KAI1 encodes a tetraspanin family member that regulates membrane organization, cell-cell adhesion, and intracellular signaling, with its COOH-terminal region being particularly critical for anti-metastatic activity [10, 11]. A significant advancement in the understanding of KAI1 biology was the identification of an alternatively spliced variant of KAI1 mRNA lacking exon 7, which results in an altered COOH-terminal region and exhibits lower metastasis-suppressive properties compared with the wild-type isoform. This discovery also led to the isolation of a novel cDNA encoding a tetraspanin protein (homologous to Drosophila Vang-like protein 1, Vangl1) that specifically binds to the COOH-terminal region of KAI1, subsequently termed KITENIN (KAI1 C-terminal interacting tetraspanin) [12]. In contrast to the metastasis-suppressive role of KAI1, KITENIN functions as an oncogenic driver by activating JNK/AP-1 signaling and promoting EMT, invasion, distant metastasis, and therapeutic resistance [13–16]. Aberrant KITENIN expression has been consistently associated with poor outcomes across multiple cancers including colorectal, gastric, hepatocellular, glioblastoma, and head and neck carcinomas [17–26]. Thus, the discovery of a KAI1-interacting tetraspanin as a metastasis-enhancing oncogenic protein was a pivotal advance in this field of metastasis research.

Despite accumulating evidence linking KITENIN to malignant transformation, metastasis, and therapeutic resistance, its molecular mechanisms remain incompletely defined. This review therefore aims to (i) delineate the structural and signaling properties of KAI1/CD82 and KITENIN, (ii) summarize their expression patterns and prognostic relevance across diverse cancers, (iii) synthesize mechanistic insights into KITENIN-mediated oncogenic pathways, and (iv) discuss emerging therapeutic strategies and future perspectives for targeting the KITENIN axis as a promising approach to suppress metastasis within the framework of precision oncology.

Molecular features of KAI1 and KITENIN: interactions and functional implications

KAI1/CD82 is a tetraspanin glycoprotein belonging to the transmembrane 4 superfamily (TM4SF), with a molecular weight ranging from 40 to 75 kDa [10, 11] (Fig. 1A). A protein homologous to Drosophila Vangl1 was identified to interact specifically with the COOH-terminal region of KAI1/CD82. This interacting partner was subsequently designated as KITENIN, a product of the VANGL1 gene mapped to chromosome 1p13 in humans. VANGL1 is a core component of the planar cell polarity (PCP) signaling pathway [27, 28] and encodes a ~ 60 kDa structural protein (www.phosphosite.org/proteinAction.action? id=10387&showAllSites=true), composed of five polypeptide chains (A–E) and 524 amino acids in total sequence length (www.rcsb.org/structure/8zxd) (Fig. 1B).

Fig. 1 — Structural and functional features of KAI1/CD82 and KITENIN. (A) Structural representation of KAI1/CD82 (predicted by AlphaFold, refer to the UniProt: http://www.uniprot.org/uniprotkb/P27701/entry). KAI1/CD82 is a member of the transmembrane 4 superfamily (TM4SF) and is structurally composed of four transmembrane domains (TM1–TM4), two extracellular loops (ECL1 and ECL2), and short cytoplasmic N- and C-terminal tails. The larger extracellular loop (ECL2) is involved in interactions with integrins (e.g., α4β1), contributing to cell-cell adhesion. N-terminal glycosylation has been associated with increased apoptotic signaling and reduced cell motility. The C-terminal region serves as a docking site for intracellular partners such as KASP and KITENIN. (B) Structural features of VANGL1/KITENIN, which oligomerizes as dimers of trimers (generated with PyMOL, refer to the UniProt: http://www.uniprot.org/uniprotkb/Q8TAA9/entry). KITENIN, encoded by the VANGL1 gene, is a planar cell polarity protein with a tetraspanin-like topology. It comprises four transmembrane helices and large intracellular C-terminal region that mediate interactions with other proteins. Structural data from the RCSB Protein Data Bank (PDB ID: 8ZXD) indicate that KITENIN adopts a conserved conformation typical of tetraspanins, facilitating its integration into the membrane and organization within tetraspanin-enriched microdomains (TEMs). (C) Functional interaction between KAI1/CD82 and KITENIN. The C-terminal intracellular domain of KITENIN interacts with the C-terminal region of KAI1/CD82. While KAI1 generally functions as a metastasis suppressor by stabilizing cell adhesion and inhibiting migration, binding with KITENIN attenuates this suppressive function. This interaction promotes cytoskeletal reorganization and enhances metastatic potential, partly through activation of AP-1 signaling pathways. In contrast, binding of KAI1 to KASP enhances its tumor-suppressive function

KAI1/CD82 and other TM4SF members contain four conserved transmembrane (TM) domains that mediate the formation of tetraspanin-enriched microdomains (TEMs) at the plasma membrane [10, 11]. These microdomains play critical roles in regulating cell adhesion, motility, and signal transduction. The TM domains of KAI1/CD82 anchor the protein to the membrane and facilitate lateral interactions with other membrane proteins. The extracellular region comprises two loops: a small extracellular loop (ECL1) and a large extracellular loop (ECL2), which mediate interactions with integrins (e.g., α4β1) and other surface proteins to maintain intercellular adhesion and tissue integrity. The intracellular portion includes a short intracellular loop (ICL), as well as N- and C-terminal cytoplasmic domains. N-terminal glycosylation of KAI1 has been associated with reduced cell motility and enhanced apoptosis.

KAI1/CD82 interacts with several intracellular binding partners, including KAI1-associated surface protein (KASP, also known as EW12/PGRL) and KITENIN. The interaction between KAI1 and KASP enhances the tumor-suppressive functions of KAI1, whereas binding to KITENIN counteracts KAI1-mediated suppression and instead promotes metastatic phenotypes in tumor cells. Interestingly, subsequent studies have identified additional KITENIN-interacting proteins, including 90 K (also known as galectin-3 binding protein; LGALS3BP) and protein kinase C inhibitor (PKCI) [13]. Of interest, 90 K represents a tumor-associated glycoprotein endowed with immunoregulatory activity. Downregulation of KITENIN in colorectal cancer (CRC) models increases 90 K release, leading to elevated IL-2 and IFN-γ production and enhanced recruitment of CD4⁺ and CD8⁺ T cells within the tumor microenvironment (TME) [29]. This suggests that while KITENIN antagonizes KAI1’s metastasis-suppressive role, its inhibition paradoxically triggers an immune-mediated tumor-suppressive axis via 90 K, revealing a potential feedback mechanism that could be therapeutically exploited. Additionally, a recent study has demonstrated that the KITENIN-CCL20 axis directly facilitates immunosuppressive TME in glioblastoma mouse models [30].

Structurally, KITENIN is classified within the tetraspanin protein family and comprises three major domains: (1) a TM domain consisting of four hydrophobic α-helical segments; (2) extracellular loops, including an extracellular loop responsible for protein-protein interactions; and (3) a cytoplasmic C-terminal domain. The TM domains mediate membrane localization and integration, while the extracellular loop contributes to cellular communication and adhesion. The C-terminal intracellular domain of KITENIN directly interacts with the cytoplasmic tail of KAI1/CD82, modulating key cellular behaviors such as adhesion, migration, and metastasis (Fig. 1C).

Expression and prognostic significance of KAI1 and KITENIN across cancers

We analyzed the transcriptomic profiles of the metastasis suppressor gene CD82/KAI1 and the oncogenic gene KITENIN (VANGL1) using TCGA pan-cancer datasets (TCGAplot v8.0.0). Consistent with its established role as a metastasis suppressor, CD82 expression was generally reduced in many tumor types compared with normal tissues, although some cancers exhibited relative upregulation (Fig. 2A), including cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), rectal adenocarcinoma (READ), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC). These findings are in line with previous reports describing context-dependent alterations of KAI1 expression across malignancies [31]. Importantly, reduced KAI1 expression has been consistently correlated with enhanced metastatic potential and poor prognosis in multiple cancers [32].

Fig. 2 — Expression and prognostic significance of CD82 and KITENIN across human cancers. (A) Differential expression of the tumor suppressor gene CD82 (KAI1) across TCGA pan-cancer datasets. CD82 expression is significantly elevated in CESC, CHOL, COAD, ESCA, READ, STAD, and UCEC compared to other tumor types. (B) Aberrant overexpression of the oncogenic gene KITENIN (VANGL1) in various cancers, with highest expression observed in BLCA, BRCA, CESC, CHOL, COAD, ESCA, GBM, HNSC, LIHC, LUAD, LUSC, STAD, and UCEC. (C) Paired analysis of tumor and adjacent normal tissues reveals significantly higher KITENIN expression in BLCA, BRCA, ESCA, HNSC, KIRC, LIHC, LUAD, LUSC, PRAD, STAD, and UCEC, indicating tumor-specific upregulation. (D) Forest plot depicting hazard ratios (HRs) for KITENIN expression across 33 TCGA cancer types. High expression of KITENIN is significantly associated with worse overall survival in ACC, BRCA, CESC, LGG, LUAD, and PAAD. In contrast, KIRC and READ show a significant association between high KITENIN expression and improved survival, suggesting a context-dependent dual role. Statistical significance was determined using Cox proportional hazards regression analysis. HR > 1 indicates poor prognosis; HR < 1 indicates favorable prognosis

In contrast, VANGL1/KITENIN exhibited widespread aberrant overexpression across diverse malignancies. Elevated levels were detected in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), CESC, CHOL, COAD, ESCA, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), STAD, and UCEC (Fig. 2B). Pairwise analysis between tumor and adjacent normal tissues further confirmed significantly higher KITENIN expression in BLCA, BRCA, ESCA, HNSC, kidney renal clear cell carcinoma (KIRC), LIHC, LUAD, LUSC, prostate adenocarcinoma (PRAD), and STAD (Fig. 2C).

To determine its clinical relevance, we next performed a pan-cancer survival analysis using univariate Cox proportional hazards models. Elevated KITENIN expression was strongly correlated with reduced overall survival in adrenocortical carcinoma (ACC), BRCA, CESC, brain lower grade glioma (LGG), LUAD, and pancreatic adenocarcinoma (PAAD) (Fig. 2D; Table 1). A non-significant trend toward poor survival was also observed in BLCA, diffuse large B-cell lymphoma (DLBC), HNSC, kidney chromophobe (KICH), kidney renal papillary cell carcinoma (KIRP), LIHC, mesothelioma (MESO), skin cutaneous melanoma (SKCM), STAD, uterine carcinosarcoma (UCS), and uveal melanoma (UVM). Conversely, high KITENIN expression showed a non-significant association with favorable survival in several cancers, including CHOL, COAD, ESCA, GBM, acute myeloid leukemia (LAML), LUSC, ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), PRAD, sarcoma (SARC), testicular germ cell tumors (TGCT), thyroid carcinoma (THCA), thymoma (THYM), and UCEC. Although elevated KITENIN expression was associated with adverse outcomes in many tumor types, the apparently favorable association observed in KIRC and READ suggests context-dependent biology rather than a uniformly oncogenic effect. These results should be interpreted cautiously because transcript-level abundance may not directly reflect active KITENIN signaling complexes, and survival associations may be influenced by lineage-specific signaling, immune and stromal composition, stage distribution, tumor purity, and treatment context. Therefore, the KIRC and READ findings are best regarded as hypothesis-generating observations that require mechanistic validation rather than evidence of a tumor-suppressive role for KITENIN in these cancers.

Table 1.

Prognostic impact of VANGL1 (KITENIN) expression across TCGA cancer types

TCGA cancer	HR (95% CI)*	P Value	High VANGL1 expression effect^#
ACC	1.644 (1.077–2.509.077.509)	0.021	Significantly associated with worse survival
BLCA	1.219 (0.936–1.586.936.586)	0.141	Non-significant trend toward worse survival
BRCA	1.389 (1.095–1.762.095.762)	0.007	Significantly associated with worse survival
CESC	1.794 (1.187–2.712.187.712)	0.006	Significantly associated with worse survival
CHOL	0.804 (0.434–1.488.434.488)	0.487	Non-significant trend toward better survival
COAD	0.774 (0.48–1.246.48.246)	0.291	Non-significant trend toward better survival
DLBC	1.075 (0.386–2.999.386.999)	0.89	Non-significant trend toward worse survival
ESCA	0.84 (0.581–1.214.581.214)	0.354	Non-significant trend toward better survival
GBM	0.986 (0.784–1.241.784.241)	0.905	Non-significant trend toward better survival
HNSC	1.158 (0.943–1.421.943.421)	0.161	Non-significant trend toward worse survival
KICH	1.795 (0.66–4.884.66.884)	0.252	Non-significant trend toward worse survival
KIRC	0.698 (0.585–0.832.585.832)	0	Significantly associated with better survival (protective role)
KIRP	1.232 (0.768–1.976.768.976)	0.387	Non-significant trend toward worse survival
LAML	0.976 (0.801–1.189.801.189)	0.808	Non-significant trend toward better survival
LGG	2.066 (1.6–2.667.6.667)	0	Significantly associated with worse survival
LIHC	1.258 (0.932–1.7.932.7)	0.134	Non-significant trend toward worse survival
LUAD	1.531 (1.192–1.967.192.967)	0.001	Significantly associated with worse survival
LUSC	0.998 (0.79–1.259.79.259)	0.984	Non-significant trend toward better survival
MESO	1.456 (0.891–2.38.891.38)	0.134	Non-significant trend toward worse survival
OV	0.862 (0.719–1.034.719.034)	0.109	Non-significant trend toward better survival
PAAD	1.468 (1.152–1.87.152.87)	0.002	Significantly associated with worse survival
PCPG	0.785 (0.226–2.723.226.723)	0.703	Non-significant trend toward better survival
PRAD	0.979 (0.34–2.823.34.823)	0.969	Non-significant trend toward better survival
READ	0.175 (0.056–0.546.056.546)	0.003	Significantly associated with better survival (strong protective role)
SARC	0.926 (0.686–1.249.686.249)	0.614	Non-significant trend toward better survival
SKCM	1.186 (0.993–1.416.993.416)	0.059	Non-significant trend toward worse survival
STAD	1.017 (0.735–1.406.735.406)	0.92	Non-significant trend toward worse survival
TGCT	0.472 (0.124–1.806.124.806)	0.273	Non-significant trend toward better survival
THCA	0.839 (0.361–1.951.361.951)	0.684
THYM	0.453 (0.173–1.183.173.183)	0.106
UCEC	0.858 (0.611–1.204.611.204)	0.375
UCS	1.14 (0.691–1.883.691.883)	0.608	Non-significant trend toward worse survival
UVM	1.565 (0.645–3.801.645.801)	0.322	Non-significant trend toward worse survival

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This table summarizes the hazard ratios (HR), 95% confidence intervals (CI), and p-values for VANGL1 (KITENIN) expression in 33 tumor types from the TCGA dataset, based on univariate Cox regression analysis. Cancer types are categorized into three groups: significantly associated with poor survival (e.g., ACC, BRCA, CESC, LGG, LUAD, PAAD), significantly associated with favorable survival (e.g., KIRC, READ), non-significant but notable trends (HR > 1 or < 1, p > 0.05). This analysis highlights the potential of KITENIN as a prognostic biomarker and supports the notion of its dual functional role depending on tumor context

ACC: Adrenocortical carcinoma; BLCA: Bladder Urothelial Carcinoma; BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: Cholangiocarcinoma; COAD: Colon adenocarcinoma; DLBC: Lymphoid Neoplasm Diffuse Large B-cell Lymphoma; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; HNSC: Head and Neck squamous cell carcinoma; KICH: Kidney Chromophobe; KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LAML: Acute Myeloid Leukemia; LGG: Brain Lower Grade Glioma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; MESO: Mesothelioma; OV: Ovarian serous cystadenocarcinoma; PAAD; Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and Paraganglioma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; SARC: Sarcoma; SKCM: Skin Cutaneous Melanoma; STAD: Stomach adenocarcinoma; TGCT: Testicular Germ Cell Tumors; THCA: Thyroid carcinoma; THYM: Thymoma; UCEC: Uterine Corpus Endometrial Carcinoma; UCS: Uterine Carcinosarcoma; UVM: Uveal Melanoma

*Hazard ratio (HR) interpretation. HR > 1: Suggests increased risk (worse survival) with high expression; HR < 1: Suggests decreased risk (better survival); HR = 1: No effect on survival

#Statistical Significance Criteria. If P < 0.05 and CI does not cross 1, the association is statistically significant. If P > 0.05 or CI includes 1, the result is not significant

In a view of clinical significance, KITENIN expression has been associated with tumor invasion, lymph node metastasis, and worse prognosis, with both primary cohort studies and later expression-signature analyses supporting its prognostic relevance in CRC (17, 33, 34, 35). In glioma, high KITENIN expression was associated with shorter progression-free survival in patients, and experimental overexpression accelerated tumor progression and reduced survival in orthotopic mouse models (21, 22, 36, 37). Additional studies have also reported prognostic or relapse-associated expression patterns in other cancers, including breast cancer (38), while public pan-cancer resources such as the Human Protein Atlas provide broader exploratory survival associations across multiple tumor types (39). Taken together, the available evidence suggests that KITENIN/VANGL1 is not only a marker of tumor invasiveness but also a potential prognostic biomarker in several malignancies, particularly CRC and glioma (Table 2).

Table 2.

Cancer type-dependent prognostic significance of KITENIN expression

Cancer type	Key findings	Prognostic direction	Evidence type
Colorectal cancer	KITENIN/VANGL1 is associated with invasion, tumor progression, lymph node metastasis, and poor survival.	Higher expression is associated with worse prognosis.	Patient tissue cohort, expression/survival analysis
Glioblastoma	High KITENIN expression is associated with shorter progression-free survival in patients, and KITENIN overexpression shortens survival in mouse tumor models.	Higher expression is associated with worse prognosis.	Human cohort, orthotopic mouse model
Breast cancer	VANGL1 is reported as a relapse-associated prognostic marker in survival analyses.	Higher expression is associated with worse outcome and increased relapse risk.	Expression-based prognostic association
Gastric cancer	KITENIN expression is elevated in tumor and metastatic tissues, supporting a pro-metastatic role.	Higher expression suggests aggressive tumor biology, though direct survival evidence remains limited.	Tumor/metastasis expression study
Pan-cancer resource	Human Protein Atlas provides VANGL1 pathology/survival data across 17 cancer types	Suitable for pan-cancer screening; not a unified clinical study	The human protein atlas database

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Taken together, these transcriptomic and prognostic findings underscore a sharp contrast: KAI1 downregulation is broadly associated with tumor aggressiveness, whereas KITENIN overexpression frequently predicts poor survival but may exert tumor-suppressive effects in specific contexts. Such dual characteristics indicate that KITENIN activity is dictated by tumor subtype and TME context, highlighting the necessity for detailed mechanistic dissection and assessment of KITENIN in both diagnostic and therapeutic settings.

Mechanistic insights into KITENIN biology

Common oncogenic mechanisms of KITENIN

Across multiple malignancies, KITENIIN functions as a central oncogenic driver by converging on several core pathways (Fig. 3):

EMT and invasion:

KITENIN promotes cytoskeletal remodeling and EMT through activation of the JNK/AP-1 axis, induction of matrix metalloproteinases (MMPs), and cooperation with scaffold proteins such as disheveled (Dvl) and PKCδ. These changes enhance motility, invasiveness, and metastatic dissemination [14].

Cancer stemness:

KITENIN sustains cancer stem-like properties by upregulating cancer stem cell (CSC) markers (e.g., CD44, ALDH1, SOX2, OCT4) and promoting neurosphere or spheroid formation. This CSC-supportive role contributes to tumor recurrence and therapy resistance [21, 22].

Therapy resistance:

KITENIN overexpression drives resistance to chemotherapeutic agents and targeted therapies, including anti-EGFR treatment in CRC [16] and temozolomide in glioblastoma [22]. Mechanisms involve c-Jun/AP-1 activation, metabolic reprogramming, and maintenance of CSC phenotypes.

TME modulation:

KITENIN regulates pro-tumorigenic mediators such as COX-2, VEGF-A, and HIF-1α, linking it to angiogenesis and immunosuppressive signaling [e.g., PGE2-driven expansion of regulatory T cells (Tregs) and tumor-associated macrophages (TAMs)] [40]. KITENIN-CCL20 axis has been proposed to lead immunosuppressive TME, through myeloid-derived suppressive cell (MDSC) [30]. In addition, KITENIN has been shown to interact with the extracellular glycoprotein 90 K (Mac-2BP/LGALS3BP) [13], a key immune-modulatory factor secreted in the tumor milieu, suggesting that KITENIN may also reprogram the immune microenvironment by engaging glycoprotein-mediated signaling networks [29]. This dual regulation of angiogenic and immune pathways underscores KITENIN’s role as a central orchestrator of the TME.

Transcriptional and epigenetic regulation of KITENIN:

KITENIN regulation appears to occur at multiple levels. At the transcriptional level, available evidence suggests that canonical Wnt/β-catenin signaling might enhance KITENIN expression through TCF4-dependent regulation, linking KITENIN to a broader network of epithelial plasticity and tumor progression [41–43]. At the post-transcriptional level, several microRNAs, including miR-124, miR-27a, and miR-30b, suppress KITENIN expression by targeting its 3′-UTR. Among these, miR-124 appears particularly important, and epigenetic silencing of miR-124 through promoter hypermethylation can indirectly derepress KITENIN expression [44, 45]. Nevertheless, major knowledge gaps remain. Direct evidence for KITENIN promoter methylation, enhancer regulation, lineage-specific transcription factor occupancy, or chromatin accessibility at the VANGL1 locus is still limited. Future ChIP-seq [46], ATAC-seq [47], CUT&Tag [48], and CRISPR interference [49] studies will be required to define the cis-regulatory architecture controlling KITENIN expression in different cancers.

Cancer type-specific insights

The shared oncogenic properties underscore KITENIN as a molecular hub connecting metastasis, stemness, immune evasion, and therapeutic resistance across multiple tumor types (Fig. 4).

Fig. 4 — Oncogenic roles and molecular mechanisms of KITENIN across multiple cancer types. KITENIN promotes cancer progression through diverse signaling pathways. In CRC, it forms a complex with Dvl and PKCδ to activate ERK/AP-1, inducing MMPs, COX-2, and CD44, thereby enhancing EMT, invasion, angiogenesis, and therapeutic resistance; inhibitors of KITENIN (DKC1125, KDIP, miR-124) restore chemosensitivity. In GC, KITENIN is overexpressed, activating MAPK pathways and driving MMPs/COX-2/CD44 expression, leading to lymph node metastasis and poor survival. In HCC, KITENIN–AP-1 signaling upregulates COX-2/PGE2–VEGF and MMP3, promoting angiogenesis, immune evasion, and EMT. In HNSC, overexpression increases invasion, metastasis, and Cyclin D1/MMPs/COX-2/CD44 via AP-1. In BLCA, loss of KAI1/CD82 enhances KITENIN-mediated cytoskeletal reorganization and invasion. In glioblastoma, KITENIN upregulates EMT and CSC markers, contributing to tumor aggressiveness and TMZ resistance; inhibitors such as usnic acid and DKC1125 suppress these effects

Colorectal cancer (CRC)

In CRC, KITENIN functions as a major oncogenic driver by engaging multiple signaling axes, metabolic pathways, and resistance mechanisms.

Oncogenic signaling from the plasma membrane via KITENIN-ErbB4-c-Jun axis

KITENIN directly interacts with the ErbB4 receptor, leading to sustained activation of c-Jun, a key subunit of the AP-1 transcription factor complex. This KITENIN-ErbB4-c-Jun signaling axis enhances tumor progression by promoting invasion and metastasis and contributes to resistance against anti-EGFR therapies commonly used in CRC [15]. Conversely, the E3 ubiquitin ligase Nrdp1 targets ErbB3/4; formation of an Nrdp1-ErbB4-KITENIN complex suppresses Dvl activity and downregulates c-Jun, thereby attenuating KITENIN-mediated oncogenic signaling [50].

For activation of signaling, the ErbB4/KITENIN complex has to be localized in the plasma membrane to interact the extracellular EGF. This EGF-stimulated ErbB4/KITENIN complex has been found to be anchored in the plasma membrane with the aid of unconventional myosin-I MYO1D [51], a molecular motor and one of ErbB4-interacting proteins. Knockdown of MYO1D leads to disengagement of ErbB4/KITENIN from the plasma membrane into the cytosol, which is processed through proteasomal degradation to cause down-regulated level of ErbB4/KITENIN on the plasma membrane and resulting the MYO1D-knockdown CRC cells to exhibit decreased cell invasion. This maintaining KITENIN on the cell surface via MYO1D is partly supported by the in vivo observation that asymmetric hyper-expression or localization of KITENIN in the tracheal mucosal surface is lost in the Myo1d-knockout rat [52].

The blockade of MYO1D function via MYO1D inhibitors is expected to offer a novel approach to block the downstream signaling of ErbB4/KITENIN in cancer cells and thereby to suppress the growth of various KITENIN-overexpressing tumors [51]. Importantly, the natural anthraquinone compound chrysophanol has been shown to bind ErbB4, disrupt the KITENIN-ErbB4 complex, and promote autophagic degradation of KITENIN [34], highlighting a potential pharmacological entry point.

Metabolic reprogramming and angiogenesis

KITENIN drives metabolic adaptation by upregulating pyruvate kinase M2 (PKM2) through the c-Myc/heterogeneous nuclear ribonucleoprotein (hnRNP) axis, thereby enhancing aerobic glycolysis (Warburg effect) to sustain rapid tumor growth and survival [35]. In addition, KITENIN overexpression induces angiogenesis by increasing vascular endothelial growth factor A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α), further supporting tumor progression [40].

Post-transcriptional regulation by microRNAs (miRs)

KITENIN expression is regulated by several miRs, including miR-124, miR-27a, and miR-30b, which bind to its 3′-UTR. Among these, miR-124 exerts the strongest inhibitory effect, markedly reducing KITENIN expression and thereby suppressing CRC cell motility, invasiveness, and tumorigenicity [44, 45]. These findings suggest that loss or downregulation of tumor-suppressive miRs can unleash KITENIN-driven oncogenic signaling.

Pharmacological inhibition of KITENIN

Preclinical data support KITENIN inhibition as a therapeutic strategy in CRC. The compound DKC1125 interacts with KH-type splicing regulatory protein (KSRP), recruits RACK1 and miR-124 to dismantle the KITENIN–DVL2 complex, and induces proteasomal degradation of the KITENIN–KSRP–RACK1–DVL2 network. Notably, exposure to DKC1125 reinstates responsiveness of CRC cells to 5-fluorouracil, oxaliplatin, and cetuximab [53]. In addition, KITENIN dimerization enhances its oncogenic activity via strong RACK1-RIM interactions, stabilized by myosin-X (Myosin10, Myo10). A recently developed KITENIN dimerization-interfering peptide (KDIP) effectively disrupts RACK1-RIM binding, thereby attenuating KITENIN-mediated tumor-promoting functions [54]. Alongside chrysophanol, these approaches underscore KITENIN as a druggable target whose inhibition can overcome metastatic progression and therapy resistance in CRC.

Collectively, KITENIN promotes CRC progression through the ErbB4-c-Jun signaling, metabolic adaptation, and angiogenesis, while escaping miRNA suppression. Pharmacological targeting strategies, including small molecules and peptide inhibitors, provide compelling proof of concept that KITENIN inhibition can suppress invasion and metastasis while restoring chemosensitivity.

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Gastric cancer (GC)

As one of the leading causes of cancer death worldwide, GC remains a major clinical challenge [1, 2]. KITENIN interferes with the metastasis-suppressive function of KAI1, and diminished KAI1 expression has been implicated in advanced tumor progression [5, 11]. Clinical specimen studies consistently show elevated KITENIN expression in tumor tissues compared with surrounding normal mucosa, highlighting its contribution to aggressive behavior [19].

Mechanistically, KITENIN activates MAPK signaling cascades (ERK1/2, JNK, and p38), leading to the upregulation of MMP-1, MMP-3, COX-2, and CD44, and subsequent activation of AP-1 transcription factors. These alterations enhance tumorigenesis and facilitate lymph node metastasis, linking KITENIN to poor clinical outcomes [19]. Indeed, high KITENIN expression correlates with unfavorable overall survival in patients with GC.

While these findings implicate KITENIN as a pro-metastatic driver in GC as tissue specific manner, the current body of evidence remains relatively limited compared with that for other solid tumors. Additional in vivo validation and mechanistic dissection are required to define the precise contribution of KITENIN to GC initiation, progression, and therapeutic resistance.

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Hepatocellular carcinoma (HCC)

HCC is a highly lethal malignancy with poor survival outcomes [1, 2]. KITENIN has been consistently implicated as tumorigenesis in HCC. Similar to its role in GC, KITENIN enhances oncogenic signaling in HCC. In HepG2 and Huh7 cell models, overexpression of KITENIN activates AP-1 transcriptional activity through MAPK signaling pathways, whereas siRNA-mediated knockdown of KITENIN reduces the expression of downstream effectors, including COX-2 and MMP-3 [20].

The COX-2/PGE2 axis plays a particularly important role in KITENIN-driven HCC progression [55]. COX-2-derived prostaglandin E2 (PGE2) not only stimulates angiogenesis through VEGF induction but also fosters an immunosuppressive TME, characterized by expansion of Tregs, TAMs, and MDSCs, and reduced antigen presentation by dendritic cells and macrophages [55, 56]. By enhancing this pro-angiogenic and immunosuppressive network, KITENIN contributes to both tumor growth and immune evasion.

In addition, KITENIN-driven upregulation of MMP-3 promotes extracellular matrix degradation and EMT, further reinforcing invasive and metastatic phenotypes in HCC [57]. Collectively, these findings suggest that KITENIN accelerates HCC progression not only through direct enhancement of EMT and invasion but also by reshaping the TME to support angiogenesis and immune escape.

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Head and neck squamous cell carcinoma (HNSC)

KITENIN has been implicated as a key promoter of invasion and metastasis in HNSC [23]. Functional studies in the SNU-1041 hypopharyngeal carcinoma model revealed that siRNA knockdown of KITENIN strongly inhibited invasion, migration, and proliferation, highlighting its role in sustaining tumor aggressiveness [58]. Similarly, mouse models confirmed that enforced KITENIN expression enhances invasive potential and promotes early dissemination to the lungs [23, 24].

Clinical evidence also highlights the relevance of KITENIN in HNSC. Cytoplasmic KITENIN immunoreactivity is observed in nearly 60% of human HNSC samples, and its high expression correlates with advanced stage and lymph node metastasis [24–26]. These findings suggest that KITENIN expression can serve as both a biomarker of tumor aggressiveness and a potential therapeutic target.

Mechanistically, KITENIN has been linked to the induction of cell cycle regulators (e.g., cyclin D1) and invasion-associated molecules [23], but compared with CRC or GCs, the detailed downstream signaling network in HNSC remains less well characterized. This knowledge gap underscores the need for further studies, particularly those aimed at developing KITENIN-targeted interventions for head and neck malignancies.

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Bladder urothelial carcinoma (BLCA)

In BLCA, KITENIN is uniformly expressed across cell lines; however, loss of the metastasis suppressor KAI1/CD82 markedly enhances invasive capacity and alters actin cytoskeletal organization, suggesting that the KITENIN-KAI1 axis critically regulates tumor cell motility [59]. Consistent with these findings, transcriptomic data from TCGA confirm that KITENIN is frequently overexpressed in BLCA, whereas reduced CD82 expression correlates with poor prognosis. These results imply that an imbalance between KITENIN overactivation and KAI1 loss underlies aggressive phenotypes in BLCA.

Although mechanistic details are less well characterized in BLCA than in CRC or GC, available evidence suggests that KITENIN promotes cytoskeletal remodeling and EMT-like changes, particularly under conditions of KAI1 downregulation, thereby enhancing metastatic potential. The KITENIN-KAI1 axis thus represents a potential determinant of BLCA aggressiveness and a candidate target for therapeutic intervention, warranting further studies to elucidate its downstream effectors.

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Glioblastoma

Glioblastoma is an aggressive primary intracranial malignancy with poor prognosis and limited therapeutic options. Analysis of patient-derived glioma specimens shows that KITENIN mRNA and protein levels are significantly higher in high-grade gliomas (WHO grades III-IV) compared with low-grade gliomas (WHO grades I-II), and elevated expression correlates with poor clinical outcomes [21]. Functionally, KITENIN promotes glioblastoma invasiveness through the activation of EMT-related transcription factors such as N-cadherin, ZEB1/2, Snail, Slug, Twist, fibronectin, and vimentin. Inhibition of KITENIN suppresses neurosphere and colony formation while downregulating CSC markers, including ALDH1, CD133, CD44, EPHB1, Nestin, OCT4, SOX2, and HES1, indicating a central role in sustaining CSC phenotypes [21].

A clinically important link between KITENIN and therapeutic resistance has also been established. In glioblastoma with an unmethylated O⁶-methylguanine-DNA methyltransferase (MGMT) promoter, a known poor prognostic factor, KITENIN enhances temozolomide (TMZ) resistance by upregulating ALDH1 and CD44. Pharmacological inhibition of KITENIN with usnic acid (UA) reduces EMT markers and CSC-associated genes, while the small-molecule inhibitor DKC1125 effectively suppresses c-Jun, c-Fos and AP-1 signaling, as well as ALDH1A1 and CD44 expression in TMZ-resistant glioblastoma cells [22]. Importantly, KITENIN expression is significantly higher in recurrent glioblastoma than in primary tumors [22], further underscoring its role in disease progression and relapse. In a recent study identifies a novel complex of Vangl1 and Fzd7, key components of the non-canonical Wnt/planar cell polarity (PCP) pathway, enhance glioblastoma malignancy by promoting cell proliferation, migration, and invasion, while activating Rho GTPases to drive cytoskeletal remodeling and actin dynamics in migrating glioblastoma cells [37]. The KITENIN-CCL20 axis is a newly identified therapeutic target in glioblastoma that drives an immunosuppressive TME, leading to decreased patient survival. KITENIN promotes tumor progression and induces CCL20, which in turn mainly recruits MDSCs while inhibiting cytotoxic T cells [30].

Thus, KITENIN drives EMT, CSC maintenance, cytoskeletal remodel, TMZ resistance, and immunosuppressive niche in glioblastoma, but its downstream effectors remain incompletely characterized, necessitating further mechanistic dissection.

Therapeutic strategies targeting KITENIN

Natural compounds

Natural compound-based strategies, targeting on KITENIN-associated oncogenic mechanisms, are summarized in Table 3.

Table 3.

KITENIN-associated oncogenic mechanisms and natural compound-based targeting strategies

Natural compound	Mode of KITENIN targeting	Key pathway/mechanism	Functional outcome	Current limitation
Chrysophanol	Indirectly suppresses KITENIN-associated signaling	Binds the ErbB4–KITENIN axis and suppresses AP-1 activity, thereby impairing glycolytic features	Suppresses migration, invasion, and oncogenic signaling; overcomes cetuximab resistance	Clinical validation is lacking
Emodin	Directly inhibits KITENIN-associated signaling with relatively greater potency	Suppresses KITENIN/ErbB4-associated signaling, induces apoptosis, and inhibits downstream pathways; demonstrates synergistic potential with the KITENIN inhibitor DKC-C14S	Exerts antitumor activity by attenuating AP-1- and TCF-mediated gene expression	Pleiotropic actions limit target specificity
Dioscin	Suppresses KITENIN-associated signaling through indirect or inferential mechanisms	Suppresses KITENIN-associated oncogenic signaling via Wnt/β-catenin and EMT-related pathways	Attenuates KITENIN-mediated EMT phenotypes	Direct mechanistic evidence for KITENIN targeting remains limited

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Chrysophanol

Chrysophanol (1,8-dihydroxy-3-methyl-9,10-anthraquinone, Fig. 5) is a naturally occurring anthraquinone derivative with established anticancer activity. It exerts pleiotropic effects, including cell-cycle arrest, apoptosis, autophagy induction, and inhibition of invasion and metastasis. Mechanistically, chrysophanol suppresses EGFR phosphorylation and downstream AKT/mTOR signaling. In glioblastoma cell lines (U251, SHG-44), chrysophanol downregulates cyclin D1, CDK2/4, and CDC2 while increasing cytochrome c (Cyt c) release and reactive oxygen species (ROS) production, leading to G1-phase arrest. Importantly, in CRC, chrysophanol binds ErbB4, disrupts the KITENIN-ErbB4 complex, and suppresses AP-1 activation, thereby impairing glycolytic energy metabolism of tumor cells. Since KITENIN promotes aerobic glycolysis through β-catenin, PKM2, and GLUT1 upregulation, chrysophanol may counteract this effect by inhibiting WNT3/β-catenin signaling [34, 60]. Furthermore, considering its recognized anticancer potential and its ability to disrupt the ErbB4-KITENIN axis, chrysophanol may potentially overcome cetuximab resistance in CRC or temozolomide resistance in glioblastoma when combined with standard therapies. These findings highlight chrysophanol as a promising natural compound that indirectly suppresses KITENIN-driven oncogenesis (Table 3).

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Emodin

The anthraquinone derivative emodin (1,3,8-trihydroxy-6-methylanthraquinone, Fig. 5), extracted from the roots of Rheum officinale, Polygonum cuspidatum, and Aloe vera, has been reported to possess wide-ranging anticancer activities. Its primary mechanisms involve apoptosis induction and blockade of cell-cycle transition at the G2/M phase [61]. Mechanistically, emodin increases ROS generation, modulates mitochondrial function, and inhibits key oncogenic signaling pathways, including PI3K/Akt, MAPK/JNK, NF-κB, Wnt/β-catenin, and STAT. These effects collectively suppress tumor cell growth, invasion, and metastasis across breast, colon, and lung cancers, in part through activation of caspases and PARP and regulation of Bcl-2 family proteins [62–65].

In lung cancer models, emodin destabilizes the DNA repair proteins Rad51 and excision repair cross-complementation group 1 (ERCC1) via ERK1/2 dephosphorylation, thereby impairing DNA repair and enhancing therapeutic vulnerability. At a concentration of 50 µM, it significantly reduces integrin β1 and the EMT marker vimentin.

Because EMT and CSC are closely associated with KITENIN overexpression−characterized by induction of Snail, Slug, vimentin, CSC markers such as CD44, ALDH1A1, and CD133 via AP-1 activation-emodin’s ability to suppress these pathways is particularly relevant. Emodin directly disrupts the KITENIN-ErbB4 complex, enhances mitochondrial release of Cyt c, and increases expression of pro-apoptotic proteins including caspases and PARP. Furthermore, emodin acts synergistically with the small-molecule inhibitor of the KITENIN complex, DKC-C14S, to promotes degradation of the KITENIN-Dvl2-KSRP-RACK1 complex, leading to reduced cell invasion, diminished aerobic glycolysis, and attenuation of AP-1 and TCF mediated gene activity in CRC cells. Although emodin demonstrates promising activity against KITENIN-driven oncogenic signaling, higher concentrations and long-term use have been associated with toxicity [66]. Therefore, dose optimization and the development of structurally modified analogs or derivatives may enhance its therapeutic potential in KITENIN-overexpressing cancers.

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Dioscin

Dioscin (Fig. 5) is a natural steroidal saponin extracted from Dioscorea nipponica Makino. It has been reported to exert anticancer effects via multiple mechanisms, including inhibition of the Wnt/β-catenin signaling pathway and induction of apoptotic cell death through activation of cleaved PARP and suppression of Bcl-2/Bcl-xL activity [67]. Mechanistically, dioscin interferes with Akt and GSK3α/β phosphorylation, promoting β-catenin degradation and reducing its nuclear translocation [67].

Dioscin has also been shown to attenuate osteosarcoma stem-like phenotypes and to inhibit tumor growth, potentially through downregulation of Akt/GSK3/β-catenin pathway, it is suggested that KITENIN expression may be modulated along with associated stem cell transcription factors. Given that KITENIN drives EMT via transcriptional upregulation of EMT-related genes, the ability of dioscin to suppress EMT-evidenced by reduced Snail, vimentin, and N-cadherin expression in lung and breast cancer models [68, 69] suggests a possible link to KITENIN pathway modulation. These findings support further investigation into dioscin as a potential KITENIN-targeted therapeutic, particularly in cancers characterized by EMT activation and stemness-associated phenotypes.

Direct inhibitors of KITENIN

KITENIN inhibitors (DKC1125 and analogs)

Multiple lines of evidence indicate that the oncogenic function of KITENIN can be suppressed by small-molecule inhibitors. A novel class of compounds, termed DKCs (disintegrator of KITENIN complex), was identified through chemical screening, with DKC1125 (Fig. 5) emerging as the most potent candidate for KITENIN inhibition. KITENIN overexpression has been shown to diminish the efficacy of various chemotherapeutic agents, including 5-fluorouracil, oxaliplatin, cetuximab, and TMZ [16, 22, 53]. Conversely, miR-124, which targets the 3′-UTR of KITENIN mRNA, effectively reduces KITENIN protein translation within the tumor microenvironment, thereby suppressing tumor progression [44]. Mechanistically, DKC1125 disrupts the interaction between RACK1 and Dvl2, leading to destabilization of the KITENIN-KSRP complex. This disruption significantly inhibits liver metastasis in murine CRC models. Additionally, the DKC-C14S, one of the DKC1125 analogs, has shown synergistic activity with other agents such as emodin in promoting KITENIN complex degradation [70]. Given the limited number of direct KITENIN inhibitors currently available, further preclinical and clinical investigations are warranted to optimize these compounds and explore their potential in KITENIN-overexpressing cancers.

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KITENIN dimerization‑interfering peptides (KDIP)

KDIP is a peptide designed to inhibit CRC progression by targeting the oncogenic protein KITENIN [54]. KDIP interferes with KITENIN dimerization through facilitating RACK1 binding to the RIM (RACK1-interacting motif) site in KITENIN and downregulation of myosin-X (Myo10), which functions as an effector to stabilize the KITENIN homodimer in the cis formation (Fig. 5). This disruption promotes autophagy-dependent degradation of KITENIN, leading to reduced CRC metastasis in vivo. Enhancing KDIP peptide stability, employing nanoparticle-based delivery systems, and increasing its half-life could improve its therapeutic efficacy by sustaining KITENIN degradation. Expanding the application of KDIP to highly invasive cancers such as glioblastoma and HNSC may broaden its clinical potential. Combination strategies incorporating KDIP with conventional chemotherapeutics or immune checkpoint inhibitors may further enhance antitumor activity in KITENIN-overexpressing cancers.

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Small-molecule inhibitors targeting KITENIN‑mediated signaling pathways

The KITENIN-Dvl-PKCδ complex plays a pivotal role in CRC progression by activating the ERK/AP-1 signaling pathway [14]. While Dvl-targeted agents such as DKC1125 have been developed to induce RACK1 recruitment and disrupt the KITENIN-Dvl complex, direct PKCδ inhibition in this context has not yet been explored. Targeting the PKCδ-Dvl interaction could result in abrogation of c-Jun phosphorylation via the ERK pathway, leading to AP-1, c-Myc, and hnRNP inactivation, thereby reducing MMP expression and actin cytoskeletal reorganization. Thus, dual blockade of PKCδ and AP-1 may yield greater inhibition of cancer cell invasion and stemness. Furthermore, disruption of the Dvl-PDZ domain using inhibitors such as NSC668036, FJ9, and 3289–8625 has been shown to abolish actin cytoskeletal organization and inactivate AP-1 [41, 42]. Future studies are warranted to validate these strategies as therapeutic approaches against KITENIN-driven cancers.

Although agents such as DKC1125, KDIP, chrysophanol, and emodin demonstrate proof-of-concept for targeting KITENIN-associated signaling, their clinical translation remains challenging. Limitations include issues with stability, delivery, and tissue penetration, as well as concerns regarding target specificity due to disruption of protein complexes rather than direct catalytic inhibition. In addition, pharmacokinetic, toxicological, and biomarker data are still lacking, and most evidence remains preclinical and largely restricted to CRC models. Future efforts should focus on improving delivery strategies, establishing safety and pharmacodynamic markers, and developing biomarker-guided combination therapies.

Indirect targeting approaches

Wnt/β-catenin pathway inhibition

The KITENIN oncogene is transcriptionally regulated via the Wnt/β-catenin signaling pathway, in which β-catenin binds to the TCF4 site on the KITENIN promoter [14]. Inhibition of upstream Wnt/β-catenin signaling could therefore suppress KITENIN transcription. Porcupine (PORCN) inhibitors such as WNT974 and CGX1321, block Wnt ligand secretion in the endoplasmic reticulum and reduce β-catenin activity. Although these agents are under clinical investigation, their potential to inhibit KITENIN expression has not yet been evaluated. Disruption of the β-catenin/TCF4 complex using small molecules such as PFK115-584 and CGP049090 has been shown to inhibit colon cancer cell proliferation, β-catenin-regulated transcription, and β-catenin-mediated axis duplication in Xenopus embryos, while KYA1797K and KY1220 destabilize β-catenin and Ras, inhibiting proliferation of colorectal and breast cancer cells. Thus, dysregulation of Wnt/β-catenin signaling is expected to modulate KITENIN expression in the specific TME [14].

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miR-based regulation

miRs also regulate KITENIN expression. Screening studies have identified miR-124, miR-27a, and miR-30b as negative regulators of KITENIN that suppress CRC progression. RACK1 enhances miR-124 and miR-27a activity at the KITENIN 3′-UTR, suppressing translation and promoting autophagic degradation of KITENIN following disruption of the KITENIN-Dvl-PKCδ complex [53]. In contrast, myosin-X stabilizes KITENIN, counteracting this degradation pathway [54]. Thus, targeting miR-KITENIN regulatory axes, or restoring the activity of dysregulated miRs, may represent future therapeutic strategies.

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Epigenetic and non-coding RNA (ncRNA) regulation

DNA methylation represents another crucial layer of KITENIN regulation. In CRC, the miR-124 promoter is often hypermethylated, leading to marked suppression of miR-124 expression; this aberrant silencing subsequently upregulates DNMT3B and enhances cellular invasion and migration [71]. Similarly, hypermethylation of the miR-124 promoter decreases miR-124 expression, leading to increased KITENIN levels and enhanced CRC malignancy [45]. Thus, analysis of DNA methylation patterns in circulating tumor DNA via liquid biopsy may provide a minimally invasive approach for KITENIN-related cancer diagnosis and monitoring. However, the methylation status of the KITENIN gene itself has not yet been investigated in cancer, representing a potential avenue for biomarker discovery.

Finally, long ncRNAs (lncRNAs, > 200 nucleotides) are known modulators of cancer metastasis and may influence KITENIN expression or function, although no direct associations have been reported to date. Future studies employing RNA-seq and RIP-seq in KITENIN-overexpressing cells could identify lncRNAs involved in KITENIN regulation.

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Immune evasion and immune checkpoint modulation

M2-polarized TAMs, MDSCs, and Tregs are key immunosuppressive cell populations that inhibit antitumor immunity, promote angiogenesis, and facilitate tumor progression and therapeutic resistance, making them critical targets for cancer immunotherapy [72–76]. Our pan-cancer correlation analysis revealed that KITENIN expression is positively correlated with these immunosuppressive populations across multiple cancer types (Fig. 6A), suggesting that KITENIN may contribute to the establishment of an immunosuppressive TME and warranting further mechanistic investigation. KITENIN promotes tumor progression by upregulating COX-2, VEGF-A, and HIF-1α, thereby coupling oncogenic signaling to angiogenesis and immunosuppression, including PGE2-driven expansion of Tregs and TAMs [40]. KITENIN also interacts with the extracellular glycoprotein 90 K (Mac-2BP/LGALS3BP) [13], an immunomodulatory factor in the TME, suggesting additional immune reprogramming through glycoprotein-dependent signaling [29]. Furthermore, KITENIN overexpression in glioblastoma cells enhances secretion of CCL20, as identified by cytokine array and Luminex multiplex assays, and is associated with increased infiltration of MDSCs, TAMs, and Tregs in an orthotopic GL261 intracranial mouse model. Conversely, CCL20 downregulation reduced monocytic MDSC accumulation, suppressed tumor growth, and prolonged survival, demonstrating that the KITENIN–CCL20 axis functionally shapes an immunosuppressive TME [30].

Fig. 6 — KITENIN association with immunosuppressive cell infiltration and immune checkpoint gene expression across cancers. (A) Heatmap showing Spearman correlation coefficients between KITENIN (VANGL1) expression and immunosuppressive cell populations, including M2 macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), across multiple cancer types. Positive correlations (red) indicate that higher KITENIN expression is associated with increased infiltration of immunosuppressive cells, suggesting a potential role of KITENIN in shaping an immunosuppressive tumor microenvironment (TME). (B) Heatmap illustrating Spearman correlations between KITENIN expression and immune checkpoint–related genes (BTLA, VSIR, TIGIT, HAVCR2, LAG3, PDCD1, CD274, CD276, and CTLA4) across cancers. Notably, KITENIN shows consistent positive associations with key checkpoint molecules, particularly CD274 (PD-L1) and HAVCR2 (TIM-3), indicating a potential link between KITENIN expression and immune evasion mechanisms. Correlation coefficients (Spearman rho) are color-coded from − 1 (blue, negative correlation) to + 1 (red, positive correlation). Cancer abbreviations and sample sizes are indicated along the x-axis

Although these findings link KITENIN to immune cell recruitment, its role in immune checkpoint regulation remains unexplored. To address this gap, we performed a pan-cancer correlation analysis between KITENIN and literature-curated immune checkpoint-related genes [77–80]. KITENIN expression showed strong positive correlations with multiple checkpoint molecules, with particularly robust associations for CD274 (PD-L1) and HAVCR2 (TIM-3) across cancer types (Fig. 6B). While these correlations do not establish direct regulatory relationships, they suggest that KITENIN may contribute to immune evasion through indirect modulation of checkpoint pathways, potentially via cytokine-mediated TME remodeling or activation of downstream signaling such as AP-1. Future studies should investigate whether KITENIN directly regulates PD-L1 and TIM-3 expression at the transcriptional or post-transcriptional level, using KITENIN knockdown or overexpression models combined with flow cytometry, transcriptomic profiling, and promoter activity assays. Complementary approaches, including computational immune deconvolution (e.g., CIBERSORT) [81, 82] and high-dimensional single-cell analyses (e.g., scRNA-seq or CyTOF) [83, 84] will be essential to delineate the impact of KITENIN on immune cell composition and checkpoint signaling within the TME. Expanding these analyses in immunocompetent tumor models will provide critical insights into KITENIN-driven immune evasion and may uncover new therapeutic opportunities.

Future perspectives and research gaps

Epigenetic regulation and immune evasion

Despite accumulating evidence for KITENIN as an oncogenic driver, its regulation at the epigenetic and immunological levels remains poorly understood. Hypermethylation of the miR-124 promoter suppresses miR-124 expression, thereby enhancing KITENIN levels and driving CRC malignancy [45], suggesting that DNA methylation and ncRNAs (miRs, lncRNAs, circRNAs) may play critical roles in modulating KITENIN expression and activity. However, these regulatory axes have not been systematically validated across diverse cancers.

In addition, KITENIN contributes to remodeling of immunosuppressive TME. KITENIN overexpression increases CCL20 secretion, leading to infiltration of immunosuppressive MDSCs in glioblastoma [30]. The role of KITENIN in regulating immune checkpoints like PD-L1 and TIM-3, and its possible involvement in T-cell impairment, remains poorly defined.

Another complicating factor is LGALS3BP (90 K), a secreted glycoprotein frequently overexpressed in multiple malignancies and implicated in immune regulation, adhesive interactions, and signaling pathways [85]. Recent studies indicate that circulating and extracellular-vesicle-associated LGALS3BP levels significantly correlate with neuroblastoma progression and dissemination [86], and that 90 K interacts with inhibitory immune receptors such as Siglec-9 [87] and is abundantly packaged in extracellular vesicles [86], thereby promoting immune evasion and dampening antitumor immunity. However, whether KITENIN regulates or cooperates with 90 K to shape immune suppression has not been investigated. Elucidating these pathways could open novel therapeutic avenues, including the combination of KITENIN inhibition with immune checkpoint blockade or 90 K-targeted interventions.

High-throughput sequencing and systems-level profiling

To date, high-throughput sequencing (HTS) approaches have not been extensively applied to characterize KITENIN biology. RNA-seq could define co-expressed oncogenes and downstream signaling pathways, while ChIP-seq may uncover transcription factor occupancy and histone modifications regulated by KITENIN [46, 88]. Whole-genome or exome sequencing (WGS/WES) could identify somatic mutations within KITENIN or its interactome that contribute to tumor susceptibility [89, 90]. Importantly, single-cell RNA-seq (scRNA-seq) offers the ability to dissect tumor heterogeneity by stratifying cancer subpopulations based on KITENIN expression levels and defining their interactions with immune and stromal compartments [91–94].

Beyond transcriptomics, multi-omics integration (proteomics, metabolomics, phosphoproteomics) and pooled CRISPR functional screens could reveal synthetic lethal partners and novel vulnerabilities in KITENIN-driven cancers [49]. Such systems-level profiling will be critical for building a comprehensive “KITENIN interactome” and for guiding the rational design of targeted therapies.

Limitations and clinical translation challenges

Despite promising preclinical data, several gaps hinder the translation of KITENIN biology into clinical application.

Lack of specific inhibitors:

Current agents such as DKC1125, KDIP, and natural compounds (e.g., chrysophanol, emodin) show inhibitory effects, but no selective KITENIN-targeted drugs have reached clinical testing. Moreover, the efficacy of these compounds beyond CRC or glioblastoma remains largely unexplored.

Clinical translation challenges:

Despite promising preclinical efficacy, KDIP and DKC-class inhibitors face several barriers to clinical translation, including suboptimal pharmacokinetics (e.g., poor bioavailability, rapid clearance) potential off-target toxicity to Wnt-dependent tissues (intestine, bone marrow), and insufficient tumor-specific delivery (95,96,97)challenges broadly shared by Wnt pathway inhibitors, where systemic exposure often fails to achieve therapeutic intratumoral concentrations without excessive adverse effects (98). Pharmacokinetic optimization via liposomal encapsulation or nanoparticle-based delivery systems can enhance tumor accumulation while minimizing systemic toxicity, as demonstrated with Wnt inhibitors such as CGX1321. Patient stratification by KITENIN expression levels and combination with chemotherapy or immunotherapy may further widen the therapeutic window. Finally, human-relevant dosing guided by clinical pharmacokinetic/pharmacodynamic data—rather than maximum tolerated doses derived from murine models—will be critical to bridging preclinical efficacy to clinical success (99).

Inadequate validation of therapeutic synergy:

Although DKC1125 restores chemosensitivity to 5-FU, its combination with other standard regimens—such as oxaliplatin, cetuximab, anti-VEGF therapy, or immune checkpoint blockade—has not been rigorously tested in vivo.

Limited exploration of ncRNA regulation:

While several miRs have been implicated in KITENIN regulation, the role of lncRNAs and circRNAs remains underexplored. Experimental validation is needed to move beyond in silico predictions.

Scarcity of clinical and comparative studies:

No validated clinical assays currently exist for KITENIN expression or activity, and large-scale cohort studies linking KITENIN to prognosis are lacking. Furthermore, functional analyses have been largely confined to human cancer cell lines. Studies in model organisms such as zebrafish, Drosophila, and genetically engineered mice may help uncover evolutionarily conserved functions of KITENIN and clarify its roles in development, tissue regeneration, and immune homeostasis.

Outlook

Future studies must therefore integrate epigenetic and immune-regulatory mechanisms, apply multi-omics and high-throughput platforms, and develop specific pharmacological inhibitors with clinical applicability. Addressing these gaps will be essential not only to define KITENIN’s role in cancer progression and therapeutic resistance but also to establish it as a viable biomarker and therapeutic target.

Conclusions

KITENIN has emerged as a pivotal oncogenic driver that orchestrates metastasis, stemness, and therapeutic resistance across diverse human cancers, including CRC, GC, HCC, HNSC, BLCA, and glioblastoma (Table 4). Through interactions with scaffolding proteins such as KSRP and Dvl2, KITENIN regulates cytoskeletal remodeling, EMT, and tumor microenvironmental reprogramming, while antagonizing tumor-suppressive miRs. These multifaceted activities place KITENIN at the intersection of signaling networks that sustain tumor aggressiveness and therapy resistance.

Table 4.

Summary of KITENIN-associated oncogenic mechanisms and clinical significance

Cancer type	Oncogenic roles of KITENIN	Key molecular mechanisms	Therapeutic targeting	Clinical correlation
Colorectal cancer	•Promotes metastasis & invasion •Induces glycolysis & angiogenesis •Confers anti-EGFR resistance	•Cell motility and invasiveness increase by ERK/AP-1 activation via KITENIN–Dvl–PKCδ complex •Binding of KITENIN-ErbB4 complex activate c-Jun/AP-1 •KITENIN upregulate PKM2 through c-Myc/hnRNPs expression led to aerobic glycolysis (Warburg effect) •KITENIN led to angiogenesis via VEGF-A, HIF-1α upregulation	•EbrB4-KITENIN-Dvl complex disrupted by binding Nrdp •Chrysophanol induces EbrB4-KITENIN degradation •miR-124 targets KITENIN •DKC1125 restores 5-FU, oxaliplatin, cetuximab sensitivity by disrupting KITENIN-KSRP-RACK1-Dvl2 complex	High KITENIN expression associated with metastasis & poor prognosis
Gastric cancer	•Enhance tumorigenesis & LN metastasis	•KITENIN regulates MMP1, MMP3, COX-2, CD44 expression through AP-1 activation via MAPK (ERK1/2, JNK, p38) phosphorylation	•Preclinical: No targeted inhibitors studied, further in vivo studies needed	High KITENIN expression associated with poor OS
Hepatocellular carcinoma	•Induces migration, EMT, angiogenesis	•KITENIN modulated AP-1 activation transcribe COX2, MMP3 expression led to angiogenesis and EMT •In TME, COX2 may help to elevate PGE₂level that modulate immune suppression	•siRNA silencing of KITENIN reduces COX-2, MMP3 •TME modulation under investigation	Elevated KITENIN in HCC; associated with aggressiveness
Head & neck squamous cell carcinoma	•Drives invasion & early lung metastasis	•KITENIN upregulates AP-1 activation led to Cyclin D1, MMP1, COX-2, CD44 translation.	•siRNA inhibits invasiveness •Gene therapy potential (early stage)	High KITENIN associated in advanced stage
Bladder cancer	•Enhance invasion, actin remodeling	•KITENIN-KAI1/CD82 interaction modulates cytoskeletal dynamics	•Hypothetical target: no inhibitors reported	Loss of KAI1/CD82 enhances KITENIN-driven invasion
Glioblastoma	•Induces EMT, stemness, temozolomide resistance	•Increase CD44, ALDH1A1, EMT through AP-1 activation in KITENIN overexpressed cells •High in recurrent & unmethylated-MGMT GBM	•DKC1125, Usnic Acid inhibit KITENIN/AP-1 •Restores chemosensitivity in TMZ-resistant GBM	High KITENIN in high-grade/recurrent GBM predicts poor prognosis

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Therapeutically, recent progress with small molecules (e.g., DKC1125), dimerization-interfering peptides (KDIP), and natural compounds (chrysophanol, emodin, dioscin) highlights the druggability of KITENIN and its associated complexes. Yet, major challenges remain: a lack of clinically validated inhibitors, insufficient pharmacokinetic and pharmacodynamic characterization, and the lack of preclinical models that recapitulate intratumoral heterogeneity and immune interactions. Moreover, the epigenetic and immunoregulatory dimensions of KITENIN biology—particularly its influence on immune checkpoint pathways—are only beginning to be recognized.

Moving forward, research efforts must focus on (i) patient stratification based on KITENIN expression and pathway activation, (ii) mechanistic dissection of resistance to KITENIN-targeted interventions, and (iii) rational combination strategies with standard chemotherapies, targeted agents, and immunotherapies. Incorporating high-throughput sequencing and multi-omics profiling will be essential to define the KITENIN interactome, identify biomarkers, and accelerate translation into clinical settings.

Ultimately, by consolidating KITENIN biology with emerging therapeutic strategies, this review underscores KITENIN as both a biomarker of aggressive disease and a promising therapeutic target. Establishing clinically effective KITENIN inhibitors has the potential to overcome metastasis and drug resistance—two of the most formidable challenges in oncology—and to provide a new frontier in precision cancer therapy.

Acknowledgements

All authors have read the journal’s authorship agreement. During the preparation of this work, the author(s) used ChatGPT5 in August 2025 in order to assist with fixing grammatical errors and organizing the contents of our manuscript. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Abbreviations

AP-1: Activator protein-1
ALDH1: Aldehyde dehydrogenase 1
BLCA: Bladder urothelial carcinoma
BRCA: Breast invasive carcinoma
CAFs: Cancer-associated fibroblasts
CSC: Cancer stem cell
CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma
CHOL: Cholangiocarcinoma
ChIP-seq: Chromatin immunoprecipitation sequencing
circRNAs: Circular RNAs
CD82: Cluster of Differentiation 82
COAD: Colon adenocarcinoma
CRC: Colorectal cancer
COX-2: Cyclooxygenase-2
Cyt c: Cytochrome c
DLBC: Diffuse Large B-cell Lymphoma
Dvl: Dishevelled
DKC: Disintegrator of KITENIN complex
EMT: Epithelial–mesenchymal transition
EGFR: Epidermal growth factor receptor
ESCA: Esophageal carcinoma
ERK: Extracellular signal-regulated kinase
GC: Gastric cancer
GBM: Glioblastoma multiforme
HNSC: Head and neck squamous cell carcinoma
HCC: Hepatocellular carcinoma
hnRNP: Heterogenous nuclear ribonucleoprotein
HIF-1a: Hypoxia-inducible factor 1 alpha
KAI1: Kangai 1
KITENIN: KAI1 COOH-terminal interacting tetraspanin
KSRP: KH-type splicing regulatory protein
KDIP: KITENIN dimerization-interfering peptide
KIRC: Kidney renal clear cell carcinoma
lncRNAs: Long non-coding RNAs
LGG: Lower grade gliom
LUSC: Lung adenocarcinoma
LUAD: Lung squamous cell carcinoma
MMPs: Matrix metalloproteinases
MESO: Mesothelioma
MGMT: O⁶-methylguanine-DNA methyltransferase
MDSCs: Myeloid-derived suppressor cells
NGS: Next-generation sequencing
ncRNAs: Non-coding RNAs
OCT4: Octamer-binding transcription factor4
OV: Ovarian serous cystadenocarcinoma
PAAD: Pancreatic adenocarcinoma
PDX: Patient-derived xenograft
PCPG: Pheochromocytoma and Paraganglioma
PARP: Poly (ADP-ribose) polymerase
PORCN: Porcupine
PD-L1: Programmed death-ligand 1
PRAD: Prostate adenocarcinoma
PKCδ: Protein kinase C delta
PGE2: Prostaglandin E2
PKM2: Pyruvate kinase isozyme M2
RACK1: Receptor for activated C kinase 1
READ: Rectum adenocarcinoma
Tregs: Regulatory T cells
SARC: Sarcoma
STAT: Signal transducer and activator of transcription
scRNA-seq: Single-cell RNA sequencing
SKCM: Skin cutaneous melanoma
STAD: Stomach adenocarcinoma
TIM-3: T-cell immunoglobulin and mucin-domain containing-3
TGCT: Testicular germ cell tumors
THCA: Thyroid carcinoma
THYM: Thymoma
TME: Tumor microenvironment
UA: Usnic acid
UCEC: Uterine corpus endometrial carcinoma
UCS: Uterine Carcinosarcoma
UVM: Uveal Melanoma
VEGF: Vascular endothelial growth factor
WES: Whole-exome sequencing
WGS: Whole-genome sequencing

Author contributions

CRediT authorship contribution statement: S M Abdus Salam: Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing. **Eshrat Jahan: ** Investigation, Methodology, Writing – original draft, Writing – review & editing. **Jeong A Bae: ** Investigation, Methodology, Writing – review & editing. **Eun-Jung Ahn: ** Methodology, Writing – review & editing. **Sung Jin Kim: ** Investigation, Methodology, Visualization, Writing – review & editing. **Kyung-Hwa Lee: ** Project administration, Writing – review & editing. **Kyung-Sub Moon: ** Conceptualization, Funding acquisition, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review & editing. **Kyung Keun Kim: ** Conceptualization, Funding acquisition, Supervision, Methodology, Project administration, Writing – original draft, Writing – review & editing. All authors read and approved the final manuscript.

Funding

This study was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry and Energy and Ministry of Health and Welfare (2710092385/RS-2025-25444375 for KKK), and by Chonnam National University (2023 − 0893 for KSM). There was no role of the funding bodies in the design of the study, in the collection, analysis, and interpretation of data or in writing the manuscript.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethic approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

S. M. Abdus Salam and Eshrat Jahan are co-first authors.

Contributor Information

Kyung-Hwa Lee, Email: mdkaylee@jnu.ac.kr.

Kyung-Sub Moon, Email: moonks@chonnam.ac.kr.

Kyung Keun Kim, Email: kimkk@chonnam.ac.kr.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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PERMALINK

Targeting KITENIN signaling in cancer progression and therapeutic resistance: mechanistic insights and future directions

S M Abdus Salam

Eshrat Jahan

Jeong A Bae

Eun-Jung Ahn

Sung Jin Kim

Kyung-Hwa Lee

Kyung-Sub Moon

Kyung Keun Kim

Abstract

Introduction

Molecular features of KAI1 and KITENIN: interactions and functional implications

Fig. 1.

Expression and prognostic significance of KAI1 and KITENIN across cancers

Fig. 2.

Table 1.

Table 2.

Mechanistic insights into KITENIN biology

Common oncogenic mechanisms of KITENIN

Fig. 3.

EMT and invasion:

Cancer stemness:

Therapy resistance:

TME modulation:

Transcriptional and epigenetic regulation of KITENIN:

Cancer type-specific insights

Fig. 4.

Therapeutic strategies targeting KITENIN

Natural compounds

Table 3.

Fig. 5.

Direct inhibitors of KITENIN

Indirect targeting approaches

Fig. 6.

Future perspectives and research gaps

Epigenetic regulation and immune evasion

High-throughput sequencing and systems-level profiling

Limitations and clinical translation challenges

Lack of specific inhibitors:

Clinical translation challenges:

Inadequate validation of therapeutic synergy:

Limited exploration of ncRNA regulation:

Scarcity of clinical and comparative studies:

Outlook

Conclusions

Table 4.

Acknowledgements

Abbreviations

Author contributions

Funding

Data availability

Declarations

Ethic approval and consent to participate

Consent for publication

Competing interests

Footnotes

Contributor Information

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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