The oncogenic potential of SOX12: a comprehensive and perspective view

Abstract

Background

Sex-determining region Y-box 12 (SOX12), a key member of the SOXC transcription factor subfamily, exerts oncogenic roles in multiple malignancies via its conserved HMG-box DNA-binding domain. Although existing studies have reported its abnormal expression and functional implications in various tumors, previous reviews lack a systematic summary of SOX12-mediated regulatory networks across cancers, failing to address research gaps and potential therapeutic targets.

Main body

This review comprehensively summarizes SOX12’s expression patterns and oncogenic functions in digestive, reproductive, hematologic, and other tumor types. We systematically dissect its core molecular mechanisms, including competing endogenous RNA (ceRNA) networks, activation of canonical signaling pathways (e.g. PI3K/AKT/mTOR, Wnt/β-catenin), metabolic reprogramming, and modulation of the tumor immune microenvironment. Additionally, we highlight SOX12’s clinical potential as a prognostic biomarker and therapeutic target, discussing novel targeting strategies such as HMG-box domain inhibitors and ceRNA network intervention.

Conclusions

SOX12 serves as a critical “metabolic-immune” cross-regulatory node in tumors, with conserved oncogenic mechanisms across cancer types. Its abnormal expression is closely associated with malignant phenotypes and poor prognosis, supporting its dual value as a prognostic indicator and therapeutic target. Future research should focus on exploring its post-translational modifications, synergistic mechanisms with other SOX family members, and conducting large-scale clinical trials to validate its translational potential.

Facts

Summarizes SOX12’s expression patterns and oncogenic roles across digestive, reproductive, and hematological tumors.

Systematically dissects SOX12-mediated regulatory networks, including ceRNA crosstalk and canonical signaling pathways.

Highlights SOX12’s dual functions in metabolic reprogramming and tumor immune microenvironment modulation.

Discusses novel targeting strategies (e.g., ubiquitination regulation) and clinical translation potential of SOX12.

Introduction

Basic characteristics of SOX12 protein

Transcription factors in the SOX family are characterized by their highly conserved high-mobility-group (HMG) box domain, which can specifically bind to the minor groove of DNA to regulate target gene transcription [1]. As a member of the SOXC subfamily, SOX12 is highly homologous to SOX4 and SOX11, and participates in key biological processes such as neurogenesis and bone formation during embryonic development [2]. A core characteristic of SOXC subfamily members is the presence of a conserved HMG box DNA-binding domain, with nuclear localization signal (NLS) motifs commonly located at both ends of this domain. This conserved arrangement is the structural basis for SOX proteins to enter the nucleus and exert transcriptional regulatory functions [3]. Existing studies have confirmed that NLS mutations in SOX4 and SOX11 significantly inhibit their nuclear translocation efficiency and transcriptional activity [4, 5]. Based on the high sequence homology between SOX12 and these two proteins, we speculate that SOX12 may have a similar nuclear localization regulatory mechanism. In adult tissues, SOX12 is mainly expressed at low levels during tissue repair and regeneration, but exhibits abnormally high expression during tumorigenesis, driving malignant transformation by regulating downstream target gene networks [6]. The oncogenic function of SOX12 is closely linked to its unique molecular structure: its HMG box domain can interact with various transcriptional coactivators, such as β-catenin and YBX1, thereby enhancing the transcriptional activity of target genes; targeted inhibition of this domain can serve as a potential therapeutic strategy (Fig. 1).

Fig. 1.

SOX12 protein structure and coactivator interaction diagram. Abbreviations:NLS: nuclear localization signal

Current state-of-the-art of SOX12 in tumorigenesis

While the dysregulation of transcription factors is a universally recognized hallmark of cancer, the specific oncogenic trajectory of SOX12 distinguishes it from other regulatory proteins. Unlike its paralogs SOX4 and SOX11, which maintain broader developmental roles [2, 4, 5], SOX12 is typically transcriptionally silenced in normal adult tissues but undergoes robust epigenetic or post-transcriptional reactivation during malignant transformation [6]. Emerging state-of-the-art research has shifted the paradigm of SOX12 from being merely a downstream effector of classical oncogenic signals (such as Wnt/β-catenin and PI3K/AKT/mTOR) [7, 8] to recognizing it as a master integrator of tumor microenvironment plasticity.

Recent investigations highlight that SOX12 orchestrates a complex, pan-cancer regulatory network characterized by two critical dimensions: metabolic reprogramming and immune evasion. For instance, SOX12 not only directly hyperactivates the serine synthesis pathway (SSP) and glycolysis to meet the energetic demands of rapidly dividing cells [9, 10], but it also simultaneously dictates immunosuppression by upregulating PD-L1 and recruiting regulatory T cells (Tregs) via chemokine cascades like CCL22 [11]. This functional duality positions SOX12 at the crucial intersection of tumor metabolism and immune tolerance. Furthermore, the ubiquitous regulation of SOX12 by competing endogenous RNA (ceRNA) networks highlights an additional layer of complexity, establishing SOX12 as a highly connected hub in the oncogenic transcriptomic landscape [12, 13].

Research significance and review objectives

Although existing studies have confirmed the abnormal expression and oncogenic function of SOX12 in various tumors, previous reviews have only summarized SOX12 -related tumors or its role in a single tumor type, lacking a systematic summary of the regulatory network of SOX12 during tumorigenesis and progression. This makes it difficult to form a macro understanding to explore undiscovered signaling pathways and therapeutic targets. With the rapid increase in relevant studies in recent years, the regulatory patterns, downstream target gene profiles, and clinical application value of SOX12 in different tumors have gradually been enriched, and there is an urgent need for a systematic summary to establish a macro framework for SOX12-mediated tumor regulation to guide further research. This article systematically combs the expression characteristics and biological functions of SOX12 in various tumors, deeply analyzes its molecular mechanisms of action through pathways such as ceRNA networks, classical signaling pathways, metabolic reprogramming, and immune regulation, comprehensively summarizes its potential as a prognostic biomarker and therapeutic target in clinical applications, and points out the limitations of current research and directions for future in-depth exploration, thereby providing a reference for basic research and clinical transformation of SOX12 -related tumors.

Literature search strategy

To identify relevant studies for this review, a targeted literature search was conducted in the PubMed database for articles published from inception up to January 2026. The search strategy was restricted to the title and abstract fields using the following Boolean logic: (“SOX12” OR “Sex-determining region Y-box 12”) AND (“tumor” OR “cancer” OR “carcinoma” OR “malignancy”).

Studies were included if they provided original experimental data regarding the molecular mechanisms, functional roles, or clinical prognostic value of SOX12 in human cancers. To maintain the rigor of this “Comprehensive” review, the following exclusion criteria were applied: (1) non-English publications; (2) studies lacking specific mechanistic validation; and (3) tumor types with extremely limited available literature (fewer than two independent peer-reviewed reports), which were excluded to ensure the reliability and generalizability of the summarized patterns. This systematic approach ensures that the oncogenic potential of SOX12 presented herein is based on established and reproducible evidence.

Expression characteristics and biological functions of SOX12 in different tumors

Digestive system tumors

Digestive system tumors are among the tumor types with the highest morbidity and mortality worldwide. SOX12 is generally highly expressed in these tumors and is closely associated with clinicopathological parameters. In colorectal cancer (CRC), SOX12 expression is significantly higher in tumor tissues than in normal tissues. It is closely correlated with poor tumor differentiation, advanced lymph node metastasis, and late TNM stage [14]. Multiple mechanisms mediate SOX12-induced CRC progression: first, downregulation of FOXN3 relieves transcriptional inhibition of EP300, which promotes H3K27ac modification enrichment to increase epigenetic upregulation of SOX12 in CRC cells, thereby enhancing tumor cell stemness (similar stemness-promoting mechanisms are also observed with FOXP4 in gastric cancer) [15, 16]; second, UCHL3 activates the AKT/mTOR signaling pathway to upregulate SOX12 expression, promoting CRC cell proliferation and epithelial-mesenchymal transition (EMT) [7]; in addition, SOX12 can enhance the metastatic capacity of CRC cells by positively regulating endogenous asparagine production [17].

In hepatocellular carcinoma (HCC), high SOX12 expression is significantly associated with tumor vascular invasion, postoperative recurrence, and poor prognosis [18]. It can transcriptionally activate C-C motif chemokine ligand 22 (CCL22) expression to recruit regulatory T cells (Treg) and simultaneously upregulate PD-L1 (encoded by the CD274 gene) to inhibit CD8+T cell infiltration, thereby constructing an immunosuppressive microenvironment [11].

The impact of SOX12 expression on tumorigenesis in gastric cancer (GC) remains controversial. Some studies have shown that SOX12 overexpression promotes tumor metastasis and stemness [12]. In contrast, others have found that low SOX12 expression is associated with lymph node metastasis and a poor prognosis in GC patients [19]. This discrepancy may be related to tumor heterogeneity or differences in the tested population, and further validation is required. During pancreatic cancer(PC) development and progression, the long non-coding RNA (lncRNA) C9orf139 regulates tumor growth by mediating the miR-663a/SOX12 axis, and patients with high C9orf139 expression have a higher risk of progression to stages III+IV, lymph node metastasis, and poor differentiation [20].

In esophageal squamous cell carcinoma (ESCC), univariate and multivariate analyses have shown that SOX12 overexpression is an independent risk factor. It plays a key role in maintaining ESCC cell viability and enhancing their motility by activating the JAK2/STAT3 signaling pathway, suggesting that SOX12 may serve as a novel biomarker and candidate target for ESCC targeted therapy [21]. In studies on TRAF7, this protein was identified as an E3 ubiquitin ligase: specifically, TRAF7 mediates K48-linked ubiquitination and degradation of SOX12, thereby exerting a tumor suppressor effect, and the expression of TRAF7 and SOX12 is negatively correlated [22].

Female reproductive system tumors

Multiple recent studies have found that SOX12 plays a vital role in many classical tumors of the female reproductive system, such as breast cancer (BC), cervical cancer(CC), and endometrial cancer.(EC) In breast cancer (BC), SOX12 expression is significantly higher at both mRNA and protein levels in tumor tissues than in adjacent normal tissues (ANTs). It is closely associated with tumor size, estrogen receptor status, lymph node metastasis, and TNM stage. More notably, as breast cancer progresses, the positive rate of SOX12 gradually increases, and multivariate analysis indicates that SOX12 is an independent prognostic factor for both overall survival and distant metastasis-free survival in breast cancer patients [6]. Mechanistically, lncRNA LGALS8–AS1 upregulates SOX12 expression by sponging miR-125b-5p. At the same time, SOX12 can directly bind to the LGALS8–AS1 promoter to activate its expression, forming a positive feedback loop that continuously activates the PI3K/AKT signaling pathway and promotes breast cancer metastasis [13]; in addition, lncRNA UCA1 regulates METTL14-mediated m6A modification of miR-375 by mediating DNA methylation of METTL14, indirectly upregulating SOX12 expression to enhance the proliferation and invasion capabilities of breast cancer cells [23].

In cervical cancer (CC), SOX12 can transcriptionally regulate the expression of lncRNA SNHG15, which acts as a miR-4735-3p sponge to upregulate HIF1a expression, thereby promoting tumor cell proliferation and resistance to the chemotherapeutic drug cisplatin [24]. For endometrial cancer (EC), studies have shown that overexpression or knockdown of SOX12 significantly enhances or inhibits the activity, proliferation, migration, and invasion capabilities of EC cells, as well as the activity and metabolism of the serine synthesis pathway (SSP). Mechanistically, SOX12 directly binds to the PHGDH promoter and activates its transcription, thereby enhancing serine synthesis pathway activity and providing metabolic support and antioxidant capacity to tumor cells. The study revealed that combined SOX12 knockdown and serine deprivation can significantly inhibit EC progression, suggesting that this strategy may serve as a new approach for molecular targeted therapy of EC [10].

In ovarian cancer (OC), lncRNA MNX1–AS1 promotes tumor cell proliferation, migration, and invasion by targeting the miR-744-5p/SOX12 axis, and high MNX1–AS1 expression is associated with advanced disease stage and low overall survival in OC patients [25].

Head and neck tumors

In tongue squamous cell carcinoma (TSCC), SOX12 is also regulated by lncRNA CASC9, which modulates TSCC cell proliferation, migration, and invasion. Study results show that CASC9 expression is upregulated in TSCC tissues and cells, suggesting a poor prognosis; it is negatively correlated with miR-423-5p and positively correlated with SOX12. Mechanistically, miR-423-5p is a predicted target miRNA of CASC9, and miR-423-5p can upregulate SOX12 expression, thereby promoting tumor cell proliferation and invasion [26].

In papillary thyroid carcinoma (PTC), recent studies have found that SOX12 drives glycolysis through the YBX1-LDHA signaling axis, thereby promoting tumor metastasis [9]; another study showed that NR2F1–AS1 can interact with miR-423-5p to induce SOX12 expression in PTC cells, thereby promoting PTC proliferation and invasion [27]; in addition, SOX12 can also affect PTC progression by regulating the expression of POU2F1 and POU3F1 [28].

Hematologic tumors

In acute myeloid leukemia (AML), recent studies suggest that SOX12 may be a therapeutic target. Antisense locked-nucleic acid GapmeRs can block SOX12 in human AML cell lines (KG1 and M07e), and downregulation of SOX12 in both cell lines induces tumor cell apoptosis [29]. miR-342-3p can inhibit AML cell growth and induce apoptosis by targeting SOX12 , and this effect can be inhibited by SOX12 overexpression [30]; another study found that circ_0012152 promotes AML cell proliferation by sponging miR-625-5p to upregulate SOX12 expression [31]; lncRNA SNHG1 regulates AML cell growth through the miR-489-3p/SOX12/Wnt/β-catenin signaling pathway [32].

In multiple myeloma (MM), SOX12 promotes tumor cell growth by enhancing Wnt/β-catenin signal transduction. Furthermore, miR-744-5p can inhibit MM cell proliferation, epithelial-mesenchymal transition, and glycolysis by targeting SOX12 [33], suggesting that SOX12 could be a new therapeutic target for MM.

Urinary system tumors

In clear cell renal cell carcinoma (ccRCC), a retrospective study based on TCGA has revealed that both SOX12 and SOX6 are significantly associated with the clinicopathological characteristics of ccRCC, and both can serve as promising biomarkers and therapeutic targets for ccRCC patients [34]; circ_001895 can promote SOX12 expression by sponging miR-296-5p, further enhancing the proliferation and invasion capabilities of ccRCC cells [35].

In bladder cancer, microRNA-370 inhibits SOX12 transcription and exerts a tumor-suppressing effect, making it a potential novel therapeutic target [36].

Other tumors

In lung adenocarcinoma(LUAD), recent studies have shown that the MAFG-AS1/miR-3196/SOX12 axis, the TMPO-AS1/E2F1/miR-326/SOX12 axis, and the LINC00680-GATA6-SOX12 axis are all involved in regulating tumor proliferation [37–39].

In melanoma, LINC01063 can upregulate SOX12 expression by sponging miR-5194, thereby promoting tumor cell malignant behaviors, suggesting that LINC01063 may serve as a potential prognostic or therapeutic biomarker for melanoma [40].

In gliomas, existing studies have shown that lncRNA DUXAP10 enhances SOX12 mRNA stability by recruiting HuR, thereby maintaining tumor cell stemness. Although DUXAP10 knockdown has little effect on glioma cell viability, it significantly reduces tumor sphere formation and aldehyde dehydrogenase (ALDH) activity [41].

Collectively, SOX12 exerts conserved oncogenic roles across a broad spectrum of human malignancies, with its regulatory mechanisms, core biological functions, and clinical relevance displaying remarkable consistency while retaining tissue-specific characteristics. Functionally, SOX12 predominantly drives tumor proliferation, invasion, metastasis, and stemness maintenance through diverse regulatory modalities, including ceRNA network-mediated post-transcriptional regulation, activation of canonical oncogenic signaling pathways (e.g., PI3K/AKT/mTOR, JAK2/STAT3, Wnt/β-catenin), and modulation of tumor metabolic reprogramming. Clinically, aberrant SOX12 overexpression is tightly correlated with advanced tumor stage, poor histological differentiation, lymph node metastasis, and unfavorable prognosis in most cancer types, highlighting its potential as a pivotal prognostic indicator. A comprehensive overview of the pan-cancer roles of SOX12 , encompassing its regulatory networks, biological effects, and clinical implications across distinct cancer categories, is systematically detailed in Table 1.

Table 1.

Expression characteristics and biological functions of SOX12 in different tumors

Tumor Type	Study Type	Sample Size	Methodologies	Key Findings	References
Colorectal Cancer (CRC)	Clinical & Experimental	647 tumors, 51 normal (TCGA); 22 tumors, 6 precancerous lesions; cell lines	Bioinformatics, ceRNA networks, RT-qPCR, Western blot, IHC	High expression correlates with poor differentiation and metastasis. FOXN3 downregulation causes EP300-mediated epigenetic upregulation of SOX12. UCHL3 activates AKT/mTOR to upregulate SOX12.	[7, 14, 15, 17]
Hepatocellular Carcinoma (HCC)	Clinical & Experimental	Cohort I (n = 260), Cohort II (n = 280); immunocompetent mice	scRNA-seq, IHC, tail vein metastasis model, flow cytometry	Overexpression predicts vascular invasion and poor prognosis. SOX12 recruits Tregs via CCL22 activation and upregulates PD-L1 to build an immunosuppressive microenvironment.	[11, 18, 42]
Gastric Cancer (GC)	Clinical & Experimental	378 gastrectomy patients; 79 paired tumor/adjacent normal tissues	IHC, Kaplan-Meier, Cox regression, Western blot, RT-qPCR	Controversial role: some studies show SOX12 promotes metastasis and stemness, while others link low expression to lymph node metastasis and poor prognosis.	[12, 19]
Pancreatic Cancer (PC)	Clinical & Experimental	54 paired tumor/normal tissues; SW-1990, PANC-1, etc.	qRT-PCR, luciferase reporter, Western blot, IHC	LncRNA C9orf139 regulates tumor growth via miR-663a/SOX12 axis; high expression correlates with advanced stage and poor differentiation.	[20]
Esophageal Squamous Cell Carcinoma (ESCC)	Clinical & Experimental	56 paired tumor/normal tissues; Eca109 cells	RT-qPCR, Western blot, shRNA, colony formation, Transwell	Independent risk factor maintaining cell viability via JAK2/STAT3 pathway. E3 ligase TRAF7 suppresses tumors by K48-linked ubiquitination and degradation of SOX12.	[21, 22]
Breast Cancer (BC)	Clinical & Experimental	524 tumor, 147 normal (IHC); 142 paired frozen tissues	IHC, RT-qPCR, In vitro/in vivo assays	Independent prognostic factor for OS and DMFS. LGALS8–AS1 and SOX12 form a positive feedback loop. LncRNA UCA1 upregulates SOX12 via METTL14-mediated m6A modification.	[6, 13, 23]
Cervical Cancer (CC)	Clinical & Experimental	28 paired tumor/normal tissues; SiHa, HeLa cells	qRT-PCR, MTT, EdU, flow cytometry, Transwell, ChIP	SOX12 transcriptionally regulates SNHG15, which sponges miR-4735-3p to upregulate HIF1a, promoting proliferation and cisplatin resistance.	[24]
Endometrial Cancer (EC)	Experimental	EC cell lines	Transwell, EdU, Hoechst staining, fluorescence microscopy	Directly binds and activates PHGDH transcription, enhancing the serine synthesis pathway (SSP) for metabolic support and antioxidant capacity.	[10]
Ovarian Cancer (OC)	Clinical & Experimental	20 OC tissues, 20 controls; SKOV-3, OVCAR-3 cells	CCK8, colony formation, Western blot	LncRNA MNX1–AS1 promotes tumor proliferation, invasion, and metastasis via the miR-744-5p/SOX12 axis.	[25]
Tongue Squamous Cell Carcinoma (TSCC)	Clinical & Experimental	94 TSCC and normal samples (Stage I-IV); TSCC cell lines	qRT-PCR, CCK-8, Transwell, luciferase reporter	LncRNA CASC9 regulates cell proliferation, migration, and invasion via the miR-423-5p/SOX12 axis.	[26]
Papillary Thyroid Carcinoma (PTC)	Clinical & Experimental	497 PTC, 59 normal (TCGA); 16 clinical PTC patients	scRNA-seq, bulk RNA-seq, CUT&Tag, IP-MS, IHC	SOX12 -YBX1-LDHA axis drives metastasis by stimulating glycolysis. Also regulated by NR2F1–AS1/miR-423-5p axis and influences POU2F1/POU3F1 expression.	[9, 27, 28]
Acute Myeloid Leukemia (AML)	Experimental	47 AML plasma; KG1, M07e, THP1 cells	Antisense LNA GapmeRs transfection, fluorescence microscopy, qRT-PCR	Blocking SOX12 using antisense GapmeRs or miR-342-3p induces apoptosis. Also regulated by circ_0012152 and lncRNA SNHG1.	[29–32]
Multiple Myeloma (MM)	Clinical & Experimental	146 bone marrow samples (73 MM, 73 healthy); MM cell lines	qRT-PCR, Western blot, xenograft mouse model	Promotes growth by enhancing Wnt/β-catenin signaling. miR-744-5p inhibits MM proliferation, EMT, and glycolysis by targeting SOX12.	[8, 33]
Clear Cell Renal Cell Carcinoma (ccRCC)	Clinical & Experimental	530 ccRCC, 72 normal (TCGA); 11 paired ccRCC tissues	RNA-seq analysis, CIBERSORT, Cox regression, qRT-PCR	Serves as a poor prognostic biomarker. circ_001895 acts as a miR-296-5p sponge to promote SOX12 expression and disease progression.	[34, 35]
Bladder Cancer	Experimental	5637 BCa cell line, nude mouse model	Subcutaneous xenograft model, cellular functional assays	miR-370 acts as a tumor suppressor by inhibiting SOX12 transcription.	[36]
Lung Adenocarcinoma (LUAD)	Experimental	Lung cancer cell lines (H1373, A549, etc.)	qRT-PCR, Transwell invasion & migration assays	Multiple axes, including MAFG-AS1/miR-3196, TMPO-AS1/miR-326, and LINC00680/GATA6, influence tumor growth by regulating SOX12.	[37–39]
Melanoma	Clinical & Experimental	Tumor and adjacent normal tissues; melanoma cell lines	qRT-PCR, Transwell, in vivo xenograft analysis	LINC01063 upregulates SOX12 by sponging miR-5194, promoting malignant behavior.	[40]
Glioma	Experimental	Glioma cell lines	ALDH activity assay, tumor sphere formation	LncRNA DUXAP10 recruits HuR to enhance SOX12 mRNA stability, maintaining cancer stemness and ALDH activity.	[41]

Core molecular mechanisms of SOX12 regulating tumor progression

Regulation mechanism of the ceRNA network

As an emerging non-coding RNA regulatory research framework in oncology, ceRNA regulatory networks have been widely used in recent years to identify potential diagnostic markers and targeted therapeutic targets for various cancers, such as endometrial, colon, and breast cancer [43–45]. It is also the most critical regulatory mode of SOX12 in tumors, accounting for more than 50% of current research on SOX12‘s regulatory mechanisms. This network mainly upregulates SOX12 expression via lncRNAs or circRNAs that act as molecular sponges, competitively binding miRNAs to relieve post-transcriptional inhibition of SOX12 [14].

As shown in the upper half of Fig. 2, in gastric cancer, lncRNA TERC upregulates SOX12 expression by directly sponging miR-423-5p, thereby promoting tumor cell proliferation and migration [12]; lncRNA H19 upregulates SOX12 by binding to miR-148a-3p, accelerating gastric cancer metastasis [46].

Fig. 2.

ceRNA regulatory network and classical signal pathway regulatory diagram

In hepatocellular carcinoma, LINC00978, circ_0006789, and PRR34–AS1 target miR-125b-5p, miR-1324, and miR-296-5p respectively, jointly regulating SOX12 expression to promote tumor progression [47–49]. In breast cancer, LGALS8–AS1 forms a positive feedback regulatory loop with SOX12: specifically, LGALS8–AS1 upregulates SOX12 expression by sponging miR-125b-5p, and SOX12 can directly activate LGALS8–AS1 transcription, thereby promoting breast cancer metastasis in a continuous loop [13].

These studies indicate that although the regulation of SOX12 by the ceRNA network may vary across tumor types, the core regulatory mode is miRNA sponging mediated by non-coding RNAs, and this regulatory mode provides multiple potential targets for tumor therapy.

Classical signaling pathway activation mechanism

SOX12 can promote tumor progression by activating multiple classical oncogenic signaling pathways. As shown in the lower half of Fig. 2, the Wnt/β-catenin pathway is one of the core pathways regulated by SOX12. It is activated in various tumors, including myeloma, colorectal cancer, and liver cancer [33]. In multiple myeloma (MM), SOX12 directly binds to β-catenin, enhancing its nuclear translocation and activating TCF/LEF transcription factor activity, thereby promoting the expression of downstream target genes. Studies have shown that SOX12 knockdown inhibits MM cell growth by downregulating the Wnt/β-catenin signaling pathway, suggesting that SOX12 could be a new therapeutic target for MM [8]. miR-744-5p can inhibit the Wnt/β-catenin pathway by targeting SOX12 , thereby exerting an anti-cancer effect [33].

Activation of the PI3K/AKT/mTOR pathway is an essential mechanism by which SOX12 promotes colorectal cancer progression. The deubiquitinase UCHL3 upregulates SOX12 expression by activating this pathway, thereby promoting tumor cell proliferation, invasion, and epithelial-mesenchymal transition, suggesting that UCHL3 can serve as a potential therapeutic target and prognostic biomarker for colorectal cancer [7].

SOX12 activates the JAK2/STAT3 pathway in esophageal squamous cell carcinoma: SOX12 can directly bind the JAK2 promoter to promote JAK2 expression, leading to STAT3 phosphorylation and subsequent upregulation of invasion-related genes such as MMP9 and VEGF [12, 21].

These signaling pathways interact and intertwine to form a complex regulatory network that jointly mediates SOX12 ‘s oncogenic function.

Metabolic reprogramming mechanism

Multiple recent studies have shown that metabolic reprogramming in tumor cells is closely linked to tumor growth and proliferation and have confirmed the feasibility of targeted cancer metabolic therapy strategies [50–52]. SOX12 also plays an essential regulatory role in this process, as shown in Fig. 3.

Fig. 3.

Metabolic reprogramming regulatory diagram. Abbreviations: ASN: Asparagine synthetase

The serine synthesis pathway (SSP) is one of the core metabolic pathways regulated by SOX12. In endometrial carcinoma, SOX12 directly binds to the promoter of 3-phosphoglycerate dehydrogenase (PHGDH) and activates its transcription, thereby enhancing SSP activity and providing energy and antioxidant substances to support tumor progression. Studies have shown that combined SOX12 knockdown and serine deprivation can significantly inhibit malignant tumor progression, suggesting a new strategy for EC treatment [10].

Abnormal activation of glycolytic pathways is a typical metabolic characteristic of tumor cells. In papillary thyroid carcinoma, SOX12 upregulates YBX1 expression and recruits it to the LDHA promoter, thereby activating the TGF-β signaling pathway, which ultimately stimulates glycolysis and drives tumor metastasis [9].

In colorectal cancer, SOX12 can positively regulate asparagine synthetase(ASN) expression, thereby promoting endogenous asparagine production and enhancing tumor cell metastatic capacity. Female CRC patients with high SOX12 expression have a poor prognosis [17].

These studies indicate that SOX12 reshapes tumor metabolic networks by regulating the expression of key metabolic enzymes, supporting tumor progression.

Immune microenvironment regulation mechanism

The formation of an immunosuppressive microenvironment is a key mechanism of tumor immune escape, and recent studies have shown that SOX12 also plays a vital role in this process, as shown in Fig. 4. In hepatocellular carcinoma, SOX12 transcriptionally activates C-C motif chemokine ligand 22 (CCL22), thereby recruiting Treg cells into the tumor microenvironment, and simultaneously upregulates PD-L1 expression to inhibit the function of CD8+T cells (CTL), ultimately leading to the formation of an immunosuppressive microenvironment. Experiments have found that blocking CCR4 (the receptor for CCL22) or TGFβR1 can improve the efficacy of anti-PD-L1 therapy in HCC with high SOX12 expression [11].

Fig. 4.

The molecular mechanisms of SOX12 in modulating the tumor immune microenvironment. Abbreviations: CTL: Cytotoxic T Lymphocyte

In colorectal cancer, m6A-modified MEF2A can attenuate cetuximab sensitivity through the PD-L1/SOX12 axis. The specific mechanism is that RBM15/IGF2BP1-mediated m6A modification can upregulate MEF2A; the upregulated MEF2A binds to the PD-L1 promoter to transcriptionally upregulate PD-L1 expression; PD-L1 can also bind to SOX12 mRNA to stabilize its expression, ultimately reducing cetuximab sensitivity [53]. In addition, as a marker of HCC stem cells, SOX12 is positively correlated with HCC immune infiltration and is involved in tumor remodeling of the immune microenvironment [42]. These findings reveal the critical role of SOX12 in tumor immune escape and provide new ideas for combination immunotherapy strategies.

Other regulatory mechanisms

In addition to the central mechanisms above, SOX12 also regulates tumor progression through epigenetic modifications, ubiquitination, and protein interactions. In terms of epigenetic modification, in colorectal cancer, FOXN3 inhibits EP300 expression by binding to the EP300 promoter, reducing EP300-mediated H3K27ac modification enrichment in the SOX12 promoter region, thereby inhibiting the epigenetic upregulation of SOX12 to suppress the stemness of colorectal cancer cells [15]

In terms of ubiquitination, in esophageal squamous cell carcinoma, TRAF7, an E3 ubiquitin ligase, can mediate K48-linked ubiquitination and degradation of SOX12 , thereby inhibiting tumor proliferation and migration [22]. In terms of protein interaction, in colorectal cancer, NRSN2 interacts with SOX12 to recruit SOX12 in SW620 colorectal cancer cells and upregulate its expression, thereby promoting tumor cell proliferation, invasion, and migration [54]; another study found that in gliomas, DUXAP10 inhibits cytoplasm-nuclear transport by recruiting HuR proteins, thereby enhancing the stability of SOX12 mRNA in the cytoplasm [41].

These diverse regulatory mechanisms collectively constitute the oncogenic network of SOX12 , providing multiple entry points for targeted therapy.(Fig. 5).

Fig. 5.

Other regulatory mechanisms of SOX12 in tumor progression

Conserved oncogenic mechanisms of SOX12 across human cancers

Collectively, the regulatory patterns of SOX12 in tumorigenesis and progression exhibit striking conservation across different cancer types, forming a set of core oncogenic regulatory frameworks independent of tumor tissue specificity. First, the ceRNA network acts as the most universal upstream regulatory mode of SOX12 , accounting for more than 50% of the current regulatory mechanisms reported. Among them, the lncRNA/miR-125b-5p/SOX12 and lncRNA/miR-423-5p/SOX12 axes are repeatedly validated in digestive system tumors, head and neck tumors, and urinary system tumors, suggesting these two axes are the core ceRNA regulatory modules of SOX12. Second, the activation of Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways is the most conserved downstream effector mechanism of SOX12. Whether in solid tumors such as colorectal cancer, hepatocellular carcinoma, and breast cancer, or hematologic tumors such as multiple myeloma and acute myeloid leukemia, SOX12 exerts its oncogenic function by enhancing the transcriptional activity of these two classical oncogenic pathways, which are the key nodes of SOX12 -mediated tumor proliferation and epithelial-mesenchymal transition (EMT). Third, the immune microenvironment regulation pattern centered on PD-L1 upregulation and Treg cell recruitment is highly conserved in solid tumors. SOX12 can construct an immunosuppressive microenvironment by transcriptionally activating CCL22/PD-L1 axis in hepatocellular carcinoma, colorectal cancer, and other solid tumors, which is a common mechanism for SOX12 to mediate tumor immune escape. In addition, the regulation of key metabolic enzymes (e.g., PHGDH, LDHA, asparagine synthetase) to drive metabolic reprogramming is also a newly discovered conserved characteristic of SOX12 in endometrial cancer, papillary thyroid carcinoma, and colorectal cancer. These cross-tumor common regulatory mechanisms not only reveal the core oncogenic logic of SOX12 but also provide universal therapeutic targets for SOX12 -based pan-tumor targeted therapy.

Clinical application potential of SOX12

The translational potential of SOX12 in clinical oncology is summarized in Table 2, which categorizes its roles into prognostic assessment, direct therapeutic targeting, indirect regulatory interventions, and synergistic combination schemes. As a promising biomarker, aberrant SOX12 expression provides critical independent prognostic value for patient survival across various malignancies, notably in colorectal and breast cancers. Moreover, the systematic identification of its direct and indirect targeting strategies highlights the potential for developing SOX12 -centered precision therapeutic frameworks.

Table 2.

Clinical application potential of SOX12 in human cancers

Application Category	Study Type/Cohort	Sample Size/Enrolled Patients	Methodology	Core Findings & Strategies	References
Independent Prognostic Biomarker	Retrospective analysis (CRC)	TCGA (647 tumors, 51 normal) & multiple GEO cohorts	Bioinformatics, ceRNA network, Kaplan-Meier	High expression significantly predicts advanced clinical stage and shortened overall survival (OS).	[14]
Independent Prognostic Biomarker	Clinicopathological study (BC)	SGH cohort (524 tumors, 147 normal)	IHC, RT-qPCR, uni/multivariate Cox	Independent adverse prognostic factor for OS and DMFS; high predictive value in Luminal/HER2+ subtypes.	[6]
Independent Prognostic Biomarker	Methylation analysis (HCC)	TCGA-LIHC (371 HCC, 50 normal)	DiseaseMeth database, immune infiltration, methylation survival	Associated with vascular invasion; high SOX12 promoter DNA methylation significantly correlates with poorer survival.	[18, 42]
Independent Prognostic Biomarker	Retrospective analysis (ccRCC)	TCGA-KIRC (530 ccRCC, 72 normal)	Deep learning, Cox regression, CIBERSORT	High expression is an independent risk factor for OS and DSS, associated with immune microenvironment remodeling.	[34]
Independent Prognostic Biomarker	Clinical analysis (OC, Osteosarcoma, AML)	TARGET/GEO data mining, AML plasma	Kaplan-Meier, RT-qPCR, stemness genes	High expression consistently indicates high recurrence risk and poor overall prognosis.	[25, 29, 55]
Direct Targeted Therapy	Preclinical pharmacology (Pan-cancer/Vascular)	Zebrafish and breast cancer mouse models	High-throughput small molecule screening, interactome binding	Small molecule inhibitor (Sm4) blocks HMG-box dimerization, destroying tumor microvessels and lymphatic metastasis.	[56]
Direct Targeted Therapy	Targeted ubiquitination (ESCC)	Human ESCC cell lines (e.g., Eca109)	Plasmid transfection, Western blot, colony formation	Targeted activation of E3 ligase TRAF7 induces K48-linked ubiquitination and degradation of SOX12 to exert tumor-suppressive effects.	[22]
Indirect Gene Therapy	Antisense nucleic acid intervention (Pan-cancer)	Preclinical in vitro models	siRNA-mediated knockdown, miRNA mimic transfection	Precision knockdown of upstream oncogenic ceRNAs (e.g., CASC9, LGALS8–AS1) or using miRNA mimics to inhibit tumor proliferation.	[12, 13, 33, 36, 57]
Indirect Gene Therapy	Bioengineered prodrugs (TNBC)	Refractory TNBC in vitro models	Hypoxic incubation, bioengineered miR-127 prodrug transfection	miR-127 prodrug matures in hypoxic microenvironment and specifically clears SOX12 mRNA, suppressing local growth and metastasis.	[58]
Synergistic Combination Therapy	Combination immunotherapy (HCC)	Immunocompetent HCC mice (DEN/CCl4 & orthotopic)	In vivo drug administration, flow cytometry, anti-PD-L1 + CCR4 inhibitor	Complete blockade of CCL22-mediated Treg recruitment reverses CD8+ T cell exhaustion, significantly enhancing immunotherapy efficacy.	[11]
Synergistic Combination Therapy	Metabolic & chemotherapy sensitization (EC, GC)	EC cell lines & GC subcutaneous xenograft	SOX12 knockdown + serine deprivation; FOXP4 small-molecule inhibitor + 5-FU	Inhibiting SOX12 -related metabolic axes triggers energy collapse and enhances sensitivity to traditional chemotherapy (e.g., 5-FU).	[10, 16]

Prognostic biomarker potential

Numerous clinical studies have confirmed that abnormal expression of SOX12 can serve as a prognostic evaluation indicator for various tumors. In colorectal cancer, high SOX12 expression is significantly associated with shortened overall survival of patients and has the potential to be a prognostic biomarker for CRC patients [14]. In breast cancer, high SOX12 expression is an independent risk factor for overall survival and distant metastasis-free survival, and has more significant prognostic value in luminal and HER2-positive breast cancer patients [6]

In hepatocellular carcinoma, as a marker of HCC stem cells, high SOX12 expression is also associated with poor prognosis in male HCC patients [42]. It is also associated with vascular invasion and postoperative recurrence, and its methylation level can predict patient survival [18]. In clear cell renal cell carcinoma, both SOX12 and SOX6 serve as independent prognostic biomarkers, and their expression levels are correlated with tumor-infiltrating immune cells [34]. In addition, high SOX12 expression is associated with poor prognosis in tumors such as ovarian cancer, osteosarcoma, and acute myeloid leukemia [25, 29, 55]. The advantage of SOX12 as a prognostic biomarker lies in its stable expression pattern and tumor specificity: it can be detected by conventional methods such as IHC and qRT-PCR, thus offering strong clinical translational potential.

Potential development of therapeutic targets

As the oncogenic mechanism of SOX12 in tumors is increasingly elucidated, it has emerged as a potential therapeutic target. Relevant targeted therapy strategies primarily fall into two categories: direct targeting of SOX12 and indirect regulation of SOX12 expression. In terms of direct targeting, the HMG box DNA-binding domain of SOX12 can serve as a key target. Theoretically, small-molecule inhibitors can be designed to block their binding to DNA or coactivators, thereby directly inhibiting their transcriptional activity. Although there are few studies on this type of direct targeting currently, small-molecule compounds that interfere with the HMG DNA-binding domain of SOX18 and thus inhibit its transcriptional activity have been identified, suggesting that this method is feasible and warrants further research.The high sequence homology between the HMG box domain of SOX12 and SOX18 provides a direct template for the development of small-molecule inhibitors targeting SOX12. Small-molecule compounds that specifically interfere with the HMG DNA-binding domain of SOX18 have been successfully identified and verified to inhibit the transcriptional activity of SOX18 by blocking its combination with DNA and coactivators [56]. Based on the conserved structural characteristics of the HMG box domain in the SOXC subfamily, these SOX18 inhibitors can be structurally optimized to develop SOX12 -specific small-molecule inhibitors, which can significantly reduce the research and development cycle and cost of targeted drugs, and have high clinical transformation potential. In addition, the post-translational modification sites of SOX12 (e.g., ubiquitination sites mediated by TRAF7 [22]) also provide alternative targets for drug development. Targeted activation of TRAF7, the E3 ubiquitin ligase mediating SOX12 K48-linked ubiquitination and degradation, can effectively inhibit tumor proliferation and migration in esophageal squamous cell carcinoma cell lines, showing good specificity and low off-target effects

In terms of indirect regulation, targeted strategies for SOX12 -related ceRNA networks have certain potential. For example, siRNAs targeting lncRNAs CASC9, LGALS8–AS1, or circ_0006789 can inhibit tumor growth by downregulating SOX12 expression [13, 48, 57]. Since ceRNA networks exhibit tumor-specific regulation of SOX12 , designing siRNAs to knock down SOX12 -regulating ceRNAs offers higher specificity than targeting SOX12 directly with small-molecule inhibitors. This approach has been successfully used in many studies, demonstrating its feasibility. miRNA mimic therapy also has specific application prospects: for example, mimics such as miR-423-5p, miR-744-5p, and miR-370 can target the 3‘UTR of SOX12 to downregulate its expression, inhibiting downstream oncogenic pathways and thus suppressing the progression of various tumors [12, 33, 36]. In a recent study, a miR-127 prodrug was prepared and shown to be processed into miR-127-3p in triple-negative breast cancer cells (TNBC). miR-127-3p inhibits the growth and metastatic potential of TNBC cells by targeting multiple genes, including SOX12. This approach avoids problems such as poor stability and high cost of miRNA mimics, and can also serve as a research idea for therapeutic strategies.The preclinical research results of SOX12 -targeted therapy in specific tumor types also provide a basis for its extension to other SOX12 high-expression tumors. For example, the bioengineered miR-127 prodrug can be efficiently processed into mature miR-127-3p in triple-negative breast cancer (TNBC) cells, and specifically downregulate SOX12 expression to inhibit the growth and metastatic potential of TNBC cells [58]. This prodrug strategy solves the problems of poor stability and low delivery efficiency of traditional miRNA mimics, and its good therapeutic effect in TNBC suggests that it can be further applied to SOX12 high-expression tumors such as colorectal cancer and hepatocellular carcinoma through appropriate drug delivery system optimization. In addition, the combination therapy strategy targeting SOX12 has shown better therapeutic efficacy in preclinical studies: the combination of SOX12 knockdown and serine deprivation can synergistically inhibit the progression of endometrial cancer by blocking the serine synthesis pathway [10], and the combination of anti-PD-L1 and CCR4 inhibitors can significantly improve the immune therapy response of hepatocellular carcinoma with high SOX12 expression [11]. These combination strategies not only overcome the single-target therapy resistance caused by the complex regulatory network of SOX12 but also conform to the development trend of clinical tumor comprehensive therapy, and are expected to enter clinical trials in the short term.

In terms of combination therapy strategies, studies have found that the combination of anti-PD-L1 and CCR4 inhibitors can improve therapeutic efficacy in hepatocellular carcinoma [11]; combined SOX12 knockdown and serine deprivation can synergistically inhibit tumors in endometrial carcinoma [10]; in gastric carcinoma, the combination of FOXP4 inhibitors and 5-fluorouracil can also enhance chemotherapy sensitivity [16].

These studies provide a range of strategies for SOX12 -targeted therapy, and some have entered preclinical research with promising transformational potential.

Research limitations and future directions

Existing research limitations

Although significant progress has been made in SOX12 research in tumors over the past few years, certain limitations remain. First, most existing studies focus on a single tumor type or a single regulatory mechanism, lacking a systematic comparative analysis of the SOX12 regulatory network across different tumors, making it challenging to identify the common and specific oncogenic mechanisms of SOX12. Second, research on the post-translational modifications of SOX12 is relatively scarce: aside from ubiquitination, the effects of changes such as phosphorylation and methylation on its function remain unclear. Third, the synergistic oncogenic mechanism between SOX12 and other SOX family members needs to be further explored: existing studies have only confirmed that SOX12 is positively correlated with the expression of SOX4 and SOX18 and can interact with them [1, 2], but the specific interaction mode and synergistic target genes are still unclear. Finally, there is insufficient clinical research on SOX12: currently, no SOX12 -targeted drugs have entered clinical trials, and the clinical validation of SOX12 as a prognostic biomarker lacks support from large, multicenter cohorts.

Future research directions

In view of the deficiencies in existing studies, future research can be carried out in the following aspects: in terms of mechanism research, new technologies such as single-cell sequencing and spatial transcriptomic should be adopted to analyze the differences in the regulatory role of SOX12 among different tumor cell subgroups; further explore the post-translational modification network of SOX12 to clarify the effects of modifications such as phosphorylation and methylation on its stability and transcriptional activity; systematically study the synergistic mechanism of SOX12 , SOX4, and SOX11 in promoting tumor progression and explore their common target genes and regulatory networks. In terms of clinical research, multi-center, large-sample clinical studies need to be carried out to verify the clinical value of SOX12 as a prognostic biomarker; develop more specific SOX12 -targeted drugs, such as HMG box domain inhibitors, SOX12 -specific siRNAs or miRNA mimics, and conduct corresponding preclinical and clinical trials; explore combination strategies of SOX12 -targeted therapy with immunotherapy, chemotherapy, and targeted therapy to improve therapeutic efficacy. In addition, the role of SOX12 in the cross-regulation of tumor metabolic reprogramming and immune microenvironment, and the impact of gender differences on SOX12 function are also worthy of in-depth study [17]

Conclusion

As a core member of the SOXC subfamily of transcription factors, SOX12 plays a key oncogenic role in various tumors through multiple mechanisms, including ceRNA networks, activation of classical signaling pathways, metabolic reprogramming, and regulation of the immune microenvironment. Its abnormal expression is closely associated with the malignant phenotype and poor prognosis of tumors, and it has dual potential as a prognostic biomarker and a therapeutic target. Although current studies have revealed some mechanisms by which SOX12 regulates tumor progression, several issues remain, including unclear regulatory networks and insufficient clinical translation. In the future, through in-depth analysis of the oncogenic network of SOX12 , the development of targeted drugs, and the conduct of large-scale clinical trials, it is expected that SOX12 -related research will yield practical tools for tumor diagnosis and treatment, providing a new approach to improve the prognosis of tumor patients.

Abbreviations

ALDH

Aldehyde dehydrogenase

AML

Acute myeloid leukemia

ANTs

Adjacent normal tissues

ASN

Asparagine Synthetase

BC

Breast cancer

ccRCC

Clear cell renal cell carcinoma

CCL22

C-C motif chemokine ligand 22

CC

Cervical cancer

CRC

Colorectal cancer

CTL

Cytotoxic T lymphocyte

EC

Endometrial cancer

EMT

Epithelial-mesenchymal transition

ESCC

Esophageal squamous cell carcinoma

FOXN3

Forkhead box N3

GC

Gastric cancer

HCC

Hepatocellular carcinoma

HMG

High-mobility-group

HIF1a

Hypoxia-inducible factor 1α

ICI

Immune checkpoint inhibitor

IHC

Immunohistochemistry

JAK2/STAT3

Janus kinase 2/signal transducer and activator of transcription 3

lncRNA

Long non-coding RNA

LDHA

Lactate dehydrogenase A

LUAD

Lung adenocarcinoma

MM

Multiple myeloma

m6A

N6-methyladenosine

miRNA

MicroRNA

NLS

Nuclear localization signal

NSCLC

Non-small cell lung cancer

OC

Ovarian cancer

PD-L1

Programmed cell death ligand 1

PHGDH

3-phosphoglycerate dehydrogenase

PI3K/AKT/mTOR

Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin

PC

Pancreatic cancer

POU2F1

POU class 2 homeobox 1

POU3F1

POU class 3 homeobox 1

PTC

Papillary thyroid carcinoma

qRT-PCR

Quantitative real-time polymerase chain reaction

SSP

Serine synthesis pathway

TCF/LEF

T cell factor/lymphoid enhancer factor

TGF-β

Transforming growth factor-β

Treg

Regulatory T cells

TSCC

Tongue squamous cell carcinoma

Wnt/β-catenin

Wingless/integrated/β-catenin

YBX1

Y-box binding protein 1

Author contributions

Hao-Kun Leng is the lead contributor for this review article through drafting the article, data curation, and visualization.Yuanqi Liu contributed to literature search assistance, data validation, and manuscript review & editing.Lei Wu contributed to the conception and design of the study, supervision and critical revision for important intellectual content.

Funding

This work was supported by the following research grants from the National Natural Science Foundation of China under Grant (No. 82203522); Natural Science Foundation of Beijing under Grant (No. 7232085); The Beijing High-Level Innovation and Entrepreneurship Talent Support Program young backbone talent projects（No. G202532365).

Data availability

Not applicable.

Declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.