KIF18B: an important role in signaling pathways and a potential resistant target in tumor development

Abstract

KIF18B is a key member of the kinesin-8 family, involved in regulating various physiological processes such as microtubule length, spindle assembly, and chromosome alignment. This article briefly introduces the structure and physiological functions of KIF18B, examines its role in malignant tumors, and the associated carcinogenic signaling pathways such as PI3K/AKT, Wnt/β-catenin, and mTOR pathways. Research indicates that the upregulation of KIF18B enhances tumor malignancy and resistance to radiotherapy and chemotherapy. KIF18B could become a new target for anticancer drugs, offering significant potential for the treatment of malignant tumors and reducing chemotherapy resistance.

Introduction

In 1985, Vale et al. identified a novel force-producing molecule in the axons of squid, which they named kinesin [1]. Researchers have now identified a kinesin superfamily that includes 45 different kinesins, each featuring a head (motor) domain, a stalk (coiled-coil, CC) domain, and a tail domain [2]. These proteins are classified into 14 families (kinesin-1 to kinesin-14) [3], mainly functioning in the cellular microtubule system by transporting organelles, protein complexes, and mRNA to specific destinations through ATP consumption [4, 5], Moreover, these proteins are critical in the processes of chromosome movement and spindle assembly [6]. However, these molecules exhibit distinct functions. For example, KIF2A is dispensable in embryonic neurogenesis, yet essential for neuronal maturation, connectivity, and maintenance in postnatal stages. Its deficiency results in early-onset neurodegeneration [7]; Moreover, mutations in KIF5A are associated with familial amyotrophic lateral sclerosis (ALS) [8, 9]; KIF13B and KIF5B can collaborate to promote the transport of secretory vesicles [10].

Kinesin-8 is commonly recognized as a microtubule (MT) depolymerase, with its main role being the regulation of microtubule lengths and chromosome movements during animal mitosis [11]. It comprises two subfamilies, KIF18 and KIF19 [5], and is structurally characterized by a specific helical neck region [12]. KIF18B collaborates with MCAK to regulate microtubule depolymerization [13, 14], with KIF18B impacting microtubule length, spindle assembly, and chromosome arrangement by delivering cargo to the microtubule’s plus-end [15].

The link between KIF18B and tumors has emerged as a focal point of study in recent years. Increasing research indicates that KIF18B is overexpressed in various cancers of the respiratory, urinary, and digestive systems, and it promotes tumor proliferation. Data from survival analyses indicate that high expression of KIF18B is closely linked to poor outcomes [16–20]. A pan-cancer study indicates that KIF18B not only participates in cell cycle regulation but is also associated with tumor immune infiltration and can serve as a prognostic biomarker [21]. In this review, we will focus on discussing the functions of KIF18B in cancer and its mechanisms of action.

Structure and regulation of KIF18B

The human KIF18B gene is located in the chromosome 17q21.31 region, encoding a protein with a molecular weight of 94kD. Structurally, KIF18B is composed of an N-terminal motor domain, a positively charged neck structural domain, and a stalk-tail domain, which includes one SIP sequence and three IP sequences (containing one SIP sequence and three IP sequences) [12, 22] (Figure 1). During interphase, KIF18B is predominantly expressed inside the cell nucleus; however, as mitosis begins, KIF18B spreads to the cell cortex and into the microtubules and adjacent areas, thereby strengthening microtubule dynamics and facilitating the reorganization of the cytoskeleton during mitosis [14, 23]. Regarding its functions, KIF18B not only adjusts microtubule length but also aids in the repair of DNA double-strand breaks [24]and assist in spindle positioning and helps in the positioning of the spindle [23].

Fig. 1.

The structure of KIF18B. A KIF18B protein structure chart (source: UniProt protein database). B Schematic diagram of KIF18B structure: Comprising an N-terminal motor domain, a positively charged neck domain, and a stalk-tail domain, which includes one SIP sequence and three IP sequences

The expression of KIF18B is specific to certain tissues and is regulated by the cell cycle [14]. Transport proteins and transcription factors can induce the transcriptional expression of KIF18B [15, 25]. FOXM1, a transcription factor that controls the progression of the cell cycle, is overexpressed in most human cancers [26]. Research by Ji and others has demonstrated that KIF18B can be transcriptionally activated as a direct downstream target of FOXM1 [15].Additional evidence suggests that knockdown of KIF18B can lead to cell cycle arrest in various cancer cells, although the phases of arrest may differ Further experiments have confirmed that knockdown of KIF18B causes cell cycle arrest in various cancer cells, with the phase of arrest varying [20, 27, 28], indicating that KIF18B’s impact on the cell cycle varies among different cancers. Regrettably, studies on the upstream regulators of KIF18B are still somewhat limited. Identifying the molecules or external stimuli that can activate KIF18B’s transcriptional expression requires additional research.

In addition, KIF18B is involved in the activation and regulation of protein kinases and signaling molecules. Gamma-actin (γ-actin), as a binding partner of KIF18B, collaboratively regulates lysosome positioning, facilitates the transport of mTOR complex 1 (mTORC1) to lysosomal membranes, and prevents p70 S6K from entering lysosomes for degradation, ultimately enhancing mTORC1 signaling [15]. Xie and colleagues’ research indicates that KIF18B’s regulatory effect on mTORC1 depends on the activation of CDCA8 [16]. This indicates that there are various pathways through which KIF18B regulates mTORC1. The influence of KIF18B on tumor cell progression is closely linked to the activation of several signaling pathways. For instance, in prostate, breast, and lung cancers, KIF18B’s regulation of tumor cell proliferation is accompanied by the activation of the AKT pathway [18, 29, 30], while in hepatocellular carcinoma, cervical cancer, and bladder urothelial cancer, KIF18B’s control over tumor cell viability involves the Wnt/β-catenin pathway [28, 31, 32]. Thus, the regulatory function of KIF18B in tumor cells relies on the cooperative effects of multiple signaling pathways, and clarifying KIF18B’s direct downstream targets and mechanisms will aid in a deeper understanding of tumor progression mechanisms.

Physiological functions of KIF18B

Previous studies have reported that KIF18B can promote chromosome congression and restrict microtubule length during mitosis [33]. Similar to other motor proteins, KIF18B employs its C-terminal non-motor microtubule-binding domain to identify and accumulate at the ends of microtubules in vitro [34]. In contrast to the effects of knocking down KIF18A, the knockdown of KIF18B in PtK cells—a cell type particularly suitable for microtubule (MT) array imaging—resulted in reduced microtubule growth speed and maintained the microtubules in a state of continuous growth. This suggests that members of the kinesin-8 superfamily can have divergent impacts on microtubule dynamics [35]. As KIF18B moves along microtubules away from areas of kinase activity, it undergoes dephosphorylation by cytoplasmic phosphatases. This dephosphorylation enables KIF18B to stay longer at microtubule tips, resulting in its accumulation at the plus-ends of elongated astral microtubules. This process leads to microtubule instability, which helps ensure correct spindle positioning [23]. Following this, additional research was carried out to delve deeper into the role of KIF18B in microtubules and spindles. In KIF18B-knockdown cell lines, the localization of MCAK at microtubule plus-ends was compromised, interrupting EB1 interactions, obstructing the accumulation of KIF18B at microtubule plus-ends, and inhibiting its capacity to control microtubule lengths on monopolar spindles. Subsequent studies confirmed that KIF18B transports MCAK to microtubule plus-ends by interacting with the N-terminus of MCAK and EB3, thereby promoting microtubule catastrophe [25, 36].

Furthermore, Shin et al. found that KIF18B exhibits two different modes of movement: directed motion and predominantly diffusive motion, which are regulated by its tail structure and mainly powered by ATP hydrolysis [33]. However, McHugh and his team’s experiments show that KIF18B is a highly processive motor. It approaches the plus-end of microtubules via directed movement instead of diffusion and negatively regulates microtubule dynamics by encouraging catastrophic events [23]. This variation might result from the N-terminal GFP tag inhibiting KIF18B’s movement characteristics or from differences in cell types affecting its diffusion.

KIF18B in tumorigenesis and related signaling pathways

Adenocarcinoma of the lung

Lung cancer is one of the most common cancers worldwide and a leading cause of cancer incidence and mortality in developed countries, with over one million deaths annually due to the disease [37, 38]. Adenocarcinoma of the lung (ADC) constitutes 40% of new lung cancer cases and is the most prevalent type among non-smokers [39]. Ji and his team, through database analysis, determined that KIF18B is significantly overexpressed in lung adenocarcinoma samples compared to normal tissues, with high levels closely correlating with poor patient outcomes. Cellular experiments have shown that reducing KIF18B suppresses the malignant proliferation of lung cancer cells. In this process, the reduction of KIF18B notably decreased the expression of Rac1-GTP, a critical marker for tumor migration and invasion. Moreover, the phosphorylation levels of AKT and mTOR were diminished following the knockdown of KIF18B, suggesting that this intervention could inhibit the proliferation, migration, and invasion of lung adenocarcinoma cells by controlling the expression of the Rac1-mediated AKT/mTOR signaling pathway [30]. Later retrospective clinical research also verified that a poor prognosis in lung adenocarcinoma patients correlates with high KIF18B expression [40, 41]. Functional analyses of KIF18B indicate that it could regulate basic physiological processes in lung adenocarcinoma cells, including cell cycle control, DNA replication, and DNA repair [27, 40]. But these predictions still need to be experimentally validated.

Bladder cancer

Bladder cancer (BCa) is the most prevalent malignant tumor in the urinary tract and ranks as the fourth most common malignancy among men, closely associated with factors such as age, gender, and smoking habits [42, 43]. Cancer stem cells (CSCs) constitute a subgroup of tumor cells that are capable of driving tumor initiation and potentially causing relapse [44]. Recently, through transcriptomic analysis, Pan and colleagues found that KIF18B is upregulated in bladder cancer, possibly playing a crucial role in sustaining bladder cancer stem cells [45]. Further research has revealed that KIF18B plays a critical role in bladder cancer, not only enhancing cell survival, proliferation, and invasion but also activating signaling molecules such as β-catenin. β-catenin, a downstream molecule of the Wnt signaling pathway, can initiate cancer development and progression upon activation [46]. Furthermore, miRNA-139-3p binds to the 3’UTR of KIF18B mRNA, negatively regulating KIF18B; concurrently, overexpression of KIF18B reverses the inhibitory effect of miRNA-139-3p on bladder cancer cells. This indicates that the miRNA-139-3p/KIF18B axis might suppress the malignant effects of BUC by modulating the Wnt/β-catenin signaling pathway, thereby offering a potential therapeutic target for BUC patients [31]. Yet, there are currently no studies reporting whether KIF18B can activate stem cell-related molecules such as SOX2 and KLF4, and affect the malignant proliferation of bladder cancer cells.

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, typically developing from chronic liver diseases or cirrhosis, with a high mortality rate [47, 48]. Early stages of hepatocellular carcinoma are managed with liver resection and various surgical interventions, while advanced stages may be treated with chemotherapy, immunotherapy, and oncolytic viruses [49]. Yang and his team found that KIF18B is frequently overexpressed in patients with liver cancer, and knocking it down substantially reduces liver cancer cell proliferation, migration, and invasion. The knockdown of KIF18B significantly reduces the activity of the Wnt/β-Catenin pathway, while treatment with the Wnt/β-Catenin pathway activator lithium chloride (LiCl) can reverse the anti-tumor effect of KIF18B knockdown, suggesting that the Wnt/β-Catenin pathway may serve as its principal effector pathway [50]. Another research indicated that high levels of KIF18B significantly correlate with shorter overall and disease-free survival in HCC patients, marking it as an independent indicator of poor prognosis [51].

Gene co-expression analysis has shown a close association between KIF18B expression and immune cell infiltration [52]. Further experiments show that KIF18B is highly expressed in two immune subtypes, C1 (wound healing) and C2 (INF-r dominant), and knockdown of KIF18B inhibits EMT and reduces the invasiveness and migration of HCC cells. These findings have been validated in in vivo experiments, but the specific mechanisms by which KIF18B regulates EMT still need further study [21]. Similar research demonstrates that among immune cells, activated regulatory T cells (Tregs) exhibit the strongest positive correlation with KIF18B (R = 0.631). Groups with high KIF18B expression show significantly increased infiltration of Tregs and a notable decrease in the infiltration of CD8 Tcells and macrophages [53]. Additionally, KIF18B functions in HCC via mTOR complex 1 (mTORC1). mTOR acts as a crucial regulator of immune system cell differentiation and function. In cancer cells, disrupted mTOR signaling alters the tumor microenvironment, impacting tumor immunity and potentially fostering cancer progression [54, 55]. KIF18B expression positively correlates with the mTORC1 signaling pathway in HCC tissues and is linked with HCC recurrence. Actin gamma 1 (γ-Actin), a binding partner of KIF18B. It also facilitates the transfer of mTORC1 to the lysosomal membrane and prevents the degradation of p70 S6K in lysosomes, thereby enhancing mTORC1 signaling [15]. Thus, an essential inquiry is whether the knockdown of KIF18B could activate immune cells, subsequently suppressing the malignant proliferation of cancer cells.

Breast cancer

Breast cancer (BC) is the deadliest cancer among women and ranks as the second leading cause of cancer-related deaths after lung cancer [56]. Breast cancer can be categorized into three main types: hormone receptor (HR) positive, HER2 negative, HER2 positive, and triple-negative breast cancer (TNBC) [57]. Recently, Li and others have determined through bioinformatics analysis that KIF18B is upregulated in breast cancer and significantly correlates with relapse-free survival (RFS) and distant metastasis-free survival (DMFS) in patients [58]. Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells acquire mesenchymal characteristics. In cancer, EMT is associated with tumorigenesis, cancer stemness, metastasis, and resistance to therapy [59, 60]. Analysis from RNA sequencing (RNA-seq) suggests that KIF18B is linked to the stemness of breast cancer tumors [61]. KIF18B directly targets thyroid hormone receptor-interacting protein 13 (TRIP13) and increases the expression level of TRIP13. Knockdown of KIF18B significantly reduces TRIP13 expression, which suppresses proliferation, invasion, and EMT in breast cancer cells, and decreases the expression of matrix metalloproteinases (MMP2, MMP9), When TRIP13 is overexpressed, it counteracts the inhibitory effects of KIF18B knockdown on the malignant progression of breast cancer cells [32]. Additionally, knocking down KIF18B significantly enhanced the chemotherapy sensitivity of breast cancer cells to doxorubicin, and overexpressing KIF18B activate the Wnt/β-catenin signaling pathway, while the use of MK-2206 (an AKT inhibitor) negates the activation of the Wnt/β-catenin pathway induced by KIF18B overexpression [29]. Therefore, KIF18B may promote tumor stemness by influencing EMT. Consequently, in malignant tumors such as BC, developing drugs targeting KIF18B could help formulate new strategies to slow cancer progression.

Gastric cancer

Gastric cancer (GC), defined as a primary epithelial malignancy of the stomach, involves various risk factors and is a complex, heterogeneous disease, ranking among the most common malignancies globally [62, 63]. The overall survival rate of gastric cancer is extremely low, largely due to its typical late-stage diagnosis [64]. Research has indicated that KIF18B is linked to the prognosis of patients with gastric adenocarcinoma and may serve as a potential therapeutic target for gastric cancer [65–67]. Further experiments have shown that KIF18B can promote the proliferation, migration, and invasion of gastric cancer cells, while silencing KIF18B causes cell cycle arrest at the G0-G1 phase in gastric cancer cells [17], consistent with findings in other cancers [27, 40]. This suggests that KIF18B is closely related to cell cycle regulation and may facilitate malignant progression by disrupting normal cell cycle functions. Multiple studies have also pointed out that KIF18B is critical in maintaining the stem cell-like properties of gastric cancer and influences the features of cancer stem cells (CSCs) in the disease [65, 68, 69]. Nonetheless, these discoveries require further experimental confirmation.

Other cancers

Beyond the previously mentioned cancers, new evidence has highlighted the abnormal expression and oncogenic potential of KIF18B in a range of malignancies, such as esophageal cancer (EC) [16], prostate cancer (Pca) [18], renal cell carcinoma (RCC) [70], colorectal cancer (CRC) [19], pancreatic ductal adenocarcinoma (PDAC) [20], soft tissue sarcoma (STS) [71], melanoma (MM) [72], squamous cell carcinoma of the skin (SCC) [73] and cervical cancer (CC) [28]. For example, in EC, the abnormal expression of KIF18B enhances cellular activity by increasing levels of CDK4 and Cyclin D3, accelerating the cell cycle, and promotes cell migration and invasion by reducing E-cadherin levels and increasing vimentin and N-cadherin levels in ESCC cells. However, the specific mechanisms by which KIF18B regulates EMT still require further elucidation [16]. Initial studies linked KIF18B with poorer overall survival in prostate cancer patients [74] and subsequent research showed that KIF18B’s role in advancing prostate cancer malignancy is associated with the activation of the PI3K-AKT-mTOR signaling pathway, although the precise regulatory mechanisms still need deeper exploration [18]. Recently, Liu and others found that silencing KIF18B or using T09 (a radiosensitizer targeting KIF18B) significantly increased the radiosensitivity of STS cells, delayed tumor growth in subcutaneous and orthotopic xenograft models, and prolonged the survival of mice [71]. Similarly, in CRC, KIF18B interacts with SP1 to induce overexpression of PARPBP, maintaining oxaliplatin resistance in oxaliplatin-resistant CRC (OR-CRC) cells [19]. This indicates that KIF18B might act as a novel target for anticancer drugs, offering considerable potential in cancer treatment and alleviating chemotherapy resistance. The roles and mechanisms of action of KIF18B across various tumors are detailed in Table 1.

Table 1.

The role and mechanism of KIF18B in diverse cancers

Type of Cancer	Cell or animals	Mechanism	Conclusion	Associated With patient prognosis	Reference
ADC	A549 cells	Activating AKT/mTOR pathway	Knockdown of KIF18B significantly inhibits the proliferation, migration, and invasion of ADC cells.	High expression is associated with poorer prognosis.	[30, 40, 41]
BCa	T24 and J82 cells	Activating Wnt/β-catenin pathway	Promotes survival, proliferation, and invasion of BCa cells.	NR	[31]
HCC	HepG2,Huh7,MHCC97H, HHCCLM3,Hep3B cells and nude mice	Activating Wnt/β-catenin pathway and mTOR pathway	Knockdown of KIF18B significantly inhibits proliferation, migration, invasion, and EMT in HCC cells, while simultaneously promoting apoptosis.	High expression is associated with poorer prognosis.	[15, 51, 21]
BC	MDA-MB231 T47D cells and nude mice.	Activating Akt/GSK-3β/β-catenin pathway	Knockdown of KIF18B significantly inhibits the proliferation, invasion, and EMT of BC cells, and enhances the chemosensitivity of paclitaxel.	High expression is associated with poorer prognosis.	[29, 32, 58]
GC	SNU-1	NR	Promotes proliferation, migration, and invasion of GC cells.	High expression is associated with poorer prognosis.	[17, 65, 66]
EC	EC9706 KYSE220	Activating CDCA8/mTORC1 pathway	Promotes migration, invasion, and EMT of ESCC cells.	High expression is associated with poorer prognosis.	[16]
Pca	DU145 PC3 cells and mice	Activating PI3K/AKT/ mTOR pathway	Promotes proliferation, migration, and invasion of Pca cells.	High expression is associated with poorer prognosis.	[18]
STS	MNNG/HOS cells and mice	NR	Silencing KIF18B can enhance the radiosensitivity of STS.	High expression is associated with poorer prognosis.	[71]
CRC	HCT116L cells	inducing PARPBP expression	Increases the resistance of colorectal cancer to oxaliplatin	High expression is associated with poorer prognosis.	[19]
PDAC	PANC1 BxPC3 cells and mice	transcriptionally activating CDCA8	Promotes PDAC proliferation	High expression is associated with poorer prognosis.	[20]
CC	Hela cells and mice	Activating Wnt/β-catenin pathway	Promotes proliferation, migration, and invasion of CC cells.	High expression is associated with poorer prognosis.	[28]

NR no reported

KIF18B in cancer therapy

KIF18B in chemoresistance

Doxorubicin (DOX) is a chemotherapy drug widely used to treat various cancers [75]. It interferes with numerous biological processes, including histone eviction, excessive ceramide production, DNA adduct formation, reactive oxygen species generation, and regulation of Ca2 + and iron homeostasis [76]. DOX serves as a primary chemotherapeutic agent for breast cancer, targeting cancer cells by inducing DNA cross-linking damage [77]. In breast cancer, KIF18B may facilitates tumor progression by regulating the Akt/GSK-3β/β-catenin signaling pathway [29]. The AKT pathway is one of the most commonly activated pathways in breast cancer [78]. Using an AKT inhibitor (MK-2206) can counteract the malignant proliferation of breast cancer cells induced by KIF18B overexpression. Furthermore, research shows that reducing KIF18B expression can enhance the sensitivity of breast cancer cells to DOX and significantly reduce their malignant characteristics [29]. Thus, in the context of breast cancer, a combination therapy involving small molecule drugs targeting KIF18B along with AKT inhibitors or DOX could offer a promising treatment avenue.

Oxaliplatin (OXA), a commonly used platinum-based chemotherapy drug for colorectal cancer [79], however, it is estimated that 50% of patients eventually develop acquired resistance and cease responding to the treatment [80]. PARPBP, also known as PARI (PCNA-associated recombination inhibitor), is significantly upregulated in oxaliplatin-resistant colorectal cancer (OR-CRC) cells, with its expression positively correlating with KIF18B levels. Reduction in PARPBP expression can decrease drug resistance in OR-CRC cells. Overexpression of KIF18B increases both mRNA and protein levels of PARPBP in OR-CRC cells, while knockdown of KIF18B reduces PARPBP expression in these cells. Further experiments show that KIF18b can bind to SP1 and competitively inhibit the interaction between SP1 and DNMT3b, thus hindering the methylation of the PARPBP promoter, activating PARPBP transcription, and subsequently increasing the resistance of OR-CRC cells, which affects patient prognosis [19].

Beyond the specified chemotherapeutic agents, diffuse large B-cell lymphoma (DLBCL) cells with KIF18B knocked out exhibit reduced cell cycle arrest and apoptosis, resulting in enhanced tolerance to vincristine [81]. Another study on gastric cancer showed that in vitro, downregulating KIF18B enhances the chemotherapy sensitivity of gastric cancer cells to cisplatin (CDDP) and 5-fluorouracil (5-FU), and reduces cell proliferation, migration, and invasiveness, with similar results obtained in a xenograft tumor model in nude mice [82]. In summary, targeting KIF18B may enhance the efficacy of cancer chemotherapy, a hypothesis that requires further experimental validation.

KIF18B in radiotherapy

Radiation therapy (RT) is a key modalities in cancer treatment, with over 70% of cancer patients undergoing RT during their treatment course [83]; Additionally, RT serves as a primary method for treating sarcoma [84]. According to the Genomic Drug Sensitivity Database (GDSC), T09 was identified as a KIF18B-sensitive drug. Silencing KIF18B or using the KIF18B-sensitive drug T09 significantly enhanced the radiosensitivity of sarcoma cells, delayed tumor growth in subcutaneous and orthotopic xenograft models, and extended the survival time of mice. Research indicates that sarcomas with low KIF18B expression may benefit from radiotherapy [71].

Conclusion and future prospects

This review comprehensively describes the critical roles of KIF18B in physiological processes and its potential mechanisms for regulating the malignant progression of tumors, examines its expression across various cancer types, explores its carcinogenic potential, and evaluates its potential clinical implications. KIF18B gene expression is markedly elevated in a variety of cancers compared to benign tissues The increased expression of KIF18B impacts several cellular activities, such as cell proliferation, migration, invasion, cell cycle regulation, and resistance to treatment. These data also suggest that the expression of the KIF18B gene or protein can serve as a prognostic marker for patients. However, these studies are mainly conducted at the cellular and animal levels and face limitations, including inadequate clinical sample sizes and limited clinical relevance.

While high expression of KIF18B in various cancers has been noted, the specific molecular mechanisms driving its expression remain unclear. Besides disrupting the cell cycle of tumors, it is still uncertain whether KIF18B also affects the stemness of tumors. Although it is established that knockdown of KIF18B reduces radiosensitivity in sarcomas, whether this effect is similar in other types of cancer remains uncertain. On the other hand, we have outlined the role of KIF18B in promoting the development of multiple tumors and its involvement in various signaling pathways, highlighting its significant potential for clinical applications. Current research on structural mutations of KIF18B and its regulatory factors is limited. Beyond database analysis, can KIF18B gene mutations be associated with clinical genetic testing? Additionally, it is known that KIF18B is involved in the resistance mechanisms of chemotherapy drugs such as DOX and OXA, but the specific mechanisms of action remain unclear. Further research should focus on the mechanisms and specific targets of KIF18B in resistance processes and explore whether KIF18B can be combined with various chemotherapy drugs to enhance anticancer effects. Regrettably, apart from T09, no other small molecule drugs specific to KIF18B have been reported, nor have they undergone clinical trials. Therefore, it is particularly urgent to develop targeted drugs against KIF18B and to advance their clinical trials.

KIF18B is closely associated with tumor progression, invasion, metastasis, and poor prognosis. Numerous studies demonstrate that KIF2C is involved in several cellular signaling pathways, including the AKT/mTOR, Wnt/β-catenin, and PI3K pathways, as summarized in Fig. 2. Thus, KIF18B plays a role in multiple aspects of tumorigenesis, and its regulatory functions may offer novel and effective targets for cancer treatment.

Fig. 2.

KIF18B is involved in the signaling pathways related to tumor occurrence and the regulatory effects of microRNAs and transcription factors on KIF18B. In prostate, breast and lung cancers, the regulation of tumor cell proliferation by KIF18B is accompanied by activation of the AKT pathway. The regulation of the life activities of cancer cells in hepatocellular carcinoma, cervical cancer, bladder urothelial carcinoma and other cancers by KIF18B requires the involvement of the Wnt/β-catenin pathway. γ-actin (γ-actin) as a binding partner of KIF18B, cooperatively regulates lysosome positioning, promotes the transport of rapamycin complex 1 (mTORC1) to the lysosomal membrane and prevents p70 S6K from entering lysosomes for degradation. In CRC, KIF18B interacts with SP1 to induce overexpression of PARPBP, maintaining oxaliplatin resistance in OR-CRC cells

Author contributions

C and Y drafted the manuscript. D and H collected and analyze data. F and Z checked the figure and table and revised the manuscript.All authors reviewed the manuscript.

Funding

This study was supported by the grants from the plan of Science and Technology of Zunyi (Grant no.: 2022-403) and the Guizhou Provincial Health Commission (Grant no.: gzwkj2023-374, 2024GZWJKJXM0704).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.