Kinesin family member 14 in digestive tract malignancies: Oncogenic mechanisms, clinical implications, and therapeutic prospects

Abstract

In this editorial, we comment on the article by Qin et al, recently published in the World Journal of Gastrointestinal Oncology. Malignant tumors of the digestive tract represent a significant health threat. Kinesin family member 14 (KIF14), a critical kinesin, is pivotal in the proliferation, migration, and invasion of tumor cells. It has emerged as a focal point in recent studies of malignant tumors in the digestive tract. This article reviews the current research on KIF14 within these tumors and details its significant role in tumor cell behaviors, including proliferation, apoptosis, migration, invasion, and angiogenesis, alongside the regulatory mechanisms of the associated intracellular signaling pathways. Additionally, it explores the clinical value of KIF14 as a potential biomarker for early diagnosis, disease monitoring, and prognostic evaluation in malignant tumors of the digestive tract. The article concludes by introducing the potential regulatory role of traditional Chinese medicine, aiming to combine the strengths of both modern and traditional medical approaches to enhance treatment outcomes and prognosis for patients with these tumors.

Key Words: Kinesin family member 14; Malignant tumors of the digestive tract; Signaling pathway; Biomarkers; Proliferation; Apoptosis; Migration; Invasion; Angiogenesis

Core Tip: Kinesin family member 14 (KIF14) is pivotal in malignant tumors of the digestive tract. As a crucial driver protein, its elevated expression is intricately linked with tumor biology, drug resistance, progression-free survival, and overall survival, highlighting its potential as a biomarker for early diagnosis, disease monitoring, and prognosis evaluation. Furthermore, recent advancements in targeting KIF14 as a therapeutic target and the regulatory effects of traditional Chinese medicine provide promising new pathways for improving treatment outcomes and enhancing patient prognosis in digestive tract malignancies.

INTRODUCTION

Malignant tumors of the digestive tract primarily include esophageal cancer (EC), gastric cancer (GC), liver cancer, and colorectal cancer (CRC). Epidemiological studies reveal that these cancers constitute over 23% of the global cancer incidence and more than 30% of cancer-related deaths worldwide[1]. These figures highlight the significant impact of digestive tract malignancies on global public health. Current treatment options for these malignancies encompass surgery, chemoradiotherapy, and targeted therapy. However, due to the absence of specific early symptoms, many patients receive diagnoses at advanced stages, which limits the effectiveness of available treatments[2]. Recent research by Qin et al[3] has assessed Kinesin family member 14 (KIF14) as a promising target for the treatment of CRC in nitidine chloride (NC). Their findings provide valuable insights into the potential therapeutic applications of targeting KIF14 in CRC[3]. Consequently, identifying potential biomarkers for early diagnosis, disease monitoring, and prognosis assessment is crucial. KIF14, a microtubule motor protein from the Kinesin-3 superfamily, features an amino-terminal subdomain of 350 residues[4]. It harnesses the energy from ATP hydrolysis to traverse microtubules and engages in essential cellular functions such as organelle transport, protein complex trafficking, mRNA transport[5], spindle formation, chromosome segregation, and cytokinesis during mitosis[6]. Elevated expression levels of KIF14 are linked with tumor cell proliferation, apoptosis, migration, invasion, angiogenesis, and resistance to anticancer drugs. Further research into the mechanisms of KIF14 could lead to significant advancements in the precise diagnosis and targeted treatment of malignant digestive tract tumors. Building upon these findings, this manuscript systematically reviews the role of KIF14 in EC, GC, liver cancer, and CRC, highlighting its potential as a clinical biomarker (Figure 1). It also discusses the potential benefits of integrating KIF14-targeted therapies with traditional Chinese medicine (TCM), laying a theoretical groundwork for developing novel therapeutic approaches.

Figure 1 Mechanism of action of Kinesin family member 14 in esophageal, gastric, liver, and colorectal cancer. ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CRC: Colorectal cancer; KIF14: Kinesin family member 14; miR-154-5p: MicroRNA-154-5p; miR-200C: MicroRNA-200C; LETM1: Leucine zipper-EF-hand containing transmembrane protein 1; SOX17: SRY-Box 17; RFC3: Replication factor C subunit 3; PI3K/AKT: Phosphoinositol-3-kinase/protein kinase B; Bax: BCL2-associated X protein; p27KIP1: Cyclin-dependent kinase inhibitor 1B; VEGF: Vascular endothelial growth factor; VEGFA: Vascular endothelial growth factor A; VEGFR1: Vascular endothelial growth factor receptor 1; VEGFR2: Vascular endothelial growth factor receptor 2; solid arrow (→): Indicates activation or promotion; T-bar arrow (⊣): Indicates inhibition.

ABERRANT EXPRESSION OF KIF14 IN EC AND ITS ONCOGENIC MECHANISMS

EC, a prevalent malignancy of the digestive system, primarily originates from the esophageal mucosal epithelium. It ranks sixth in global cancer-related mortality and is classified into two major histological subtypes: Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC)[7]. Key risk factors include geographical variations, obesity, gastroesophageal reflux disease (GERD), and Barrett's esophagus[8]. Metastasis remains the leading cause of death among patients with EC[9]. The vascular endothelial growth factor (VEGF) signaling pathway is pivotal in the metastasis of EC[10], and anti-angiogenic therapy has shown effectiveness in treating solid tumors, including this type of cancer[11]. Han et al[12] conducted a bioinformatics analysis on integrated datasets and found significantly elevated KIF14 expression levels in ESCC tissues compared to adjacent normal tissues, suggesting new directions for research. Wang et al[13] identified nine hub genes, including KIF14, that are associated with ESCC patient survival rates. Shou et al[14] discovered through bioinformatics analysis that exosome-derived miR-154-5p inhibits ESCC cell migration, invasion, and angiogenesis by targeting KIF14 protein expression[14]. Furthermore, Zhao et al[15] confirmed through co-immunoprecipitation assays that the mitochondrial inner membrane protein LETM1 interacts with KIF14, regulating its expression and inhibiting the production of angiogenic factors VEGFA and VEGFR2. This interaction suppresses ESCC cell proliferation, invasion, migration, and angiogenesis. Although the role of KIF14 in ESCC has been extensively investigated, its functional significance and underlying mechanisms in EAC remain poorly understood. Given the distinct molecular and pathological features that differentiate EAC from ESCC, it is imperative to explore whether KIF14 exerts similar or divergent oncogenic roles in EAC. Such investigations are essential to uncover potential subtype-specific therapeutic targets and advance precision medicine approaches for EC.

KIF14: A KEY FACTOR IN GC DEVELOPMENT AND PROGNOSIS

GC ranks as the fifth most common cancer worldwide and the fourth leading cause of cancer-related mortality[7]. It is categorized based on its anatomical location into cardia cancer and non-cardia cancer. GERD is a significant risk factor for cardia cancer, whereas Helicobacter pylori infection is primarily linked with non-cardia cancer, with both types also associated with adverse lifestyle factors[16]. The insidious nature of early symptoms frequently results in a poor prognosis at the time of diagnosis[17]. Currently, perioperative chemotherapy significantly enhances survival rates for patients with resectable GC[18]. Research is progressively concentrating on biomarker-directed therapies and the implementation of immunotherapy in both perioperative and advanced stages of GC treatment. Huang et al[19] utilized The Cancer Genome Atlas data and found that KIF14 is highly expressed in GC tissues, identifying it as a key gene associated with characteristics of GC stem cells, facilitating tumor cell adhesion, invasion, and chemoresistance. Yang et al[20] observed that KIF14 is markedly overexpressed in GC tissues and cell lines, correlating strongly with advanced tumor stages, lymph node metastasis, and poor prognosis. In vivo, xenograft models confirmed that KIF14 plays a crucial role in tumor formation and dissemination of GC cells to the lungs and peritoneum. Moreover, the activation of the AKT signaling pathway by KIF14 promotes robust proliferation, enhances invasive capabilities, and increases the migratory activity of GC cells. However, these oncogenic effects mediated by KIF14 can be effectively mitigated by the AKT inhibitor MK-2206. The high expression of KIF14 correlates with poorer survival outcomes and is considered an independent prognostic factor in GC[20]. GC exhibits significant molecular and phenotypic diversity, which may influence the role and expression patterns of KIF14 across different subtypes. Future studies should explore whether the expression level of KIF14 differs between different molecular subtypes. Understanding these changes can provide insights into subtype-specific treatment strategies. Additionally, the potential of targeting KIF14 in combination with immunotherapy or standard chemotherapy warrants further exploration. Given the growing emphasis on immunotherapy in GC treatment, KIF14 could serve as a promising target to enhance therapeutic efficacy. Furthermore, investigating the role of KIF14 in modulating the tumor microenvironment, particularly its effects on immune cell infiltration and cytokine production, could provide a more comprehensive understanding of its oncogenic mechanisms and therapeutic potential.

EXPLORATION OF TARGETING KIF14 IN THE TREATMENT OF LIVER CANCER

Primary liver cancer is the third leading cause of cancer-related mortality globally, with approximately 906000 new cases and 830000 deaths reported in 2020. Among these, hepatocellular carcinoma (HCC) constitutes 75%-85%, intrahepatic cholangiocarcinoma 10%-15%, and other rare types the remainder. The primary risk factors include chronic infection with hepatitis B virus or hepatitis C virus, compounded by adverse lifestyle factors[7]. The three-year survival rate for advanced HCC is notably low at only 12.7%[21], showing the urgent need for new biomarkers and therapeutic strategies to enhance treatment outcomes. Cheng et al[22] utilized comprehensive gene expression databases to validate the biological functions of potential hub genes in vitro, discovering that KIF14 mRNA expression is significantly upregulated in HCC cell lines such as SMMC-7721 and HCC-LM3. Studies have shown that downregulating KIF14 can inhibit HCC cells proliferation, invasion, and migration while increasing sensitivity to chemotherapy drugs such as cisplatin. This suggests that KIF14 may influence HCC cell behavior by promoting apoptosis. Furthermore, high KIF14 expression has been associated with shortened progression-free, recurrence-free, and disease-specific survival, indicating its potential as a biomarker for poor prognosis in HCC patients[22]. Yang et al[23] confirmed that SOX17, an inhibitor of the Wnt/β-catenin signaling pathway, can transcriptionally downregulate KIF14 expression, inhibiting HCC cell proliferation and migration. This highlights the significant role of SOX17 in HCC progression and prognosis. Silencing KIF14 also increases p27Kip1 Levels in HCC cells, leading to failed cell division and suggesting that high KIF14 expression may promote uncontrolled cell cycle and disease progression[24]. Additionally, silencing KIF14 has been shown to reverse resistance to sorafenib in HCC[25]. Future research should concentrate on the clinical application potential of targeting KIF14 to improve the prognosis and survival rates of HCC patients.

TARGETING KIF14: A NEW DIRECTION FOR CRC TREATMENT

CRC is a heterogeneous disease influenced by genetic mutations, accounting for approximately 10% of global cancer cases and deaths, making it the third most common cancer worldwide. The incidence of CRC shows substantial regional variation, primarily due to genetic susceptibility and adverse lifestyle habits[7]. Schumacher et al[26] identified six new susceptibility genes through genome-wide association studies, highlighting the significant role of single nucleotide polymorphisms in CRC risk. Given the pivotal role of gene instability in CRC development and progression, identifying suitable biomarkers and therapeutic targets is crucial. Neska-Długosz et al[27] analyzed the expression of KIF11 and KIF14, concluding that these genes could serve as potential biological and molecular markers to stratify CRC patients into different risk categories. Notably, KIF14 has been recognized as an independent prognostic factor for CRC[27]. Yu et al[28] demonstrated that deleting Replication Factor C (RFC3) impairs tube formation in human umbilical vein endothelial cells and decreases the protein expression of VEGF and VEGFR1. However, high expression of KIF14 partially restores the angiogenesis-related indicators reduced by RFC3 loss, thereby promoting CRC cell proliferation and migration[28]. Chen et al[29] found that KIF14 enhances cancer cell proliferation in CRC by activating the AKT signaling pathway. High KIF14 expression positively correlates with tumor stage, TNM stage, metastasis, and poor survival time[29]. Wang et al[30] confirmed through in vitro and in vivo experiments that KIF14 is abnormally overexpressed in CRC samples, facilitating the transition of human CRC cells (e.g., LoVo) from G1 to S and G2 phases, activating AKT signaling, accelerating cell cycle progression, and directly targeting miR-200c, which contributes to genomic amplification and transcriptional activation, ultimately promoting tumor cell proliferation[30]. Zhu et al[31] analyzed prognostic genes in colon cancer and found that KIF14's role is closely linked to its function in cell division. The high expression of KIF14 in colon cancer cells indicates that it is one of the prognostic genes associated with poor outcomes[31]. These findings suggest that regulating KIF14 expression may offer new insights and directions for CRC treatment.

POTENTIAL APPLICATION OF CHINESE HERBAL MEDICINE IN REGULATING KIF14 FOR THE TREATMENT OF MALIGNANT TUMORS OF THE DIGESTIVE TRACT

Chinese herbal medicine has shown multiple beneficial effects in treating malignant tumors of the digestive tract. Firstly, it can directly inhibit tumor cell proliferation and induce apoptosis. For example, herbs such as Chuanxinlian (Andrographis paniculata) and Yinyanghuo (Epimedium) have demonstrated capabilities to suppress the growth of digestive tract tumor cells[32,33]. Secondly, Chinese herbal medicine possesses significant immunomodulatory properties, enhancing immune function and boosting the activity of T lymphocytes and natural killer cells, thereby indirectly suppressing tumor progression[34]. Additionally, it offers unique advantages in mitigating the side effects of chemotherapy, such as alleviating gastrointestinal reactions and bone marrow suppression, thus improving patients' tolerance to chemotherapy[35]. Most Chinese herbs are known for their safety and generally do not cause severe adverse reactions when used appropriately. Their biological activities are diverse, encompassing anti-inflammatory, antioxidant, and other beneficial effects[36], contributing to their multi-target and multi-pathway mechanisms. Consequently, Chinese herbal medicine holds broad prospects for improving the quality of life and extending the survival time of patients with malignant digestive tract tumors. In the context of KIF14 regulation, Chinese herbal medicine also shows potential application value. Song et al[37], through bioinformatics analysis, identified KIF14 as one of the characteristic genes of ESCC. Studies have indicated that herbs such as Xiangyuan (Citrus medica L.), Zhishi (Citrus aurantium L.), Fuling [Poria cocos (F.A. Wolf) Ryvarden and Gilb], Danshen (Salvia miltiorrhiza Bunge), and Renshen (Panax ginseng C. A. Mey) may regulate KIF14 expression, potentially offering therapeutic benefits for ESCC[37]. In the framework of TCM, cancer is viewed not as an isolated ailment but as a symptom of systemic imbalance within the body. Modern medicine's significant advancements have garnered increased interest in integrative cancer treatment approaches that meld conventional Western therapies with TCM practices. These integrative strategies focus on restoring the overall homeostasis of the human body[38,39]. Although research on TCM-based regulation of KIF14 in the context of gastrointestinal malignancies is still in its early stages, future studies are anticipated to focus on the precise mechanisms by which these herbal components modulate KIF14. This exploration may pave the way for novel therapeutic strategies and methods for treating digestive tract tumors.

As a pivotal molecular target, the role of KIF14 extends well beyond malignant tumors of the digestive tract, playing a significant role in the development and progression of various other cancers (Table 1). Regarding cell proliferation, high KIF14 expression in breast and prostate cancers promotes the phosphorylation of the AKT pathway, thereby enhancing cancer cell proliferation[40,41]. For instance, elevated KIF14 expression in breast cancer has been demonstrated to promote the proliferation of MDA-MB-231 cells[40]. Conversely, silencing KIF14 inhibits the proliferation of cancer cells in endometrial cancer and human glioblastoma[39,43]. Regarding cell migration and invasion, KIF14 facilitates the recruitment of adhesion molecules CDH11 and MCAM to the cell membrane in lung cancer, promoting the migration and invasion of CL1-5 and A549 cells[42]. In terms of tumor resistance, high expression of KIF14 increases resistance to docetaxel in breast cancer, enhances resistance to cabazitaxel and docetaxel in prostate cancer, and augments resistance to cisplatin in endometrial cancer[39-41]. While KIF14 has emerged as a promising therapeutic target across multiple cancer types due to its roles in cell proliferation, migration, invasion, and chemoresistance, its clinical application faces significant challenges related to specificity and potential toxicity. As a kinesin family member, KIF14 is integral to fundamental cellular processes such as mitosis and cytokinesis, raising concerns that its inhibition could disrupt normal cell division in healthy tissues, leading to adverse effects such as myelosuppression or gastrointestinal toxicity. Additionally, the potential for off-target effects and the development of resistance to KIF14-targeted therapies further complicate its therapeutic use. To address these limitations, future research must focus on developing highly specific inhibitors, understanding resistance mechanisms, and exploring combination therapies to minimize toxicity while maximizing efficacy. A thorough evaluation of these factors is essential to ensure the safe and effective translation of KIF14-targeted strategies into clinical practice.

Table 1 Mechanisms of Kinesin family member 14 in different cancer types.

Cancer types	Related proteins, factors and signaling pathways	Related tumor cell proliferation, migration, apoptosis and so on	Representatives of relevant tumor resistance	Ref.
Endometrial cancer	After KIF14 was silenced, the expression of KI-67 protein decreased, while the expression levels of Bax and cleaved-caspase-3 increased	After KIF14 was silenced, the number of cervical cancer resistant cell lines Ishikawa/DDP increased and apoptosis decreased	Silencing KIF14 can inhibit the proliferation of Ishikawa/DDP resistant endometrial cancer cells, promote apoptosis and increase their sensitivity to cisplatin	[39]
Breast cancer	KIF14 high expression promotes AKT pathway phosphorylation	Promote MDA-MB-231 cell proliferation, migration and inhibition of apoptosis	KIF14 high expression increases docetaxel resistance in chemotherapy	[40]
Prostatic cancer	The high expression of KIF14 promotes the phosphorylation of downstream AKT pathway	To be verified	The high expression of KIF14 promoted the drug resistance of DU145/DTX50 and PC-3/DTX30 cells to cabazitaxel-doxorubicin	[41]
Lung cancer	Recruit the adhesion molecules CDH11 and MCAM to the cell membrane	Promote the adhesion, migration, and invasion of CL1-5 and A549 cells	To be verified	[42]
Glioblastoma human	Silencing KIF14 inhibited AKT phosphorylation (S473 and T308 sites) and increased the expression of apoptotic proteins caspase-3 and PARP	Silence KIF14 inhibited the proliferation and migration of U251 glioblastoma cells and promoted apoptosis	To be verified	[43]

KIF14: Kinesin family member 14.

CONCLUSION

KIF14, exhibiting elevated expression levels in various malignant tumors, is closely associated with tumor cell proliferation, apoptosis, invasion, metastasis, and angiogenesis, making it a promising therapeutic target in precision oncology. The future of KIF14 applications in cancer treatment is expected to evolve towards multi-target combination therapies and personalized medicine. Firstly, monotherapy targeting a single molecule often falls short of achieving complete remission, highlighting the need to develop multi-target drugs and combination therapies. By simultaneously inhibiting KIF14 and other key signaling pathways, this approach aims to more comprehensively and effectively suppress tumor growth and dissemination, thereby enhancing therapeutic efficacy. Secondly, advancements in precision medicine are poised to drive the individualization of KIF14-targeted therapies. Leveraging omics technologies such as genomics and proteomics, combined with patient-specific characteristics, will enable the formulation of personalized treatment regimens that improve outcomes while minimizing adverse effects. Moreover, integrating emerging technologies presents new opportunities for KIF14-targeted therapies. Artificial intelligence and big data analytics will play pivotal roles in accelerating the identification and validation of novel targets, optimizing drug design and synthesis, and improving clinical trial efficiency and success rates. This will facilitate the development of more efficacious and safer KIF14-targeting agents, offering patients with gastrointestinal malignancies additional treatment options and improved prognoses. Additionally, combining TCM with KIF14-targeted therapies may yield synergistic effects, providing a more comprehensive and effective strategy for treating malignant tumors.