The Role of KIF22 in Promoting Gastric Cancer Proliferation and Metastasis Through MAPK-ERK Signaling Pathways

Gastric cancer remains a leading cause of cancer-related mortality worldwide, with limited targeted therapeutic options. Among molecular drivers of tumor progression, members of the kinesin superfamily proteins (KIFs) have emerged as critical regulators of mitotic processes and oncogenesis. This study focuses on kinesin superfamily protein 22 (KIF22), a microtubule-associated motor protein implicated in spindle formation and chromosome segregation, to elucidate its role in gastric cancer pathogenesis.

KIF22 Expression and Prognostic Relevance in Gastric Cancer

The study analyzed KIF22 expression in 67 gastric cancer tissues and 20 adjacent non-cancerous tissues using immunohistochemistry. Results revealed significantly higher KIF22 protein levels in tumor tissues compared to normal counterparts (P < 0.05). High KIF22 expression correlated with poor differentiation (χ² = 12.842, P = 0.002) and advanced clinicopathological features, including higher T (tumor invasion depth) and N (lymph node metastasis) classifications. Kaplan-Meier survival analysis demonstrated that patients with high KIF22 expression had significantly shorter overall survival (median survival: 28 months vs. 44 months in low-expression groups, P < 0.05). These findings position KIF22 as a potential prognostic biomarker for gastric cancer.

KIF22 Drives Cell Proliferation and Colony Formation

To investigate KIF22’s functional role, the study evaluated its expression across six gastric cancer cell lines (AGS, BGC-823, HGC-27, MGC-803, MKN-45, SGC-7901) and the non-tumorigenic GES-1 line. Western blotting confirmed elevated KIF22 levels in cancer cells, particularly in MGC-803 and BGC-823, which were selected for subsequent experiments. siRNA-mediated knockdown of KIF22 reduced cell viability by 40–50% in MTT assays (P < 0.01) and suppressed colony formation by 60–70% (P < 0.01), highlighting its critical role in sustaining proliferative capacity.

KIF22 Enhances Migration and Invasion

Functional assays further demonstrated KIF22’s contribution to metastatic behavior. Scratch-wound healing assays showed that KIF22 silencing reduced migration rates by 50% in MGC-803 and 45% in BGC-823 cells (P < 0.01). Similarly, trans-well invasion assays revealed a 65–75% decrease in invasive cell numbers following KIF22 knockdown (P < 0.01). These results underscore KIF22’s dual role in promoting both proliferative and migratory phenotypes in gastric cancer.

Cell Cycle Regulation and MAPK-ERK Pathway Activation

Gene set enrichment analysis (GSEA) of KIF22-associated pathways identified significant enrichment in cell cycle regulation, DNA replication, and mitotic processes (P < 0.001). Flow cytometry analysis revealed that KIF22 silencing induced G1/S phase arrest, with a 20% increase in G1-phase cells and a 15% reduction in S-phase populations (P < 0.05). Corresponding Western blot data showed downregulation of cyclin A2 and cyclin D1 (key S-phase regulators) and upregulation of the cyclin-dependent kinase inhibitor p21.

Mechanistically, KIF22 knockdown suppressed the MAPK-ERK signaling pathway. Phosphorylated MEK and ERK levels decreased by 50–60% in siRNA-treated cells (P < 0.01), while total MEK/ERK remained unchanged. This inhibition of MAPK-ERK activity aligns with reduced cyclin D1 expression, which is transcriptionally regulated by ERK. These findings establish KIF22 as a modulator of MAPK-ERK signaling, linking mitotic regulation to oncogenic growth.

Clinical Implications and Future Directions

The study provides robust evidence that KIF22 overexpression drives gastric cancer progression through MAPK-ERK pathway activation. The correlation between KIF22 levels and aggressive clinicopathological features suggests its utility as a diagnostic marker. Furthermore, siRNA-mediated knockdown experiments highlight KIF22’s potential as a therapeutic target. Future studies should explore small-molecule inhibitors targeting KIF22’s motor domain or its interaction with downstream effectors to disrupt mitotic processes in cancer cells.

Technical Methodology and Validation

Human gastric cancer tissues were obtained from 52 patients who underwent radical gastrectomy, with follow-up data spanning five years. Immunohistochemical scoring integrated staining intensity (0–3) and positive cell proportion (0–4), yielding a composite score (0–12). A cutoff score of 6 distinguished high- and low-expression groups.

In vitro experiments utilized siRNA sequences validated for KIF22 suppression efficiency (70–80% protein reduction). Functional assays included MTT for proliferation, colony formation under 14-day culture, scratch assays monitored over 24 hours, and trans-well invasion assays using Matrigel-coated membranes. Cell cycle analysis via propidium iodide staining quantified phase distributions. Western blotting antibodies targeted KIF22, phosphorylated/total MEK/ERK, cyclins, and p21, with β-actin as a loading control. Statistical analyses employed t-tests, ANOVA, and Chi-squared tests using SPSS v23.

Strengths and Limitations

The study’s strengths include multidimensional validation from clinical samples to mechanistic pathways. However, limitations include the modest sample size (52 patients) and lack of in vivo models to confirm therapeutic efficacy. Additionally, while MAPK-ERK was identified as a key pathway, upstream regulators of KIF22 in gastric cancer remain unexplored.

Conclusion

This study establishes KIF22 as a driver of gastric cancer progression through MAPK-ERK signaling, promoting cell proliferation, migration, and cell cycle progression. High KIF22 expression correlates with poor prognosis, offering a novel biomarker and therapeutic target. Further investigations into KIF22 inhibition strategies may pave the way for precision therapies in gastric oncology.

doi.org/10.1097/CM9.0000000000000742

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