A novel molecular mechanism regulates gastric cancer cell homeostasis

Background

Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide, with incidence and mortality rates expected to rise in the coming years. Standard treatments typically involve surgical resection combined with chemotherapy using platinum-based agents, 5-fluorouracil (5-FU), or capecitabine. The discovery of novel biomarkers associated with GC progression is critical to improving therapeutic strategies and enhancing patient outcomes. In this study, we investigated the role of Hormonally Upregulated Neu tumor-associated Kinase (HUNK) in driving the progression of gastric cancer.

Methods

To evaluate the functional effects of HUNK overexpression, we conducted a cell viability assay in gastric cancer cell lines stably transfected with HUNK. To confirm the physical interaction between HUNK and p38 MAP kinase, we performed a co-immunoprecipitation assay. Additionally, to investigate the role of HUNK in apoptosis, we employed siRNA-mediated HUNK knockdown and assessed apoptotic activation by measuring the levels of cleaved PARP and cleaved caspase-3 via Western blot. Apoptotic cell populations were further quantified using flow cytometry after staining with Annexin V-FITC and propidium iodide (PI). NGS analysis was performed to identify HUNK-induced genes.

Results

We demonstrate that HUNK promotes gastric cancer cell proliferation through direct interaction and phosphorylation of p38 MAP kinase. Functional depletion of HUNK significantly reduced cell viability in both gastric cancer cell lines and patient-derived organoids, underscoring its role in tumor cell survival. Moreover, HUNK positively regulates the expression of MUC16/CA-125, a glycoprotein linked to tumor progression and poor prognosis, suggesting its potential as both a biomarker and therapeutic target in gastric cancer.

Conclusions

Our results identify a novel HUNK-mediated molecular mechanism in gastric cancer, supporting its potential as a promising target for the development of targeted therapies.