Abstract
Patients with colorectal cancer (CRC) carrying KRAS mutations face a challenging prognosis, especially due to their reduced response to EGFR inhibitor therapies. Despite the use of drugs targeting the KRAS(G12C) mutation, the KRAS(G12V) mutation is more common in CRC, and unfortunately, there are currently no effective targeted treatments for it. Our study shows that patients harboring KRAS(G12V) mutation often have larger tumors, increased lymph node metastasis, elevated EGFR expression, and a tendency for right-sided colon tumors. This indicates distinct clinical and pathological traits in CRC patients with KRAS(G12V). Cellular studies reveal increased proliferation and decreased cell apoptosis in KRAS(G12V) CRC cells. Bioinformatics analysis revealed a notable decrease of aquaporin 9 (AQP9) in KRAS(G12V) CRC, confirmed by immunohistochemistry and Western blot tests. These tests showed a consistent AQP9 decrease in tissue and cell samples, linked to an increased risk of lymph node metastasis in patients with low AQP9. Importantly, AQP9 overexpression was found to hinder CRC cell proliferation and encourage apoptosis, thereby implying a potential therapeutic role for AQP9 modulation. Our study finds a link between ZHX2 and AQP9 in CRC cells, confirmed by histopathological and in vitro evidence. Increased ZHX2 expression elevates AQP9 levels, reduces CRC cell growth, and boosts apoptosis. CO-IP experiments further prove the interaction between ZHX2 and AQP9 proteins. Molecular docking studies reveal that ZHX2 can form stable complexes with AQP9, involving multiple residues. This research enhances our understanding of the molecular mechanisms regulating the growth and death of KRAS(G12V) CRC cells, paving the way for new therapeutic strategies.