GAB2 regulates lipid metabolism by activating the MEK/ERK/c-Myc pathway: impact on renal cell carcinoma progression.

BACKGROUND: Grb2-associated binding protein 2 (GAB2) is a scaffold protein in the cytoplasm involved in the progression of various cancers, but its significance in renal cell carcinoma (RCC) development remains unclear. The investigation sought to explore the mechanisms of GAB2 in RCC. METHODS: GAB2 mRNA levels were examined in normal renal tubular epithelial cells (HKC) and RCC cell lines (ACHN and OS-RC-2). GAB2 was knocked down or overexpressed in RCC cells, and changes in cell proliferation, apoptosis, migration, and lipid metabolism were assessed. Moreover, p-MEK, p-ERK, and c-Myc levels were measured. The MEK inhibitor U0126 was introduced to validate the underlying mechanisms. Nude mice were subcutaneously injected with ACHN cells transfected with either oe-NC or oe-GAB2 , and then treated with U0126. The MEK/ERK/c-Myc pathway, tumor growth, and lipid metabolism were subsequently evaluated. RESULTS: GAB2 expression was notably elevated in RCC cells compared to HKC. GAB2 knockdown markedly reduced RCC cell viability, induced apoptosis, and inhibited cell migration and lipid accumulation, whereas overexpression of GAB2 had the opposite effects. Notably, the MEK/ERK/c-Myc pathway in RCC cells was inhibited by GAB2 knockdown and activated by its overexpression. U0126 treatment altered the effects of GAB2 overexpression in RCC cells. In RCC mice, GAB2 overexpression upregulated MEK/ERK/c-Myc pathway, which was suppressed by U0126. Moreover, GAB2 overexpression promoted tumor growth and lipid synthesis in RCC mice, and U0126 counteracted these changes. CONCLUSION: GAB2 enhances lipid accumulation by activating MEK/ERK/c-Myc pathway, thereby promoting RCC progression. GAB2 is a potential target for RCC management.