High MICAL-L2 promotes cancer progression and drug resistance of renal clear cell carcinoma cell via stabilization of ACTN4 and following vimentin expression

Abstract

Kidney clear cell carcinoma (KIRC) continues to be a substantial contributor to cancer-associated fatalities nowadays. Targeted therapies persist as the conventional method of KIRC treatment. Nevertheless, the development of resistance to those drug emerges as a significant impediment to renal cancer management. MICALL2, a member of the molecules that interact with the CasL family (MICALs), plays pivotal roles in cytoskeleton rearrangement. This study sought to elucidate the clinical relevance of MICAL-L2 in KIRC and its regulatory mechanism in cancer progression and resistance to therapy. The Cancer Genome Atlas data mining was utilized to assess the expression of MICAL-L2 in KIRC tissues. Statistical analysis of immunohistochemistry and the Kaplan–Meier Plotter database were employed to investigate the clinical significance of MICALL2. A series of in vitro experiments, encompassing assays for CCK-8, EDU staining, wound healing and transwell migration, flow cytometry, RT-PCR, co-immunoprecipitation analysis were conducted to demonstrate the effects of MICAL-L2 on the drug sensitivity of KIRC cells and to elucidate the underlying molecular mechanisms. MICAL-L2 is overexpressed in KIRC tissues. Elevated MICAL-L2 levels correlate with reduced survival rate and a diminished response to drug therapy in KIRC patients. MICAL-L2 overexpression stimulates cell proliferation, migration and renders KIRC cells insensitive to Sunitinib and Everolimus, two traditional therapeutics for KIRC. Furthermore, MICAL-L2 promotes progression and resistance to therapy in KIRC cells by interacting with its downstream regulator Alpha-actinin-4 (ACTN4) in a Rab13-dependent manner, then reducing ACTN4 degradation, and thereby leading to augmented vimentin expression in KIRC cells. These findings indicate that MICAL-L2 plays a critical role in the progression of KIRC and suggest that MICAL-L2 may function as a therapeutic target in KIRC patients.