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

Abstract

Targeted therapies persist as the conventional method of treatment of kidney clear cell carcinoma (KIRC). However, resistance to these drugs emerges as a significant impediment to the management of renal cancer. MICAL-L2 plays a pivotal role in cytoskeleton rearrangement. This study sought to elucidate the clinical relevance of MICAL-L2 in KIRC and its regulatory mechanism driving cancer progression and resistance to therapy. TCGA data mining was utilized to assess the expression of MICAL-L2 in samples from patients with KIRC. Kaplan-Meier analysis and immunohistochemistry were employed to explore the clinical significance of MICAL-L2. In vitro experiments, including assays for wound healing and Transwell migration, CCK-8, EDU staining, RT-PCR, flow cytometry, and co-immunoprecipitation analysis were conducted to investigate the effects of MICAL-L2 on the drug sensitivity of KIRC cells and to elucidate the molecular mechanisms involved. The results showed that MICAL-L2 was overexpressed in KIRC tissues. High levels of MICAL-L2 were associated with poor survival and a poor response to drug therapy among patients with KIRC. Overexpression of MICAL-L2 stimulated cell migration, proliferation, and rendered KIRC cells insensitive to sunitinib and everolimus, two traditional therapies for KIRC. Furthermore, MICAL-L2 overexpression accelerated cancer progression and resistance to therapy in KIRC cells by interacting with its downstream regulator α-actinin-4 (ACTN4) in a Rab13-dependent manner, which reduced the degradation of ACTN4, leading to increased Vimentin expression. All these findings indicate that MICAL-L2 plays a crucial role in the progression of KIRC and suggest that MICAL-L2 may serve as a potential therapeutic target for KIRC treatment.