FLCN Regulates HIF2? Nuclear Import and Proliferation of Clear Cell Renal Cell Carcinoma.

ABSTRACT: Aims and Hypothesis: This study aims to explore the specific molecular mechanism of folliculin (FLCN)-induced proliferation, migration, and invasion in clear cell renal cell carcinoma (ccRCC) and to investigate the relationship of FLCN and HIF2?. Folliculin was identified as a tumor suppressor gene. Its deletions and mutations are associated with a potential risk of renal cancer. At present, the specific molecular mechanism of FLCN-induced proliferation, invasion, and migration in ccRCC remains elusive. Methods: Cell proliferation was measured by flow cytometry analysis, while cell migration and invasion were measured by wound healing assay and Matrigel invasion assay. The expression of FLCN, HIF2?, MMP9, and p-AKT was examined by Western blotting. The cells were transfected with plasmids or siRNA to upregulate or downregulate the expression of FLCN. Immunofluorescence microscopy was carried out to display the HIF2? location. We also determined the correlation of FLCN and HIF2? in human renal cancer samples. Results: FLCN was combined with HIF2? in renal tubular epithelial and cancer cells, and it effectively alleviates the deterioration of renal cancer cells by degrading HIF2?. The silencing of FLCN showed a promotion of HIF2? protein expression via PI3K/mTORC2 pathway, which in turn led to an increase in downstream target genes Cyclin D1 and MMP9. Moreover, interfering with siFLCN advanced the time of HIF2? entry into the nucleus. Conclusions: Our study illustrated that FLCN could be a new therapeutic target in ccRCC. FLCN combined with HIF2? and identified a novel PI3K/mTORC2/HIF2? signaling in ccRCC cells.

SUBMITTER: Zhao X 

PROVIDER: S-EPMC7399043 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature