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 HIF2α. 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, HIF2α, 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 HIF2α location. We also determined the correlation of FLCN and HIF2α in human renal cancer samples.Results: FLCN was combined with HIF2α in renal tubular epithelial and cancer cells, and it effectively alleviates the deterioration of renal cancer cells by degrading HIF2α. The silencing of FLCN showed a promotion of HIF2α 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 HIF2α entry into the nucleus.Conclusions: Our study illustrated that FLCN could be a new therapeutic target in ccRCC. FLCN combined with HIF2α and identified a novel PI3K/mTORC2/HIF2α signaling in ccRCC cells.
Highlights
Renal cell carcinoma is a malignant tumor originating in the renal tubular epithelial system, most of which are clear cell renal cell carcinoma (Kovacs et al, 1997)
FLCN was combined with HIF2α in renal tubular epithelial and cancer cells, and it effectively alleviates the deterioration of renal cancer cells by degrading HIF2α
The silencing of FLCN showed a promotion of HIF2α protein expression via PI3K/mTORC2 pathway, which in turn led to an increase in downstream target genes Cyclin D1 and MMP9
Summary
Renal cell carcinoma is a malignant tumor originating in the renal tubular epithelial system, most of which are clear cell renal cell carcinoma (ccRCC, ∼75%) (Kovacs et al, 1997). Birt–Hogg–Dubé syndrome is caused by inactivating the mutations of FLCN, a tumor suppressor gene which encodes folliculin (Linehan et al, 2010). It is reported that the inactivation of FLCN is an initial step in the development of renal tumors in BHD (Hasumi et al, 2009). Schmidt has confirmed a tumor suppressor role for FLCN (Khoo et al, 2001; Schmidt et al, 2001; Schmidt and Linehan, 2015b). This paper suggested that FLCN-deficient kidney tumors showed the activation of mTOR and AKT (Chen et al, 2008), and this regulation mechanism is established in humans (Hartman et al, 2009; Linehan et al, 2010; Schmidt and Linehan, 2015a)
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