TRPM7 Regulates AKT/FOXO1-dependent Tumor Growth and is an Independent Prognostic Indicator in Renal Cell Carcinoma

Abstract: Transient receptor potential melastatin 7 (TRPM7) is important for the tumorigenesis and progression of several cancers. However, little is known about TRPM7 expression and its clinical significance in clear cell renal cell carcinoma (ccRCC). The expression dynamics of TRPM7 was examined in a clinical cohort of RCC specimens by quantitative PCR (qPCR), immunoblotting and immunohistochemical (IHC) staining. A series of in vitro and in vivo assays were performed to elucidate the function of TRPM7 in RCC and the underlying mechanisms. For the first time, results demonstrate that TRPM7 expression is markedly higher in RCC cell lines and clinical samples, and had a positive correlation with T status, tumor size, and poor patients9 overall survival and progression-free survival. Preclinical studies using multiple RCC cells and a mouse model indicate that TRPM7 promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Mechanistically, TRPM7 promotes AKT phosphorylation, leading to repression the FOXO1 expression and transcriptional activity. Moreover, luciferase reporter assays demonstrate that miR-129-3p directly targets the 39-UTR of TRPM7, and acts as a negative regulator of TRPM7.These findings reveal an important role for TRPM7 in the regulation of RCC growth and represent a novel prognostic biomarker for this disease. Implications: TRPM7 is an independent prognostic indicator in RCC and targeting the TRPM7 signaling pathway may be a novel therapeutic approach for the treatment of RCC.