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 qPCR, immunoblotting, and 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 patients' 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 of the FOXO1 expression and transcriptional activity. Moreover, luciferase reporter assays demonstrate that miR-129-3p directly targets the 3'-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. Mol Cancer Res; 16(6); 1013-23. ©2018 AACR.

Highlights

  • Clear cell renal cell carcinoma is the most common adult kidney cancer, with a 5-year disease-specific survival rate of 50% to 69% [1, 2]

  • The multivariate Cox proportional hazards regression analyses were conducted to Elevated expression of Transient receptor potential melastatin 7 (TRPM7) expression in RCC First, to examine the expression status of TRPM7 in Clear cell renal cell carcinoma (ccRCC), western blotting and qPCR analysis were conducted in 4 RCC cell lines (786-O, A498, ACHN, and OSRC-2), one normal human renal epithelial cell line (HK-2), and IHC staining in 35 matched pairs of ccRCC tissues and adjacent normal tissues

  • This variation suggests that abnormal gene regulation and/or protein functions of TRPM7 in tumorigenesis are complicated and are likely to be tumortype specific [7, 12, 13, 20,21,22]

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Summary

Introduction

Clear cell renal cell carcinoma (ccRCC) is the most common adult kidney cancer, with a 5-year disease-specific survival rate of 50% to 69% [1, 2]. A previous study has demonstrated that the median survival of patients with metastatic RCC is approximately 13 months [2]. Because of the lack of early signs, diverse clinical manifestations, and the resistance of radiotherapy and chemotherapy, early diagnosis and prognosis is important. CcRCC is an aggressive tumor with unpredictable outcome, which are hard to accurately predict by the currently used clinical parameters. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

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