Downregulation of ATP1A1 promotes cancer development in renal cell carcinoma

Abstract

Background: Aberrant expression of Na+/K+-ATPase α1 subunit (ATP1A1) is widely observed in multiple types of tumors, and its tissue-specific expression relates to cancer development. However, the functions and molecular mechanisms in renal cell carcinoma (RCC) are not fully understood. Methods: We investigated the ATP1A1 expression changes and possible roles in RCC through a quantitative proteomic approach and an integrative biochemical assessment. We detected ATP1A1 in RCC with LC-MS/MS, and further validated its expression with immunohistochemical analyses of 80 pairs of the RCC tumor and non-tumor tissues samples. The association of ATP1A1 expression with RCC pathology was statistically analyzed. Cell proliferation, migration and apoptosis were measured by CCK-8, boyden chamber assay and flow cytometry, respectively. The production of reactive oxygen species (ROS) was labeled with a single staining using a commercial kit, and was further detected with flow cytometry. Results: The ATP1A1 shows a significantly decreased expression in human RCC tissues than in the adjacent non-tumor tissues. The RCC patients with ATP1A1-positive expression exhibit longer overall survival time than the ATP1A1-negative patients. The exogenous overexpression of ATP1A1 inhibits RCC cell proliferation and cell migration by increasing the production of ROS. In addition, ATP1A1-mediated Raf/MEK/ERK signaling pathway is suppressed in RCC cells, indicating the possible occurrence of induced cell apoptosis. Conclusions: Our in vitro and in vivo data of ATP1A1 inhibitory roles in RCC progression suggest that ATP1A1 is a potential novel suppressor protein for renal cancer.