KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

Article type: Research Article

Authors: Xu, Ping^{a; 1} | Mo, Xiao^{a; 1} | Xia, Ruixue^{c; 1} | Jiang, Long^{d; 1} | Zhang, Chengfei^a | Xu, Haojun^a | Sun, Qi^{a; e} | Zhou, Guoren^{b; *} | Zhang, Yijie^{c; *} | Wang, Yongsheng^{e; *} | Xia, Hongping^{a; b; c; *}

Affiliations: [a] Department of Pathology, School of Basic Medical Sciences and Sir Run Run Hospital and Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, Jiangsu, China | [b] Jiangsu Cancer Hospital and the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China | [c] Department of Respiratory and Critical Care Medicine, Henan University Huaihe Hospital, Kaifeng, Henan, China | [d] Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China | [e] Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, Jiangsu, China

Correspondence: [*] Corresponding authors: Guoren Zhou, Jiangsu Cancer Hospital and the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, China. E-mail: zhouguoren888@126.com. Yijie Zhang, Department of Respiratory and Critical Care Medicine, Henan University Huaihe Hospital, Kaifeng, Henan 475000, China. E-mail: 13903782431@ 163.com. Yongsheng Wang, Nanjing Drum Tower Hospital Affiliated to Medical school of Nanjing University, Nanjing, Jiangsu 210008, China. E-mail: 15150580136@163.com. Hongping Xia, Department of Pathology, School of Basic Medical Sciences and Sir Run Run Hospital and Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, Jiangsu 211166, China. E-mail: xiahongping@njmu.edu.cn.

Note: [1] These authors contributed equally to this work.

Abstract: BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

Keywords: KCNN4, lung adenocarcinoma, AKT, ERK, proliferation

DOI: 10.3233/CBM-201045

Journal: Cancer Biomarkers, vol. 31, no. 2, pp. 187-201, 2021