Research Paper Volume 10, Issue 10 pp 2570—2584

CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling

Zhao Liu 1, , Mi Chen 1, , Lin-Ka Xie 1, , Ting Liu 2, , Zhen-Wei Zou 1, , Yong Li 3, , Peng Chen 1, , Xin Peng 1, , Charlie Ma 4, , Wen-Jie Zhang 5, , Pin-Dong Li 1, ,

  • 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
  • 2 Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
  • 3 Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, China
  • 4 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
  • 5 Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, China

received: May 30, 2018 ; accepted: September 24, 2018 ; published: October 11, 2018 ;

https://doi.org/10.18632/aging.101571
How to Cite

Copyright: Liu et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Calcium activated Chloride Channel A4 (CLCA4), as a tumor suppressor, was reported to contribute to the progression of several malignant tumors, yet little is known about the significance of CLCA4 in invasion and prognosis of hepatocellular carcinoma (HCC). CLCA4 expression was negatively correlated with tumor size, vascular invasion and TNM stage. Kaplan-Meier analysis showed that CLCA4 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, CLCA4 status could act as prognostic predictor in different risk of subgroups. Moreover, combination of CLCA4 and serum AFP could be a potential predictor for survival in HCC patients. Furthermore, CLCA4 may inhibit cell migration and invasion by suppressing epithelial-mesenchymal transition (EMT) via PI3K/ATK signaling. Knockdown of CLCA4 significantly increased the migration and invasion of HCC cells and changed the expression pattern of EMT markers and PI3K/AKT phosphorylation. An opposite expression pattern of EMT markers and PI3K/AKT phosphorylation was observed in CLCA4-transfected cells. Additionally, immunohistochemistry and RT-PCR results further confirmed this correlation. Taken together, CLCA4 contributes to migration and invasion by suppressing EMT via PI3K/ATK signaling and predicts favourable prognosis of HCC. CLCA4/AFP expression may help to distinguish different risks of HCC patients after hepatectomy.

Abbreviations

HCC: Hepatocellular carcinoma; CLCA: Calcium activated Chloride Channel; EMT: epithelial to mesenchymal transition; AFP: alpha fetoprotein; TNM: tumor-node-metastasis; BCLC: Barcelona Clinic Liver Cancer; OS: Overall survival; TTR: Time to recurrence; PI3K: Phosphatidylinositol 3-kinase; AKT: protein kinase B; GGT: gamma-glutamyltransferase.