Bradykinin promotes migration and invasion of hepatocellular carcinoma cells through TRPM7 and MMP2

Yijie Chen; Yang Yu; Shuya Sun; Zhaotong Wang; Peiqing Liu; Shenglan Liu; Jianmin Jiang

doi:10.1016/j.yexcr.2016.09.022

Bradykinin promotes migration and invasion of hepatocellular carcinoma cells through TRPM7 and MMP2

Exp Cell Res. 2016 Nov 15;349(1):68-76. doi: 10.1016/j.yexcr.2016.09.022. Epub 2016 Sep 30.

Authors

Yijie Chen¹, Yang Yu¹, Shuya Sun¹, Zhaotong Wang², Peiqing Liu³, Shenglan Liu¹, Jianmin Jiang⁴

Affiliations

¹ Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
² Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
³ Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; National and Local Joint Engineering Laboratory of Druggabilitiy Assessment and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
⁴ Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. Electronic address: lssjjm@mail.sysu.edu.cn.

PMID: 27693494
DOI: 10.1016/j.yexcr.2016.09.022

Abstract

Tumor metastasis is the main reason of death for hepatocellular carcinoma (HCC) patients. Cell migration and invasion are two prerequisites for tumor metastasis, in which TRPM7 and MMPs play an important role. In our study, we found that bradykinin (BK) could upregulate the expression of TRPM7 and dynamically regulate the phosphorylation of non-muscle myosin IIA heavy chain (NMHC-IIA) Ser-1943 in HepG2 cells. The influx of Ca²⁺ via TRPM7 was necessary for elevating the activity of m-calpain and μ-calpain. Additionally, we observed that BK stimulated HepG2 cells to secrete more MMP2 but not MMP9. Src was critical in the process of MMP2 secretion and invadopodia formation. The heat map showed that BDKRB2, TRPM7 and MMP2 had higher overexpression proportions in 25 HCC cell lines. Some clinical specimens of HCC also indicated that BDKRB2 and MMP2 were overexpressed. In conclusion, BK promoted migration and invasion of HCC cells through TRPM7 and MMP2.

Keywords: Bradykinin; Invasion; MMP2; Migration; TRPM7.

MeSH terms

Bradykinin / pharmacology*
Calcium / metabolism
Calpain / metabolism
Carcinoma, Hepatocellular / enzymology
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology*
Cell Movement / drug effects*
Exocytosis / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Hep G2 Cells
Humans
Liver Neoplasms / enzymology
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology*
Matrix Metalloproteinase 2 / metabolism*
Molecular Motor Proteins / metabolism
Myosin Heavy Chains / metabolism
Neoplasm Invasiveness
Phosphorylation / drug effects
Phosphoserine / metabolism
Podosomes / drug effects
Podosomes / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
RNA Interference
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptor, Bradykinin B2 / metabolism
Signal Transduction / drug effects
TRPM Cation Channels / genetics
TRPM Cation Channels / metabolism*
Up-Regulation / drug effects
src-Family Kinases / metabolism

Substances

MYH9 protein, human
Molecular Motor Proteins
RNA, Messenger
Receptor, Bradykinin B2
TRPM Cation Channels
Phosphoserine
src-Family Kinases
Protein Serine-Threonine Kinases
TRPM7 protein, human
Calpain
Matrix Metalloproteinase 2
Myosin Heavy Chains
Bradykinin
Calcium