c-Myc transactivates GP73 and promotes metastasis of hepatocellular carcinoma cells through GP73-mediated MMP-7 trafficking in a mildly hypoxic microenvironment

Yiming Liu; Sining Zhou; Jieyao Shi; Xiaodi Zhang; Linhui Shentu; Zhi Chen; Linfu Zhou

doi:10.1038/s41389-019-0166-7

c-Myc transactivates GP73 and promotes metastasis of hepatocellular carcinoma cells through GP73-mediated MMP-7 trafficking in a mildly hypoxic microenvironment

Oncogenesis. 2019 Oct 7;8(10):58. doi: 10.1038/s41389-019-0166-7.

Authors

Yiming Liu^{1

2

3}, Sining Zhou², Jieyao Shi², Xiaodi Zhang², Linhui Shentu⁴, Zhi Chen⁵, Linfu Zhou^{6

7}

Affiliations

¹ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
² Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
³ Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
⁴ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁵ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. chenzhi@zju.edu.cn.
⁶ Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, 310058, China. 239zlf@zju.edu.cn.
⁷ Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. 239zlf@zju.edu.cn.

Abstract

Golgi phosphoprotein 73 (GP73), encoded by GOLM1, is a highly expressed factor in hepatocellular carcinoma (HCC) cells and has been regarded for several years as a remarkable serum biomarker for the diagnosis of HCC. Recently, it was found that upregulation of GP73 promotes cancer metastasis, but the mechanism is complex, and it is even unclear how the gene is transactivated in HCC cells. In this study, it was discovered that c-Myc transactivated GP73 in a mildly hypoxic microenvironment and that the activation of c-Myc upregulated the expression of matrix metalloproteinase-7 (MMP-7). Moreover, it is shown that GP73 interacted with intracellular MMP-7 in the region of the cytoplasmic domain and facilitated the trafficking and secretion of MMP-7, resulting in cell metastasis. This study indicates that GP73 is transactivated by c-Myc and serves as a transporter in the trafficking of intracellular MMP-7 in HCC cells. These findings suggest that GP73 is a potential target for combating metastatic HCC.