mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs

Xiaochen Gai; Bufu Tang; Fangming Liu; Yuting Wu; Fang Wang; Yanling Jing; Fuqiang Huang; Di Jin; Ling Wang; Hongbing Zhang

doi:10.1016/j.jgg.2019.03.013

mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs

J Genet Genomics. 2019 May 20;46(5):235-245. doi: 10.1016/j.jgg.2019.03.013. Epub 2019 May 18.

Authors

Xiaochen Gai¹, Bufu Tang², Fangming Liu¹, Yuting Wu¹, Fang Wang¹, Yanling Jing¹, Fuqiang Huang¹, Di Jin³, Ling Wang⁴, Hongbing Zhang⁵

Affiliations

¹ State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
² First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China; Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, 323000, China; Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 323000, China.
³ Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
⁴ First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China. Electronic address: lingwang2006@hotmail.com.
⁵ State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China; Department of Neurology, Institute of Neural Regeneration and Repair, The First People's Hospital of Yichang, College of Medicine, Three Gorges University, Yichang, 443000, China. Electronic address: hbzhang@ibms.pumc.edu.cn.

PMID: 31186161
DOI: 10.1016/j.jgg.2019.03.013

Abstract

Golgi membrane protein 1 (GOLM1/GP73) is a serum marker of hepatocellular carcinoma (HCC). We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression. In this study, we demonstrated that the mammalian target of rapamycin (mTOR) was a negative regulator of microRNA-145 (miR-145) expression. miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1 gene. GOLM1 and miR-145 were inversely correlated in human HCC tissues. GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases (GSK-3β/MMPs) signaling axis of recipient cells and accelerated cell proliferation and migration. In contrast, miR-145 suppressed tumorigenesis and metastasis. We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.

Keywords: Exosome; GOLM1; Hepatocellular carcinoma; mTOR; miR-145.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis / genetics
Carcinoma, Hepatocellular / pathology*
Cell Movement / genetics
Cell Proliferation / genetics
Exosomes / metabolism
Glycogen Synthase Kinase 3 beta / metabolism*
Hep G2 Cells
Humans
Liver Neoplasms / pathology*
Matrix Metalloproteinases / metabolism*
Membrane Proteins / metabolism*
MicroRNAs / genetics*
Neoplasm Invasiveness / genetics
Neoplasm Metastasis / genetics
TOR Serine-Threonine Kinases / metabolism*

Substances

GOLM1 protein, human
MIRN145 microRNA, human
Membrane Proteins
MicroRNAs
Glycogen Synthase Kinase 3 beta
TOR Serine-Threonine Kinases
Matrix Metalloproteinases