C1GALT1 promotes invasive phenotypes of hepatocellular carcinoma cells by modulating integrin β1 glycosylation and activity

Chiung-Hui Liu; Rey-Heng Hu; Miao-Juei Huang; I-Rue Lai; Chia-Hua Chen; Hong-Shiee Lai; Yao-Ming Wu; Min-Chuan Huang

doi:10.1371/journal.pone.0094995

C1GALT1 promotes invasive phenotypes of hepatocellular carcinoma cells by modulating integrin β1 glycosylation and activity

PLoS One. 2014 Aug 4;9(8):e94995. doi: 10.1371/journal.pone.0094995. eCollection 2014.

Authors

Chiung-Hui Liu¹, Rey-Heng Hu², Miao-Juei Huang³, I-Rue Lai⁴, Chia-Hua Chen¹, Hong-Shiee Lai², Yao-Ming Wu⁵, Min-Chuan Huang³

Affiliations

¹ Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
² Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
³ Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
⁴ Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.

Abstract

Cancer cell invasion and metastasis are the primary causes of treatment failure and death in hepatocellular carcinoma (HCC). We previously reported that core 1 β1,3-galactosyltransferase (C1GALT1) is frequently overexpressed in HCC tumors and its expression is associated with advanced tumor stage, metastasis, and poor survival. However, the underlying mechanisms of C1GALT1 in HCC malignancy remain unclear. In this study, we found that overexpression of C1GALT1 enhanced HCC cell adhesion to extracellular matrix (ECM) proteins, migration, and invasion, whereas RNAi-mediated knockdown of C1GALT1 suppressed these phenotypes. The promoting effect of C1GALT1 on the metastasis of HCC cells was demonstrated in a mouse xenograft model. Mechanistic investigations showed that the C1GALT1-enhanced phenotypic changes in HCC cells were significantly suppressed by anti-integrin β1 blocking antibody. Moreover, C1GALT1 was able to modify O-glycans on integrin β1 and regulate integrin β1 activity as well as its downstream signaling. These results suggest that C1GALT1 could enhance HCC invasiveness through integrin β1 and provide novel insights into the roles of O-glycosylation in HCC metastasis.

Publication types

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

MeSH terms

Animals
Antibodies, Neutralizing / pharmacology
Carcinoma, Hepatocellular / drug therapy
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / secondary
Cell Adhesion / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Extracellular Matrix Proteins / genetics
Extracellular Matrix Proteins / metabolism
Female
Galactosyltransferases / antagonists & inhibitors
Galactosyltransferases / genetics*
Galactosyltransferases / metabolism
Gene Expression Regulation, Neoplastic*
Glycosylation
Humans
Integrin beta1 / genetics*
Integrin beta1 / metabolism
Liver Neoplasms, Experimental / drug therapy
Liver Neoplasms, Experimental / genetics*
Liver Neoplasms, Experimental / metabolism
Liver Neoplasms, Experimental / pathology
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / secondary
Mice
Mice, SCID
Neoplasm Invasiveness
Polysaccharides / chemistry
Polysaccharides / metabolism
Protein Binding
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction

Substances

Antibodies, Neutralizing
Extracellular Matrix Proteins
Integrin beta1
Polysaccharides
RNA, Small Interfering
C1GALT1 protein, human
Galactosyltransferases

Grants and funding

This study was supported by the grants from the National Taiwan University 101R7808 (Dr. Min-Chuan Huang), the National Science Council NSC NSC 99-3111-B-002-006 (Dr. Yao-Ming Wu), NSC 101-2314-B-002-053-MY2 (Dr. Rey-Heng Hu), and NSC 101-2320-B-002-007-MY3 (Dr. Min-Chuan Huang). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.