Mucin Glycosylating Enzyme GALNT2 Regulates the Malignant Character of Hepatocellular Carcinoma by Modifying the EGF Receptor

Abstract

Extracellular glycosylation is a critical determinant of malignant character. Here, we report that N-acetylgalactosaminyltransferase 2 (GALNT2), the enzyme that mediates the initial step of mucin type-O glycosylation, is a critical mediator of malignant character in hepatocellular carcinoma (HCC) that acts by modifying the activity of the epidermal growth factor receptor (EGFR). GALNT2 mRNA and protein were downregulated frequently in HCC tumors where these events were associated with vascular invasion and recurrence. Restoring GALNT2 expression in HCC cells suppressed EGF-induced cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that the status of the O-glycans attached to the EGFR was altered by GALNT2, changing EGFR responses after EGF binding. Inhibiting EGFR activity with erlotinib decreased the malignant characters caused by siRNA-mediated knockdown of GALNT2 in HCC cells, establishing the critical role of EGFR in mediating the effects of GALNT2 expression. Taken together, our results suggest that GALNT2 dysregulation contributes to the malignant behavior of HCC cells, and they provide novel insights into the significance of O-glycosylation in EGFR activity and HCC pathogenesis. Cancer Res; 71(23); 7270-9. Ó2011 AACR.

C1GALT1 Enhances Proliferation of Hepatocellular Carcinoma Cells via Modulating MET Glycosylation and Dimerization

“…However, glycogenes responsible for these O-glycans and their functions in hepatocellular carcinoma remain largely unknown. Previously, we reported that GALNT1 and GALNT2 are the major GalNAc transferases in liver tissues and that GALNT2 modulates the sialyl Tn expression on EGF receptor in hepatocellular carcinoma cells and suppresses their malignant properties (18). Here, we further report that C1GALT1 expression is dysregulated in hepatocellular carcinoma and C1GALT1 modulates the expression of mucin-type O-glycans on hepatocellular carcinoma cell surfaces.…”

“…Primers for GAPDH were 5 0 -GACAAGCTTCCCGTTCTCAG-3 0 and 5 0 -ACAGTCAGCCG-CATCTTCTT-3 0 . Quantitative real-time PCRs were carried out as described previously (18).…”

“…O-glycans on major histocompatibility complex class I-related chain A (MICA) enhance bladder tumor metastasis (16), and O-glycosylation of death receptor controls apoptotic signaling in several types of cancer (17). In addition, our previous study showed that GALNT2, an O-glycosyltransferase, regulates EGF receptor activity and cancer behaviors in hepatocellular carcinoma cells (18). Therefore, understanding the roles of O-glycosylation in hepatocellular carcinoma may provide novel insights into the pathogenesis of hepatocellular carcinoma.…”

Decreased Expression of Hepatocyte Nuclear Factor 4α (Hnf4α)/MicroRNA-122 (miR-122) Axis in Hepatitis B Virus-associated Hepatocellular Carcinoma Enhances Potential Oncogenic GALNT10 Protein Activity

“…Several lines of evidence indicate that changes in O-linked glycans allow neoplastic cells to differentiate, invade, and spread throughout the organism (20,21). The alteration of O-glycans attached to the epidermal growth factor receptor (EGFR) mediated by the down-regulation of GALNT2 plays a critical role in the malignant phenotype of HCC cells (22). Moreover, overexpression of core 1␤-1,3-galactosyltransferase activates hepatocyte growth factor signaling in hepatocellular carcinoma (23).…”

Establishment of a highly metastatic model with a newly isolated lung adenocarcinoma cell line

“…Besides, by means of ITRAQ labeled proteomics profiling study, we also found 50 dysregulated proteins in XL-2sci, some of which played an important role in tumor metastasis. For example, FSCN1 has been reported to be relevant with NSCLC metastasis, and G3V1S6 was said to be involved in the distant metastasis of breast cancer (51), gastric cancer (52) plus liver cancer (53). In addition, NDRG1 was connected with colorectal cancer and liver cancer, whereas, it was highly expressed in lung cancer.…”