Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis

Abstract

BackgroundHepatocyte growth factor (HGF) induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC). MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s) is in hepatocarcinogenesis.ResultsMUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion.ConclusionsThese findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.

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

“…It is likely that, in addition to EGFR, other glycoproteins, including surface and secreted molecules, may be modified by GALNT10 to cooperatively mediate phenotypic changes in HCC. Muc1 (Mucin-1), one of several high molecular weight glycoprotein families that are often heavily O-glycosylated, is often overexpressed in HCC and associated with migration and invasion (71). Glycopro- teomic technology will be helpful to further understand the precise mechanisms.…”

Intermedin promotes hepatocellular carcinoma cell proliferation through the classical Wnt signaling pathway

“…HCC is commonly diagnosed numerous countries with a high incidence of viral hepatitis (3). HCC contributes 85-90% of all primary liver cancers, with 500,000 new cases and 250,000 HCC-associated mortalities occurring worldwide every year (4). The main reasons for the high mortality rate of HCC patients are ascribed to the lack of effective treatments and the increasing resistance to conventional radiotherapy and chemotherapy (5).…”

“…Cell proliferation was detected using CCK-8. HepG2 cells in the logarithmic growth phase were inoculated in flat-bottomed 96-well plates at a density of 1x10 4 /100 cells/µl, and cultured in 5% CO 2 incubator at 37˚C. After 12 h, the medium was replaced with fresh culture medium (Shanghai Yuan Long Biology Technology Company.…”

534 Expression of c-MET in invasive meningioma

“…In contrast, studies by Karja et al 3 and Lamszus et al 18 use enzyme-linked immunosorbent assay and immunohistochemistry to argue that HGF is not related to tumor recurrence in meningioma. 3,21 Few studies demonstrate an association of c-MET/HGF with brain and bone invasion of meningiomas. The present study provides data on the expression of c-MET and HGF in a large scale studies of meningiomas, as well as on the relationships of the meningiomas with brain and bone/soft tissue invasion in patients.…”

“…Evaluation of c-MET and HGF expression was assessed according to previous reports. 21 As a positive control for c-MET and HGF, tubular cells of a normal kidney and normal colonic mucosa were used, respectively. Immunostaining without the primary antibody was used as the negative control.…”