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

Bozkaya Giray, Korhan Peyda, Çokaklä± Murat, Erdal Esra, Saäÿol Özgül, Karademir Sedat, Korch Christopher, Atabey, Atabey Neåÿe

Description

Hepatocyte 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. Results MUC1 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. Conclusions These 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.

Sujets

• Différentiation
• Invasión

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 10
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Bozkayaet al. Molecular Cancer2012,11:64 http://www.molecularcancer.com/content/11/1/64

R E S E A R C HOpen Access Cooperative interaction of MUC1 with the HGF/cMet pathway during hepatocarcinogenesis 1†1†2 31 1 Giray Bozkaya, Peyda Korhan, Murat Çokaklı, Esra Erdal , Özgül Sağol , Sedat Karademir , 4 1* Christopher Korchand Nee Atabey

Abstract Background:Hepatocyte 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. Results:MUC1 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 ofβ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. Conclusions:These findings indicate that the crosstalk between MUC1 and cMet in HCC could provide an advantage for invasion to HCC cells through theβcatenin/cMyc pathway. Thus, MUC1 and cMet could serve as potential therapeutic targets in HCC. Keywords:Hepatocellular carcinoma (HCC), Hepatocyte Growth Factor (HGF)/cMet, Mucin 1 (MUC1), Differentiation, Invasion

Background Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary liver cancers and is the fifth most com mon cancer worldwide [1,2]. More than 250,000 deaths and 500,000 new cases occur globally each year [1,3]. One of the main reasons for the high mortality rate is the lack of effective treatments and the development of resistance to conventional chemotherapy and radiother apy [4]. In recent years, improved knowledge of signal ing pathways regulating HCC growth and progression

* Correspondence: [e-mail] † Equal contributors 1 Department of Medical Biology and Genetics, Dokuz Eylul University, Medical School, 35340, BalcovaIzmir, Turkey Full list of author information is available at the end of the article

has led to the identification of several novel molecular targets. One of the most promising signaling pathways for molecular therapy of HCC appears to be the Hepato cyte Growth Factor (HGF)/cMet cascade [47]. HGF was first characterized as a factor that induces hepatocyte proliferation and as a motility factor of epi thelial cells [811]. HGF acts on cMet, a high affinity tyrosine kinase receptor, and mediates several cellular behaviors including cell survival, proliferation, migration morphogenesis, and angiogenesis [721]. Both cMet and HGF are overexpressed during liver development and it is known that the signal elicited through binding of HGF to cMet is one of the main stimuli for the G1S pro gression in hepatocytes [13]. In mice, deficiency of either HGF or cMet expression causes embryonic lethality

© 2012 Bozkaya et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.