Abstract
BackgroundHepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 have been utilized as cell surface markers to identify mesenchymal tumor-initiating stem-like cells (TISC) in several cancers including HCC. In this work, we examine the complex relationship between c-Met and CD44s (standard form), and investigate the specific role of CD44s as a tumor initiator and stemness marker in HCC.MethodsGene and protein expression assays were utilized to investigate the relationship between CD44s and c-Met in HCC cell lines. Tumor-sphere assays and in vivo tumor assays were performed to investigate the role of CD44+ cells as TISCs. Student’s t-test or one-way ANOVA with Tukeys post-hoc test was performed to test for differences amongst groups with a p < .05 as significant.ResultsIn an immunohistochemical and immunoblot analysis of human HCC samples, we observed that more than 39% of human HCC samples express c-Met and CD44. To study the relationship between c-Met and CD44, we used MHCC97-H cells, which are CD44+/c-Met+. The knockdown of c-Met in MHCC97-H cells decreased CD44s, reduced TISC characteristics and decreased tumorsphere formation. Furthermore, we demonstrate that the inhibition of PI3K/AKT signaling decreased CD44s expression and subsequently decreased tumorsphere formation. The down-regulation of CD44s leads to a significant loss of a TISC and mesenchymal phenotype. Finally, the down-regulation of CD44s in MHCC97-H cells decreased tumor initiation in vivo compared with the scrambled control.ConclusionsIn summary, our data suggest that CD44s is modulated by the c-Met-PI3K-AKT signaling cascade to support a mesenchymal and TISC phenotype in HCC cells. Moreover, c-Met could be a potential therapeutic drug for targeting HCC cells with TISC and mesenchymal phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1166-4) contains supplementary material, which is available to authorized users.
Highlights
Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 standard variant (CD44s) have been utilized as cell surface markers to identify mesenchymal tumorinitiating stem-like cells (TISC) in several cancers including HCC
Using HCC cell lines, we have previously demonstrated that pharmacologic inhibition of c-Met results in the decreased expression of CD44, which indicates a potential link between CD44s and c-Met activation [11]
CD44 expression correlates with c-Met expression in human HCC To investigate the correlation between c-Met and CD44, we performed immunohistochemistry staining on 68 HCC tumors (Figure 1B) and immnoblotted 33 HCC tumors (Figure 1A)
Summary
Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 have been utilized as cell surface markers to identify mesenchymal tumorinitiating stem-like cells (TISC) in several cancers including HCC. Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. Evidence suggests that HCC arises as a direct consequence of dysregulated proliferation of hepatic progenitor cells [2,3] Such progenitors, called tumor-initiating stem-like cells (TISCs), have been described in many different malignancies, including HCC, and may account for poor survival and chemotherapy resistance within specific tumors [4,5]. Transcriptome analysis of HCC has demonstrated that a progenitor-based (TISC-phenotype) expression profile is c-Met is a receptor tyrosine kinase that, upon activation by its ligand hepatocyte growth factor (HGF), promotes malignant progression and metastasis in multiple cancers, Dang et al BMC Cancer (2015) 15:161 including HCC [11,12]. Following c-Met phosphorylation and activation, multiple signaling pathways are involved as downstream targets, such as the PI3K/AKT and MAPK/ERK1/2 pathways [17,18]
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