Abstract
BackgroundCarcinoma associated fibroblasts (CAFs), an important component of tumor microenvironment, are capable of enhancing tumor cells invasion and migration through initiation of epithelial–mesenchymal transition (EMT). MRC-5 fibroblasts are one of the CAFs expressing alpha-smooth muscle actin. It is ascertained that medium conditioned by MRC-5 fibroblasts stimulate motility and invasion of breast cancer cells. However, its role in hepatocellular carcinoma (HCC) is less clear. The aim of our study was to investigate the effect of MRC-5-CM on HCC and explore the underlying mechanisms.Methods and resultsUsing a combination of techniques, the role of MRC-5-CM in HCC was evaluated. We determined that MRC-5-CM induced the non-classical EMT in Bel-7402 and MHCC-LM3 cell lines. Initiation of the non-classical EMT was mainly via quintessential redistribution of α-, β- and γ-catenin, P120 catenin, E-cadherin, and N-cadherin, rather than up-regulation of typical EMT-related transcription factors (i.e., Snail, Twist1, ZEB-1 and ZEB2). We also found that MRC-5-CM potentiated both the migration and invasion of Bel-7402 and MHCC-LM3 cells in mesenchymal movement mode through activation of the α6, β3, β4, β7 integrin/FAK pathway and upregulation of MMP2. The flow cytometric analysis showed that MRC-5-CM induced G1 phase arrest in Bel-7402 cells with a concomitant reduction of S phase cells. In contrast, MRC-5-CM induced S phase arrest in MHCC-LM3 cells with a concomitant reduction of cells in the G2/M phase. MRC-5-CM also inhibited apoptosis in Bel-7402 cells while inducing apoptosis in MHCC-LM3 cells.ConclusionCollectively, MRC-5-CM promoted HCC cell motility and invasiveness through initiation of the non-classical EMT, including redistribution of α-, β- and γ-catenin, P120 catenin, E-cadherin, and N-cadherin, activation of the integrin/FAK pathway, and upregulation of MMP2. Hence, MRC-5-CM exerted distinct roles in Bel-7402 and MHCC-LM3 cell viability by regulating cyclins, cyclin dependent kinases (CDKs), CDK inhibitors (CKIs), Bcl-2 family proteins and other unknown mechanosensors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0588-8) contains supplementary material, which is available to authorized users.
Highlights
Carcinoma associated fibroblasts (CAFs), an important component of tumor microenvironment, are capable of enhancing tumor cells invasion and migration through initiation of epithelial–mesenchymal transition (EMT)
(which is implicated in a range of cellular functions such membrane aggregation, actin configuration, and signaling) was up-regulated slightly (Figure 3). These results revealed that membrane expression of α, β- and γ-catenin, P120 catenin and E-cadherin were reduced in MHCC-LM3-(MRC-5)-CM compared with the control, and N-cadherin was localized in a disorderly fashion on the MHCC-LM3-(MRC-5)-CM cell membrane
We found that MRC-5-CM inhibited apoptosis in Bel-7402 cells while inducing apoptosis in MHCC-LM3 cells (Figure 5b), further suggesting variations in the effect of MRC-5-CM on different cancer cell types
Summary
Carcinoma associated fibroblasts (CAFs), an important component of tumor microenvironment, are capable of enhancing tumor cells invasion and migration through initiation of epithelial–mesenchymal transition (EMT). It is ascertained that medium conditioned by MRC-5 fibroblasts stimulate motility and invasion of breast cancer cells. Its role in hepatocellular carcinoma (HCC) is less clear. The epithelial–mesenchymal transition (EMT) has been suggested to be involved in the progression of various cancers, including HCC [6]. Recent reports have highlighted that integrins and laminins as the main components of the cell adhesion functional unit [13], and these molecules are often correlated with cancer progression by potentiating the EMT via cooperation with other signaling effectors [14, 15]. There is a compelling need to distinguish the specific roles of laminins and integrins in HCC
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