Laminin-332 γ2 Monomeric Chain Promotes Adhesion and Migration of Hepatocellular Carcinoma Cells

SIMPLE SUMMARY: Extracellular matrix (ECM) molecules are believed to being critically involved in the progression of hepatocellular carcinoma (HCC). Laminin332 (Ln332) is an ECM protein complex that has been found to be implicated in the acquisition of aggressive phenotype of HCC cancer cells. Here, we focus on the pro-invasive function of the γ2 chain of Ln332 in monomeric form, highlighting its ability to stimulate the motility of HCC cell, independent of and to the same extent as the entire Ln332. Our data provide proof of principle that blocking interactions between the γ2 chain and related receptors on the HCC cell surface may be strategic to counteract HCC aggravation. ABSTRACT: Extracellular matrix (ECM) has a well-recognized impact on the progression of solid tumors, including hepatocellular carcinoma (HCC). Laminin 332 (Ln332) is a ECM molecule of epithelial basal lamina, composed of three polypeptide chains (α3, β3, and γ2), that is usually poorly expressed in the normal liver but is detected at high levels in HCC. This macromolecule was shown to promote the proliferation, epithelial-to-mesenchymal transition (EMT), and drug resistance of HCC cells. The monomeric γ2 chain is up-regulated and localized preferentially at the invasive edge of metastatic intrahepatic HCC nodules, suggesting its potential involvement in the acquisition of invasive properties of HCC cells. HCC cells were tested in in vitro adhesion, scattering, and transwell migration assays in response to fibronectin and the Ln332 and Ln332 γ2 chains, and the activation status of major signaling pathways involved was evaluated. Here, we show that the Ln332 γ2 chain promotes HCC the cell adhesion, migration, and scattering of HCC cells that express the Ln332 receptor α3β1 integrin, proving to be a causal factor of the EMT program achievement. Moreover, we found that efficient HCC cell adhesion and migration on γ2 require the activation of the small cytosolic GTPase Rac1 and ERKs signaling. These data suggest that the γ2 chain, independently from the full-length Ln332, can contribute to the pro-invasive potential of aggressive HCC cell subpopulations.