The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma

• Published in: Oncogene Vol. 36; no. 47; pp. 6605 - 6616
• Main Authors: Govaere, O, Petz, M, Wouters, J, Vandewynckel, Y-P, Scott, E J, Topal, B, Nevens, F, Verslype, C, Anstee, Q M, Van Vlierberghe, H, Mikulits, W, Roskams, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-11-2017; Nature Publishing Group
• Subjects: 13/109; 13/89; 13/95; 631/67/1504/1610; 692/53/2422; 82/51; 82/80; 96/1; Animals; Apoptosis; Autoantigens - metabolism; Benzimidazoles - pharmacology; Biomarkers, Tumor - metabolism; Biopsy, Needle; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - surgery; Cell Biology; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Gene Knockdown Techniques; Hep G2 Cells; Human Genetics; Humans; Immunohistochemistry; Integrin alpha2beta1 - metabolism; Internal Medicine; Keratin-19 - genetics; Keratin-19 - metabolism; Laminin - genetics; Laminin - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Liver Neoplasms - surgery; Medicine; Medicine & Public Health; Mice; Neoplasm Invasiveness; Oncology; Original; original-article; Piperidines - pharmacology; Proto-Oncogene Mas; Proto-Oncogenes; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; rho-Associated Kinases - metabolism; Ribonucleoproteins - metabolism; RNA, Small Interfering; Signal Transduction; SS-B Antigen; Survival Analysis; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.260

Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor α (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce
de novo
synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFRα expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFRα expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFRα-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of α2β1 integrin (ITG) receptor, both
in vitro
and
in vivo
.
In vitro
activation of PDGFRα signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFRα-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFRα-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression.