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The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma
- Source :
- ONCOGENE, Oncogene
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- 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.Oncogene advance online publication, 7 August 2017; doi:10.1038/onc.2017.260. ispartof: Oncogene vol:36 issue:47 pages:6605-6616 ispartof: location:England status: published
- Subjects :
- 0301 basic medicine
Cancer Research
Receptor, Platelet-Derived Growth Factor alpha
CANCER GENOMICS
Autoantigens
Proto-Oncogene Mas
ANGIOGENESIS
Cohort Studies
Mice
chemistry.chemical_compound
Piperidines
Medicine and Health Sciences
RNA, Small Interfering
rho-Associated Kinases
Biopsy, Needle
Liver Neoplasms
Hep G2 Cells
Immunohistochemistry
3. Good health
Ribonucleoproteins
IRES-MEDIATED TRANSLATION
Gene Knockdown Techniques
Disease Progression
Female
Original Article
Integrin alpha2beta1
Signal transduction
Tyrosine kinase
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Crenolanib
EXPRESSION
Carcinoma, Hepatocellular
Biology
03 medical and health sciences
Growth factor receptor
POOR-PROGNOSIS
LIVER-DISEASE
Proto-Oncogenes
Biomarkers, Tumor
Genetics
Animals
Humans
Neoplasm Invasiveness
RECURRENCE
Protein kinase A
Autocrine signalling
Molecular Biology
Keratin-19
MESENCHYMAL TRANSITION
CYTOKERATIN-19
Survival Analysis
Xenograft Model Antitumor Assays
030104 developmental biology
chemistry
Tumor progression
METASTASIS
Immunology
Cancer research
Benzimidazoles
Laminin
Follow-Up Studies
Subjects
Details
- ISSN :
- 14765594, 09509232, and 66056616
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....227358ac9144de77c0824e19886b0d3a