An oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma
Copyright policy )An oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma
AbstractHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The identity and role of cell surface molecules driving complex biological events leading to HCC progression are poorly understood, hence representing major lacunae in HCC therapies. Here, combining SILAC quantitative proteomics and biochemical approaches, we uncover a critical oncogenic role of Agrin, which is overexpressed and secreted in HCC. Agrin enhances cellular proliferation, migration and oncogenic signalling. Mechanistically, Agrin’s extracellular matrix sensor activity provides oncogenic cues to regulate Arp2/3-dependent ruffling, invadopodia formation and epithelial–mesenchymal transition through sustained focal adhesion integrity that drives liver tumorigenesis. Furthermore, Agrin signalling through Lrp4-muscle-specific tyrosine kinase (MuSK) forms a critical oncogenic axis. Importantly, antibodies targeting Agrin reduced oncogenic signalling and tumour growth in vivo. Together, we demonstrate that Agrin is frequently upregulated and important for oncogenic property of HCC, and is an attractive target for antibody therapy.
- National Cancer Centre Singapore Singapore
- National University of Singapore Libraries Singapore
- Agency for Science, Technology and Research Singapore
- Institute of Molecular and Cell Biology Singapore
- National University of Singapore Singapore
Integrins, cell migration, Carcinogenesis, epithelial mesenchymal transition, Apoptosis, cholinergic receptor, confocal microscopy, gene silencing, Cell Movement, antibody, muscle specific tyrosine kinase, breast carcinoma, focal adhesion, Liver Neoplasms, cell surface protein, gene control, MUSK protein, cell invasion, Endocytosis, unclassified drug, enzyme activity, secretion, adhesion, female, LRP4 protein, Gene Knockdown Techniques, Isotope Labeling, low density lipoprotein receptor related protein, agrin, carcinogenesis, amino acid, tumor, Carcinoma, Hepatocellular, Epithelial-Mesenchymal Transition, integrin, extracellular matrix, gene overexpression, animal experiment, cell motility, Article, animal tissue, proteomics, Membrane Microdomains, tumor protein, Cell Line, Tumor, 616, 617, Cell Adhesion, biochemistry, cancer, Animals, human, Agrin, Antibodies, Blocking, LDL-Receptor Related Proteins, Cell Proliferation, Focal Adhesions, animal model, human cell, focal adhesion kinase, protein tyrosine kinase, blocking antibody, actin related protein 2-3 complex, small interfering RNA, cell proliferation, Focal Adhesion Protein-Tyrosine Kinases, gene expression, cells and cell components
Integrins, cell migration, Carcinogenesis, epithelial mesenchymal transition, Apoptosis, cholinergic receptor, confocal microscopy, gene silencing, Cell Movement, antibody, muscle specific tyrosine kinase, breast carcinoma, focal adhesion, Liver Neoplasms, cell surface protein, gene control, MUSK protein, cell invasion, Endocytosis, unclassified drug, enzyme activity, secretion, adhesion, female, LRP4 protein, Gene Knockdown Techniques, Isotope Labeling, low density lipoprotein receptor related protein, agrin, carcinogenesis, amino acid, tumor, Carcinoma, Hepatocellular, Epithelial-Mesenchymal Transition, integrin, extracellular matrix, gene overexpression, animal experiment, cell motility, Article, animal tissue, proteomics, Membrane Microdomains, tumor protein, Cell Line, Tumor, 616, 617, Cell Adhesion, biochemistry, cancer, Animals, human, Agrin, Antibodies, Blocking, LDL-Receptor Related Proteins, Cell Proliferation, Focal Adhesions, animal model, human cell, focal adhesion kinase, protein tyrosine kinase, blocking antibody, actin related protein 2-3 complex, small interfering RNA, cell proliferation, Focal Adhesion Protein-Tyrosine Kinases, gene expression, cells and cell components
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).136 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!