title: A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion.
abstract: Increased activation of epidermal growth factor receptor (EGFR) family members such as HER2/Erbb2 can result in more aggressive disease, resistance to chemotherapy and reduced survival of head and neck squamous cell carcinoma (HNSCC) patients. In order to identify mechanisms through which these receptor tyrosine kinases accelerate tumor progression, the regulation of metalloprotease expression by EGFR family members was investigated in 11 squamous cell carcinoma (SCC) cell lines. HER2 expression was significantly correlated with ADAM12 (A Disintegrin And Metalloprotease 12) expression in these cell lines and was co-expressed in human head and neck cancers. Inhibition of HER2 or EGFR decreased ADAM12 transcripts whereas HER2 transfection upregulated ADAM12 expression. To understand the molecular mechanisms underlying HER2 regulation of ADAM12, we investigated the signaling pathways directing ADAM12 production in SCC cells. Inhibition of phosphatidyl inositol-3-kinase or mammalian target of rapamycin decreased ADAM12 transcripts in HER2-expressing SCC cells, whereas transfection with AKT increased ADAM12 mRNA. Experiments utilizing ADAM12 transfection or siRNA targeting of ADAM12 revealed that the protease increased both the migration and invasiveness of oral SCC cells. Surprisingly, ADAM12 also increased HER2 message, protein levels and activity through an Ets1-dependent mechanism. Collectively, these results reveal a novel positive activation loop between ADAM12 and HER2 that may contribute to HNSCC progression.
authors: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors: V H
authors: VH
authors: Rao
authors: A
authors: A
authors: Kandel
authors: D
authors: D
authors: Lynch
authors: Z
authors: Z
authors: Pena
authors: N
authors: N
authors: Marwaha
authors: C
authors: C
authors: Deng
authors: P
authors: P
authors: Watson
authors: L A
authors: LA
authors: Hansen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D051722:ADAM Proteins; D000072199:ADAM12 Protein; D066246:ErbB Receptors; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C494041:ETS1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C000606480:ADAM12 protein, human