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A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion
- Source :
- Oncogene
- Publication Year :
- 2011
- Publisher :
- Springer Science and Business Media LLC, 2011.
-
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.
- Subjects :
- Cancer Research
Receptor, ErbB-2
ADAM12 Protein
Fluorescent Antibody Technique
migration
Receptor tyrosine kinase
Immunoenzyme Techniques
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Cell Movement
Tumor Cells, Cultured
Epidermal growth factor receptor
Phosphorylation
skin and connective tissue diseases
Feedback, Physiological
0303 health sciences
Reverse Transcriptase Polymerase Chain Reaction
ADAM12
Transfection
Cell cycle
invasion
ErbB Receptors
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Carcinoma, Squamous Cell
Signal Transduction
MAP Kinase Signaling System
Blotting, Western
Biology
Real-Time Polymerase Chain Reaction
Article
Proto-Oncogene Protein c-ets-1
03 medical and health sciences
Growth factor receptor
HER2
Genetics
medicine
Humans
Neoplasm Invasiveness
RNA, Messenger
neoplasms
Molecular Biology
Cell Proliferation
030304 developmental biology
Membrane Proteins
oral cancer
medicine.disease
Head and neck squamous-cell carcinoma
ADAM Proteins
stomatognathic diseases
Tumor progression
Cancer cell
biology.protein
Cancer research
head and neck cancer
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....8e78e786ce60e2a225d9c459694e3ad1