A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion

V. H. Rao, A. Kandel, D. Lynch, Z. Pena, N. Marwaha, C. Deng, P. Watson, Laura A. Hansen

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2888-2898
Number of pages11
JournalOncogene
Volume31
Issue number23
DOIs
StatePublished - Jun 7 2012

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Disintegrins
Metalloproteases
Head and Neck Neoplasms
Cell Movement
Squamous Cell Carcinoma
Epidermal Growth Factor Receptor
Transfection
Cell Line
Disease Resistance
Receptor Protein-Tyrosine Kinases
Sirolimus
Phosphatidylinositols
Small Interfering RNA
Peptide Hydrolases

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion. / Rao, V. H.; Kandel, A.; Lynch, D.; Pena, Z.; Marwaha, N.; Deng, C.; Watson, P.; Hansen, Laura A.

In: Oncogene, Vol. 31, No. 23, 07.06.2012, p. 2888-2898.

Research output: Contribution to journalArticle

Rao, V. H. ; Kandel, A. ; Lynch, D. ; Pena, Z. ; Marwaha, N. ; Deng, C. ; Watson, P. ; Hansen, Laura A. / A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion. In: Oncogene. 2012 ; Vol. 31, No. 23. pp. 2888-2898.
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