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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.

SUBMITTER: Rao VH

PROVIDER: S-EPMC3302945 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Rao V H VH Kandel A A Lynch D D Pena Z Z Marwaha N N Deng C C Watson P P Hansen L A LA

Oncogene 20111010 23

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 ...[more]

PMID: 21986939

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Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis, high lymph node metastasis and early recurrence. However, the molecular events regulating HNSCC tumorigenesis remain poorly understood. Therefore, uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC. In this study, we aimed to explore the role of pleckstrin-2 (PLEK2) in regulating HNSCC tumorigenesis.MethodsThe expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort. In vitro and in vivo experiments, including cell proliferation, colony formation, Matrigel invasion, tumor sphere formation, ALDEFLUOR, Western blotting assays and xenograft mouse models, were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells. The underlying molecular mechanisms for the tumor-promoting role of PLEK2 were elucidated using co-immunoprecipitation, cycloheximide chase analysis, ubiquitination assays, chromatin immunoprecipitation-quantitative polymerase chain reaction, luciferase reporter assays and rescue experiments.ResultsThe expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues, and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance. Additionally, PLEK2 was important for maintaining the proliferation, invasion, epithelial-mesenchymal transition, cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells. Mechanistically, PLEK2 interacted with c-Myc and reduced the association of F-box and WD repeat domain containing 7 (FBXW7) with c-Myc, thereby avoiding ubiquitination and subsequent proteasome-mediated degradation of c-Myc. Moreover, the c-Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells. c-Myc also directly bounded to the PLEK2 promoter and activated its transcription, forming a positive feedback loop.ConclusionsCollectively, these findings uncover a previously unknown molecular basis of PLEK2-enhanced c-Myc signaling in HNSCC, suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.

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

Publications

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

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