SCCRO (DCUN1D1) Induces Extracellular Matrix Invasion by Activating Matrix Metalloproteinase 2
| Autor: | Ashok R. Shaha, Bhuvanesh Singh, Pornchai O-charoenrat, Ivan Ngai, Pabbathi G. Reddy, Su Dao, Valerie W. Rusch, Y. Ramanathan, Jatin P. Shah, Dennis H. Kraus, Inderpal S. Sarkaria, Simon G. Talbot |
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| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Cancer Research Lung Neoplasms MMP2 Cell Biology MMP9 Mice Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Neoplasm Metastasis Aged Aged 80 and over Oncogene Proteins Reporter gene Oncogene Activator (genetics) Intracellular Signaling Peptides and Proteins Proteins Oncogenes Middle Aged Genes p53 Extracellular Matrix medicine.anatomical_structure Transcription Factor AP-2 Oncology Head and Neck Neoplasms Carcinoma Squamous Cell Cancer research Matrix Metalloproteinase 2 Female Ectopic expression Chromatin immunoprecipitation |
| Zdroj: | Clinical Cancer Research. 14:6780-6789 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-08-0719 |
| Popis: | Purpose: Ectopic expression of squamous cell carcinoma–related oncogene (SCCRO or DCUN1D1) in NIH-3T3 cells induces invasion in vitro and produces highly invasive xenografts in nude mice with a propensity for regional lymphatical metastasis. The aim of this study was to identify the molecular mechanism underlying SCCRO-induced invasion and metastasis. Experimental Design: The molecular mechanism of SCCRO-mediated effects on matrix metalloproteinase-2 (MMP2) levels and activity were assessed using a combination of cell biological and molecular methods, including real-time PCR, reporter assay, RNA interference, and chromatin immunoprecipitation assay. Tumor specimens from primary upper aerodigestive tract carcinomas (n = 89) were examined for levels of SCCRO, MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA by real-time PCR. Results: Overexpression of SCCRO increases MMP2 levels and activity, which is required for SCCRO-induced invasion. Modified McKay assays reveal that SCCRO does not bind to the MMP2 promoter, suggesting that its transcriptional effects are indirect. Deletion or mutation of the activator protein-2 (AP2) and p53 binding element within the MMP2 promoter abrogates SCCRO-driven activation. Ectopic expression of SCCRO increases AP2 levels and promotes the binding of p53 to the MMP2 promoter. Consistent with these findings, SCCRO and MMP2 are coexpressed (P < 0.0001; r2 = 0.58; 95% confidence interval, 0.46-0.69) in primary (upper aerodigestive tract) carcinomas (n = 89), and this coexpression is associated with an increased prevalence of regional nodal metastasis (P = 0.04; relative risk, 1.53). Conclusions: SCCRO-induced invasion involves activation of MMP2 transcription in an AP2- and p53-dependent manner. SCCRO is a potential marker for metastatic progression in affected cancers. |
| Databáze: | OpenAIRE |
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