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DDB2 regulates Epithelial-to-Mesenchymal Transition (EMT) in Oral/Head and Neck Squamous Cell Carcinoma
- Source :
- Oncotarget
- Publication Year :
- 2018
- Publisher :
- Impact Journals, LLC, 2018.
-
Abstract
- DDB2 is a sensor of DNA damage and it plays an important role in Global Genomic Repair (GG-NER). Our previous studies show that DDB2 is involved in the regulation of metastasis in colon adenocarcinoma. Squamous Cell Carcinomas in the Oral/Head & Neck region (HNSCC) are particularly aggressive due to high incidence of recurrence and distant metastasis. In this study, we show that DDB2 expression is downregulated in advanced HNSCCs and loss of DDB2 expression coincides with reduced survival. Recent meta-analysis of gene expression data characterized the mesenchymal-type (EMT-type) as one most aggressive cancer cluster in HNSCC. Here, we report that DDB2 constitutively represses mRNA expression of the EMT- regulatory transcription factors SNAIL, ZEB1, and angiogenic factor VEGF in HNSCC cells. As a result, re-expression of DDB2 in metastatic cells reversed EMT with transcriptional upregulation of epithelial marker E-cadherin, and downregulation of mesenchymal markers N-cadherin, Vimentin, and Fibronectin. Interestingly, in a reverse assay, depletion of DDB2 in non-metastatic cells induced expression of the same EMT-regulatory transcription factors. TGFβs are major regulators of Snail and Zeb1, and we observed that DDB2 transcriptionally regulates expression of TGFB2 in HNSCC cells. Re-expression of DDB2 in mouse embryonic fibroblasts (MEFs) isolated from Ddb2 (−/−) knockout-mice resulted in repression of EMT-regulatory factors Zeb1, Snail and Tgfb2. Taken together, these results support the active role of DDB2 as a candidate suppressor of the EMT-process in HNSCC. Early detection leads to significantly higher survival in HNSCC and DDB2 expression in tumors can be a predictor of EMT progression.
- Subjects :
- 0301 basic medicine
tumor suppressor
Cell
Vimentin
Biology
Metastasis
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Gene expression
medicine
Epithelial–mesenchymal transition
Transcription factor
oral/head and neck squamous cell carcinoma (HNSCC)
damaged DNA binding protein 2 (DDB2)
medicine.disease
Head and neck squamous-cell carcinoma
3. Good health
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
transforming growth factor beta (TGFβ)
epithelial-to-mesenchymal transition (EMT)
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....9a0ee44ab5e0b2da3b62ed4b74a336ba