期刊
CARCINOGENESIS
卷 35, 期 5, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgu024
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资金
- Taipei Veterans General Hospital [VN99-05, V102C-062]
- Ministry of Science and Technology [NSC-99-2628-B-010-013-MY3, NSC-101-2314-B-010-051-MY2]
- Department of Education (Aim for the Top University Plan)
- Ministry of Health and Welfare (for Excellence for Cancer Research), Taiwan) [MOHW103-TD-B-111-02]
Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial for tumorigenesis. Previously, we have identified that miR-31 is frequently upregulated in OSCC and that this miR-31 increase, together with downstream effector modulation, enhances oral carcinogenesis. We have identified higher levels of miR-31 expression in oral potential malignant disorder (OPMD) tissues compared with normal oral mucosa. Exogenous miR-31 and human telomerase reverse transcriptase (hTERT) expression were introduced into cultured normal oral keratinocytes (NOKs), which led to the immortalization; these lines were designated M31OK1 and M31OK3. These immortalized lines maintained the capability to undergo squamous differentiation. In addition, migration by both cell lines was attenuated by hTERT and miR-31 knockdown. M31OK1 carries a p53 gene mutation at codon 273. A serum-tolerant subline, M31OK1-D, exhibits potent anchorage-independent growth that is attenuated by knockdown of both hTERT and miR-31. miR-31-targeted factors inhibiting HIF (FIH), which upregulated vascular endothelial growth factor (VEGF), was found crucial for oral tumorigenesis. The proliferation, migration and epithelial-mesenchymal transition of M31OK1-D are associated with downregulation of FIH and upregulation of VEGF, which require miR-31 expression. High miR-31 expression is correlated with higher VEGF expression and lower E-cadherin expression in OPMD tissue. It can be concluded that miR-31 collaborates with hTERT to immortalize NOKs and that this may contribute to early stage oral carcinogenesis. The targeting of downstream factors by miR-31 may further advance the neoplastic progression of immortalized NOKs, allowing them to become malignant.Both miR-31 and hTERT are upregulated in oral carcinoma. This study identifies that exogenous expression of miR-31 and hTERT renders the immortalization of oral keratinocytes. The aberrance of p53 and FIH secondary to miR-31 expression may underlie further neoplastic induction.
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