Oral cancer is the fourth foremost case of death from cancer, and the major causes of death are local recurrence and distant metastasis. The strong associations between oral squamous cell carcinoma (OSCC) and dietary habits such as alcohol consumption (A), betel quid chewing (B) and cigarette smoking (C) and its predominance in men have been well documented. Evidences have shown that miRNAs are involved in tumorigenesis of various cancers through regulating their downstream targets. In order to identify changes in miRNAs specific for betel quid-associated oral squamous cell carcinoma (OSCC), we investigated the expression profiles of miRNAs in a panel of 40 pairs of OSCC specimens and their matched non-tumorous epithelial counterparts. Our data showed that the expression levels of mir-455-5p are significantly (P<0.0001) higher in tumor tissue than in their counterpart normal tissue. In addition, the expression levels of mir-455-5p in oral cancer cell lines are also higher than normal oral epithelial cell line. Knockdown of mir-455-5p reduces both anchorage-independent growth and proliferative ability in two head and neck cancer cells, and vice versa in mir-455-5p overexpressing cells. Collectively, these evidences showed that mir-455-5p serves as an oncomir in betel quid-associated oral cancer. Furthermore, by analyzing both the array data from cancer patients and cell lines, and then intersected with the results from website tools, we have identified ubiquitin-conjugating enzyme E2B (UBE2B) to be the target of mir-455-5p, which was further validated by 3′-UTR luciferase reporter assay and Western blot analysis. We also revealed that UBE2B suppression actually rescued both cell transformation and growth ability in mir-455-5p knockdown cells. Our data further demonstrated that the expression level of mir-455-5p is regulated by transforming growth factor-β (TGF-β) pathway. Moreover, mir-455-5p expression was suppressed by the treatment of TGF-β downstream regulators. In conclusion, our results showed that the expression of mir-455-5p is regulated by TGF-β-dependent pathway, which subsequently leads to alteration the expression of UBE2B and contribute to the tumorigenesis of betel quid-associated oral cancer.
Date:
2014-10
Relation:
Cancer Research. 2014 Oct;74(19 Suppl.):Abstract No. 4348.
