miRNA-mediated post-transcriptional regulation of targeted genes plays crucial roles in neoplastic process. miR-372 has been shown an oncogenic miRNA which is hypoxia-inducible and is conspicuously up-regulated in oral squamous cell carcinoma (OSCC). Zinc finger and BTB domain containing 7A (ZBTB7A) is a transcriptional repressor modulating a great diversities of physiological or oncogenic regulation. This study identified that ZBTB7A was a direct target of miR-372. ZBTB7A was down-regulated in 75% of OSCC tumors relative to adjacent oral mucosa. Reverse correlation across miR-372 expression and ZBTB7A expression was found in tumor samples. In OSCC cells with the stable knockdown of ZBTB7A, the oncogenic potential and drug resistance increased. Whereas, such increase was attenuated by ZBTB7A expression. High throughput screening and validation assay confirmed that ZBTB7A was able to repress multiple oncogenic factors and activate the expression of Trail-R1, Trail-R2 and Fas to increase the drug sensitivity in OSCC cells. miR-372 induction drastically repressed the expression of apoptosis genes by inhibiting ZBTB7A. This was accompany with the enrichment of oncogenicity and the increased tolerance to the toxicity of cisplatin and taxol. This study signifies the importance of miR-372-ZBTB7A-downstream effectors in mediating pathogenesis and drug resistance of OSCC. Interception of this pathogenic cascade would confer therapeutic benefits against oral carcinoma. Citation Format: Li-Yin Yeh, Chung-Hsien Chou, Chung-Ji Liu, Shu-Chun Lin, Kuo-Wei Chang. miR-372 enhances tumorigenesis and drug resistance in oral carcinoma by targeting ZBTB7A transcription factor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 479.

Oral squamous cell carcinoma (OSCC) is one of the prevalent neoplasms worldwide. Recent studies have shown that miRNAs were involved in the pathogenesis of various human malignancies, which function by post-transcriptional down-regulation of target genes. Also, hypoxia is a feature of most tumors and plays an important role in regulating tumor progression and resistance to therapy. In our previous study, we found that miR-372 was highly expressed in OSCC tissues. Other studies have shown the oncogenic roles of miR-372 in regulating the cell cycle and apoptosis in tumor cells by targeting different targets. This study identified that miR-372 was up-regulated by hypoxia in OSCC cells. The plasma level of miR-372 in OSCC patients significantly increased with the advance of OSCC. p62 is a multidomain protein that interacts with key components to drive diverse impacts on signaling regulation including detoxification pathway. Using in silico prediction modules, qRT-PCR analysis, Western blot analysis, reporter assay and exogenous expression construct, we discovered that p62 was a novel target of miR-372. Ectopic miR-372 expression and knockdown of p62 both enhanced the migration of OSCC cells, but it did not affect the proliferation of OSCC cells. Furthermore, we demonstrated that p62 was able to induce the expression of phase II enzyme NQO1, which resulted in the attenuation of reactive oxygen species and migration in OSCC cells. Furthermore, correlation among the expression of miR-372, p62 and NQO1 was found in OSCC tissues. This study concludes that hypoxia-induced miR-372 expression modulates the progression of OSCC by targeting p62, which disrupts the ROS homeostasis in tumor cells. Citation Format: Li-Yin Yeh, Shu-Chun Lin, Chung-Ji Liu, Yong-Kie Wong, Kuo-Wei Chang. Hypoxia-induced miR-372 targets p62 to affect the progression of oral carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4360. doi:10.1158/1538-7445.AM2014-4360