Int J Biol Sci 2021; 17(2):430-447. doi:10.7150/ijbs.54014

Research Paper

Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma

An Song1,2, Yuanyuan Wu1,2, Weiming Chu1,3, Xueming Yang1,4, Zaiou Zhu1,2, Enshi Yan5, Wei Zhang1, Junbo Zhou6, Xu Ding1,2, Jie Liu1,2, Hongxia Zhu1,2, Jinhai Ye1,2, Yunong Wu1,2, Yang Zheng1,2✉, Xiaomeng Song1,2✉

1. Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
2. Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
3. Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, People's Republic of China.
4. Department of Stomatology, the Affiliated People's Hospital of Jiangsu University, Zhenjiang 21200, Jiangsu Province, China.
5. Department of Anesthesiology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
6. Department of Stomatology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu, People's Republic of China.

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Citation:
Song A, Wu Y, Chu W, Yang X, Zhu Z, Yan E, Zhang W, Zhou J, Ding X, Liu J, Zhu H, Ye J, Wu Y, Zheng Y, Song X. Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma. Int J Biol Sci 2021; 17(2):430-447. doi:10.7150/ijbs.54014. Available from https://www.ijbs.com/v17p0430.htm

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Abstract

MicroRNAs are major post-transcriptional regulators responsible for the development of human cancers, including OSCC. The specific role of miR-619-5p in OSCC, however, is rarely reported. Cisplatin is one of the mostly applied chemotherapy drugs of OSCC. Nevertheless, drug resistance of cisplatin following the initial chemotherapy largely restricts its clinical benefits, and the mechanism of cisplatin resistance is unclear. This study intends to explore the biological function of miR-619-5p in the development of cisplatin resistance in OSCC cell lines and a xenograft model, as well as the potential molecular mechanism. Our results showed that miR-619-5p was down-regulated in OSCC samples and cisplatin-resistant OSCC cells. Ectopically expressed miR-619-5p inhibited proliferative, migratory and invasive abilities of OSCC cisplatin-resistant cells. The putative target gene ATXN3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Importantly, ATXN3 was responsible for the regulatory effects of miR-619-5p on biological behaviors of cisplatin-resistant OSCC cells. Moreover, miR-619-5p mimics and ATXN3-siRNA significantly enhanced ATXN3 knockdown in both HN6/CDDPR and CAL27/CDDPR cells and inhibited expression of PI3K and AKT. In vivo evidences demonstrated that intratumoral injection of miR-619-5p agomir remarkably slowed down the growth of OSCC in xenograft mice. Collectively, microRNA-619-5p was the vital regulator for regulating cisplatin resistance of OSCC, which may be served as a potential therapeutic target.

Keywords: OSCC, miR-619-5p, cisplatin-resistance, ATXN3