J Cancer 2020; 11(11):3375-3386. doi:10.7150/jca.40339

Research Paper

miR-488-3p sponged by circ-0000495 and mediated upregulation of TROP2 in head and neck squamous cell carcinoma development

Yanru Hao, Dejun Zhang, Yingyuan Guo, Zeming Fu, Duojiao Yu, Guofang Guan

Department of Otolaryngology, Head and Neck Surgery, The Second Hospital of Jilin University, Changchun 130041, P. R. China

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Hao Y, Zhang D, Guo Y, Fu Z, Yu D, Guan G. miR-488-3p sponged by circ-0000495 and mediated upregulation of TROP2 in head and neck squamous cell carcinoma development. J Cancer 2020; 11(11):3375-3386. doi:10.7150/jca.40339. Available from http://www.jcancer.org/v11p3375.htm

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TROP2 (trophoblast cell surface antigen 2) overexpression has been reported in many human cancers. The correlation between TROP2 and tumor aggressiveness has implied it could be a prognostic indicator. However, the roles of TROP2 and their underlying mechanisms remain of great interest in head and neck squamous cell carcinoma (HNSCC) biology. In the current study, the prognostic significance of TROP2 in HNSCC archival samples was determined using immunohistochemistry. Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the phenotypic effects of TROP2 knockdown, miR-488-3p re-expression, and circRNAs expression. Cell viability, migration/invasion as well as in vivo tumor formation assays were accessed. The interactions of miRNAs-TROP2 or circRNAs-miRNAs were determined by qRT-PCR, western blot analysis and luciferase assays. TROP2 was demonstrated overexpression in HNSCC patients and cancer cell lines. High expression of TROP2 was significantly associated with patient relapse. TROP2 promoted tumor cell proliferation, migration, invasion, and tumor growth, through AKT and MAPK pathways. Further investigation revealed that TROP2 is a direct target of miR-488-3p, while circ-0000495 bounds to miR-488-3p. Our study unraveled a novel mechanism by which down-regulation of miR-488-3p sponged by circ-0000495 releases its epigenetic silencing to TROP2. The increased TROP2 promotes tumor proliferation, therefore, providing evidence in support of targeting the circ-0000495/miR-488-3p/TROP2 axis in contributing to HNSCC therapy and preventing tumor metastasis.

Keywords: TROP2, prognostic marker, microRNA, circular RNA, head and neck squamous cell carcinoma