MicroRNA-1251-5p Promotes Carcinogenesis and Autophagy via Targeting the Tumor Suppressor TBCC in Ovarian Cancer Cells

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Abstract

Accounting for more than 70% of ovarian cancer cases, epithelial ovarian malignancy has a low 5-year survival rate. MicroRNAs may be targeted in the clinical treatment of the disease. In this study, we first found that miR-1251-5p was significantly upregulated in human ovarian cancer cell lines and tissues with the cancer progression and stages. Overexpression or inhibition of miR-1251-5p promoted or impeded cell proliferation and cell cycle progression. Subsequently, TBCC, one of the tubulin-binding cofactors (TBCs), was identified as a target of miR-1251-5p to be negatively associated with cell cycle and autophagy. Exogenous overexpression of TBCC inhibited the expressions of CDK4 and LC3BII, but it promoted the expressions of α/β-tubulin and p62 to suppress cell growth and autophagy, particularly under the starving condition; whereas the introduction of miR-1251-5p in TBCC-overexpressing cells rescued the suppressive effects of TBCC on cell cycle and autophagy through the inverse regulation of the above proteins. Finally, miR-1251-5p was proven to enhance xenograft tumor growth through the downregulation of TBCC but upregulation of Ki67 and LC3B in xenograft tumor tissues. Collectively, these results suggest that miR-1251-5p functions as an oncogene to suppress TBCC and α/β-tubulin expression. Thus, the miR-1251-5p/TBCC/α/β-tubulin axis may be targeted for ovarian cancer treatment. This study demonstrated that miR-1251-5p was upregulated in ovarian cancer (OC) cell lines and closely related to OC recurrence and stages. Overexpression of miR-1251-5p promoted cell proliferation and cell cycle progression in OC cells. TBCC was proven to be a direct target of miR-1251-5p. Upregulation or downregulation of TBCC repressed or promoted cell proliferation, cell cycle progression, and autophagy, whereas miR-1251-5p inversely regulated these effects. miR-1251-5p could also drive tumor growth in vivo. Thus, our findings suggest that the miR-1251-5p/TBCC/α/β-tubulin axis may function as an oncogenic pathway to promote cell cycle and autophagy through the dysregulation of microtubular formation and folding.

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Shao, Y., Liu, X., Meng, J., Zhang, X., Ma, Z., & Yang, G. (2019). MicroRNA-1251-5p Promotes Carcinogenesis and Autophagy via Targeting the Tumor Suppressor TBCC in Ovarian Cancer Cells. Molecular Therapy, 27(9), 1653–1664. https://doi.org/10.1016/j.ymthe.2019.06.005

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