MicroRNA-195 inhibits cell proliferation, migration and invasion by targeting defective in cullin neddylation 1 domain containing 1 in cervical cancer

摘要

MicroRNAs (miRs), a class of small non-coding RNAs, have been demonstrated to perform promoting or suppressive roles in various types of human malignancy. Deregulation of miR-195 has been observed in numerous types of human cancer, including cervical cancer; however, the detailed molecular mechanism of miR-195 underlying the malignant progression of cervical cancer remains largely unclear. In the present study, miR-195 was significantly down-regulated in cervical cancer tissue samples compared with adjacent non-tumor tissue samples, and the reduced expression level of miR-195 was associated with node metastasis and an advanced clinical stage in cervical cancer. Furthermore, the patients with low miR-195 expression levels demonstrated shorter survival times when compared with those with high miR-195 expression levels. In vitro experiments indicated that miR-195 exerted suppressive effects on the proliferation, migration and invasion of cervical cancer cells. Luciferase reporter gene assay identified defective in cullin neddylation 1 domain containing 1 (DCUN1D1) as a novel target gene of miR-195 and the expression level of DCUN1D1 was identified to be negatively regulated by miR-195 in cervical cancer cells. DCUN1D1 was significantly upregulated in cervical cancer, with a negative correlation to miR-195 expression. Furthermore, upregulation of DCUN1D1 was associated with the malignant progression and poor prognosis of cervical cancer. DCUN1D1 overexpression attenuated the suppressive effects of miR-195 on the malignant phenotypes of cervical cancer cells. Notably, the expression levels of miR-195 were significantly lower in HeLa [human papilloma virus (HPV)18(+)] and SiHa (HPV16(+)) cells compared with those in C33A (HPV-) cells, and knockdown of E6 using small interfering RNA significantly increased the miR-195 expression while the DCUN1D1 expression level was reduced in HeLa and SiHa cells. Thus, these findings indicate that miR-195 exerts a suppressive role in cervical cancer by targeting DCUN1D1. Therefore, miR-195 may present as a potential therapeutic candidate for cervical cancer.