MicroRNA-130a regulated by HPV18 E6 promotes proliferation and invasion of cervical cancer cells by targeting TIMP2

Exp Ther Med. 2019 Apr;17(4):2837-2846. doi: 10.3892/etm.2019.7226. Epub 2019 Jan 31.

Abstract

Human papillomaviruses (HPVs) have important roles in the development and progression of cervical cancer, but the underlying mechanisms are yet to be fully elucidated. MicroRNA-130a (miR-130a) has previously been reported to promote cervical cancer growth. However, the underlying molecular mechanisms by which miR-130a promotes cervical cancer progression have remained largely elusive. In the present study, polymerase chain reaction and western blot analyses were performed to examine the expression levels of miR-130a and associated proteins. A wound healing assay and a Transwell assay were applied to study cell migration and invasion. A luciferase reporter gene assay was performed to confirm the targeting associations of miR-130a. It was observed that miR-130a was significantly upregulated in cervical cancer tissues compared with that in adjacent non-tumorous tissues. High expression of miR-130a was significantly associated with lymph node metastasis and an advanced clinical stage of cervical cancer. Furthermore, the expression of miR-130a was also higher in HPV(+) cervical cancer cell lines compared with that in HPV(-) cells. Knockdown of HPV18 E6 significantly inhibited the expression of miR-130a in HeLa cervical cancer cells. Furthermore, knockdown of miR-130a reduced the migration and invasion of HeLa cells. Tissue inhibitor of metalloproteinase 2 (TIMP2), an antagonist of matrix metalloproteinase 2 (MMP2), was identified as a novel, direct target gene of miR-130a. The expression of TIMP2 was negatively mediated by miR-130a, and HPV18 E6 inhibited the expression of TIMP2 in HeLa cells. Furthermore, knockdown of TIMP2 rescued the suppressive effects of miR-130a downregulation on the migration and invasion of HeLa cells. In summary, the present study suggests that HPV18 E6 promotes the expression of miR-130a, which further inhibits the expression of TIMP2 and promotes cervical cancer cell invasion. Therefore, HPV/miR-130a/TIMP2 signaling may be a potential target for the prevention of cervical cancer metastasis.

Keywords: cervical cancer; invasion; microRNA; migration; tissue inhibitor of metalloproteinase 2.

Publication types

  • Retracted Publication