Has-miR-141 plays a crucial role in ovarian cancer metastatic progression

Abstract

Epithelial ovarian cancer is the most lethal gynecologic malignancy worldwide. This disease is generally called the “silent killer” because there are no symptoms and thus, the majority of patients are found in advanced stages accompanied by extensive metastasis. Most deaths from this cancer are attributed to metastatic progression. Therefore, understanding the molecular mechanisms of related metastases may assist in the development of “targeted” oncologic therapies to this disease. The cancer metastasis is determined by the priming of metastatic niche and the intrinsic properties of cancer cells to adapt the microenvironemntal stresses. However, the associated molecular mechanisms remain unclear. Anoikis resistance is a fundamental feature of metastatic cancer cells, allowing for their survival during metastatic cancer progression. Emerging evidence has documented that deregulation of miRNAs is strongly involved in cancer metastases. In this tudy, we have identified Hsa-miR-141 (miR-141) is highly expressed in advanced serous subtype ovarian cancers. The overexpressed miR-141 could enhance cell survival of ovarian cancer cells against anoikis by targeting Krüppel-related zinc finger protein AP-2rep (KLF12). Restoration of KLF12 in miR-141-expressing cells remarkably reduced, or knockdown of KLF12 similar to miR-141 overexpression augmented, anoikis resistance of ovarian cancer cells through alteration of survival-associated factor, survivin. Luciferase reporter assay using survivin promoter luciferase plasmid (luc-survivin) indicated that survivin could be transcriptionally inhibited by KLF12. On the other aspect, we also found that miR-141 could be secreted from ovarian cancer cells and taken up by hFF-1 fibroblast cells. Ovarian cancer cells cultured in miR-141-expressing fibroblast cell medium displayed increased cell growth and cell migration in the presence of GRO and EMMPRIN chemokines. Taken together, these data suggest that miR-141 not only plays a key role in altering cancer cell plasticity against anoikis but also be able to reprogram stroma to be a pre-metastatic niche facilitating the ovarian cancer metastatic colonization.