Has-miR-141/KLF12/Survivin is a crtical pathway required for enhancing anoikis resistance of advanced ovarian cancer

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. The high mortality of this cancer is attributed to metastatic progression. Therefore, understanding the molecular mechanisms of related metastases may assist in the development of “targeted” oncologic therapies to improve the cure rate of 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. Here, we report that Hsa-miR-141 (miR-141) is upregulated and significantly associated with the advanced and distant metastatic serous ovarian cancers. Mechanistic studies demonstrated that Krüppel-related zinc finger protein AP-2rep (KLF12) is the direct downstream target of miR-141. Functionally, 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. Knockdown of Survivin is similar to the effect of miR-141 suppression in reducing anokis resistance of ovarian cancer cells. These findings suggest that miR-141/KLF12/survivin signaling axis plays a critical role in mediating anoikis resistance of ovarian cancer cells and targeting this pathway may inhibit metastatic colonization of this cancer.