Role of Has-miR-141 as a therapeutic target and predictive biomarker for ovarian cancer

Abstract

Although recent advances have improved the treatment of ovarian cancer, this disease is still the most deadly of female malignancies worldwide. The poor prognosis and late diagnosis of ovarian cancer are the primary causes of its high mortality rate. Therefore, understanding the molecular mechanisms of this disease may assist in the development of “targeted” oncologic therapies and the identification of reliable biomarkers to improve the curative rate of this disease. Anoikis resistance is a fundamental feature of metastatic cancer cells, allowing for their survival during cancer invasion and dissemination. Emerging evidence indicates that deregulation of miRNAs has been associated with different aspects of tumorigenesis. Using miRCURY™ LNA Array profiling analysis, we identified the Has-miR-141 (miR-141) as a highly expressed miRNA in ovarian cancer cells with increased capacities in anchorage-independence, anoikis resistance, tumor growth and metastatic colonization in a xenograft mouse model. Further studies demonstrated that a tumor suppressor, Krüppel-related zinc finger protein AP-2rep (KLF12), is a direct target of miR-141. In contrast to miR-141, KLF12 inhibits colony formation and the cell growth potential of ovarian cancer cells exposed to metabolic stress, whereas the depletion of KLF12 augments the anchorage independence of ovarian cancer cells through the upregulation of survival-associated factors. Clinical study revealed the upregulated miR-141 was significantly associated with the advanced and distant metastatic ovarian cancers accompanied with downregulated KLF12. On the other hand, miR-141 was found to be a secretary miRNA and detected in the serum of ovarian cancer patients. Subsequent analysis showed that the circulating miR-141 was correlated to the levels of CA125. Importantly, the serum miR-141 level was significantly correlated with the tumor burden of patients in pre- and post-neoadjuvant chemotherapy. Taken together, miR-141 may play a role in oncogene-enhancing anoikis resistance in ovarian cancer cells through the downregulation of KLF12 and may be used as a non-invasive biomarker for diagnosis and treatment outcome of ovarian cancer.