Abstract
Ovarian cancer (OVCa) stem cells are associated with tumor growth, metastasis, and recurrence, which are driving forces behind a majority of the OVCa-related mortality. This subpopulation of cancer cells are characterized by uncontrolled proliferation, high invasiveness, and resistance against the current platinum-based therapy. Thus, targeting OVCa cancer stem cells has been focused in recent therapeutic development. Isolation and purification of cancer stem cells are, however, challenging for the lack of sensitive and specific markers. In this study, we demonstrated that miR-551b was upregulated in OVCa stem cells, by using a quantitative PCR array, correlating with the pathological grades of this malignancy. In vitro experiments indicated that miR-551b promoted the proliferation, invasion, and chemoresistance of OVCa cells and cancer stem cells. Further analysis suggested that miR-551b functioned through the suppression of Foxo3 and TRIM31, two important tumor suppressors. In support of this, our in vivo experiments using mouse xenograft models showed that inhibiting miR-551b significantly increased the susceptibility of OVCa cells to cisplatin and prolonged the survival of the host mice. In conclusion, our study suggested miR-551b as a potential biomarker for OVCa stem cells and explored its functional mechanism, providing a potential therapeutic target for future drug development.Electronic supplementary materialThe online version of this article (doi:10.1007/s12032-016-0842-9) contains supplementary material, which is available to authorized users.
Highlights
Ovarian cancer (OVCa) is the most common and one of the most lethal gynecological malignancies in the world [1]
The 24-well plate was fit with inserts, which were sealed with 8-lm membranes at the bottom, and the inserts were pre-coated with Matrigel
Cells were serum starved for 24 h and added into the top chamber at 1 9 104 cells in 100 ll serum free medium, while 600 ll medium with 1 % fetal bovine serum (FBS) was added to the bottom
Summary
Ovarian cancer (OVCa) is the most common and one of the most lethal gynecological malignancies in the world [1]. Cancer stem cells (CSCs) comprise of a small number of cells with stem cell features among the highly heterogeneous mixture of various populations of cells in tumor. CSCs play a crucial role in maintaining tumor heterogeneity and promoting cancer cell growth and metastasis [7, 8] They are generally less susceptible to chemotherapeutic drugs and likely the re-initiator of the recurrent cancer [9, 10]. A few studies isolated a side population (SP) of cells based on their exclusion of Hoechst 33342 fluorescence These cells demonstrate extensive features of CSCs with respect to their proliferation, tumorigenicity, migration, and chemoresistance, suggesting that they can be ideal subjects in CSC studies [19]. We isolated SP cells from a primary OVCa cell line established from OVCa patient ascites and characterized their self-renewal, differentiation, and tumorigenicity [22]
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