Abstract
Dysregulation of miR-488 has been implicated in several human cancers. In this study, we aim to explore its expression and biological function in ovarian cancers. We found miR-488 expression was downregulated in ovarian cancer tissues. Using CCK8 and colony formation assay showed that miR-488 inhibited SKOV3 cell proliferation and colony formation, with downregulation of cyclin D1 and cyclin E protein. While miR-488 inhibitor promoted OVCAR3 cell growth and colony formation. Cell viability and Annexin V/PI staining showed that miR-488 downregulated cell survival and increased apoptosis rate when treated with cisplatin and paclitaxel. Further experiments using MitoTracker and JC-1 staining indicated that miR-488 regulated mitochondrial fission/fusion balance and inhibited mitochondrial membrane potential, with p-Drp1, Drp1 and Fis1 downregulation. Luciferase reporter assay showed that Six1 is a target of miR-488. We also found a negative association between Six1 and miR-488 in ovarian cancer tissues. In addition, Six1 overexpression induced mitochondrial fission and increased mitochondrial potential, with upregulation of Drp1 signaling. Six1 depletion showed the opposite effects. Restoration of Six1 in SKOV3 cells rescued decreased p-Drp1 and Drp1 expression induced by miR-488 mimic. Six1 plasmid also reversed the effects of miR-488 on chemoresistance and apoptosis. Taken together, the present study showed that, by targeting Six1, miR-488 inhibits chemoresistance of ovarian cancer cells through regulation of mitochondrial function.
Highlights
Ovarian cancer is one of the leading cause of death in women worldwide [1, 2]
Dysregulation of microRNA contributes to ovarian carcinogenesis and malignant progression [7,8,9,10]. miR488 participates in the process of several human diseases www.impactjournals.com/oncotarget such as peritoneal fibrosis and panic disorder [11, 12]. miR-488 dysregulation is involved in carcinogenesis. miR-488 inhibits proliferation and induces apoptosis by targeting androgen receptor in prostate cancer [13]. miR488 targets ZIP8 in osteoarthritis which reduced cartilage degradation [14]. miR-488 is downregulated in gastric cancers and functions as a tumor suppressor by targeting PAX6 expression [15]
Real-time PCR was used to examine the expression of miR-488 in three ovarian cancer cell lines including SW626, SKOV3 and OVCAR3
Summary
Ovarian cancer is one of the leading cause of death in women worldwide [1, 2]. Despite recent advances of combined therapies including surgery and chemotherapies, the prognosis of advanced stage ovarian cancers remains poor. The molecular mechanisms involved in ovarian carcinogenesis and chemoresistance are poorly defined, which limits the efficiency of clinical treatment. Identifying molecular targets which are responsible for ovarian cancer progression and drug resistance is crucial for the development of novel diagnostic and therapeutic strategies [3, 4]. MicroRNAs (miRNA) exert their biological function through post-transcriptional downregulation of target genes [5, 6]. Dysregulation of microRNA contributes to ovarian carcinogenesis and malignant progression [7,8,9,10]. MiR-488 is downregulated in gastric cancers and functions as a tumor suppressor by targeting PAX6 expression [15]. Clinical significance of miR488 and its biological function in ovarian cancers have not been explored
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