MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

Abstract

Background Ovarian cancer (OC) is a life-threatening gynecological malignancy where dysregulation of microRNAs (miRNAs) is frequently implicated. This study focuses on the function of miR-545 on OC development and the molecules involved. Methods miR-545 expression in OC tissues and cell lines was determined, and its link to the survival of patients was analyzed. Altered expression of miR-545 was induced to determine its role in proliferation, apoptosis, migration and invasion of OC cells and the angiogenesis ability of human umbilical vein endothelial cells (HUVECs). The targeting mRNAs of miR-545 were predicted and validated through luciferase assays. Gain-of-function studies of KDM4B and PLK1 were performed to explore their involvements in OC development. In vivo experiments were conducted by inducing xenograft tumors in nude mice. Results Poor expression of miR-545 was found in OC tissues and cells compared to the normal ones and it indicated unfavorable prognosis in patients. Overexpression of miR-545 suppressed growth, migration, invasion and angiogenesis of OC cells as well as the angiogenesis ability of HUVECs. miR-545 was found to target mRNAs of KDM4B and PLK1, while KDM4B promoted the transcription of the PLK1 promoter through demethylation of H3K9me3. Either overexpression of KDM4B or PLK1 partially blocked the inhibitory effects of miR-545 mimic on OC cell growth, especially the former one. The in vitro results were reproduced in vivo. Conclusion This study evidenced that miR-545 suppresses progression of OC through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation.

MicroRNA‑545‑5p regulates apoptosis, migration and invasion of osteosarcoma by targeting dimethyladenosine transferase 1

“…The results of the present study demonstrated that miR-545-5p has antiproliferative and proapoptotic roles in osteosarcoma. Notably, miR-545-5p target several downstream targets in multiple signaling pathways that might serve critical roles in tumorigenesis and development, such as murine double minute 2, polo-like kinase 1 and δ-anubikevulinic acid dehydratase, suggesting that miR-545-5p functions as a major switch for a series of cellular processes (21,32,33). In the present study, activating miR-545-5p alone inhibited cancer growth by regulating the expression of DIMT1.…”

MicroRNAs in the Regulation of RIG-I-like Receptor Signaling Pathway: Possible Strategy for Viral Infection and Cancer

“…MicroRNAs have been established to modulate tumor progression through the regulation of RLR signaling. Notably, microRNA-545 has been demonstrated to exert significant effects in various cancers, including breast cancer [ 130 ], bladder cancer [ 131 ], ovarian cancer [ 132 ], cervical cancer [ 133 ], and other malignancies [ 134 , 135 , 136 ]. However, further investigation demonstrated that the overexpression or knockdown of miR-545 could promote or inhibit cancer cell proliferation by targeting RIG-I [ 137 , 138 , 139 ].…”

“…MicroRNAs have been established to modulate tumor progression through the regulation of RLR signaling. Notably, microRNA-545 has been demonstrated to exert significant effects in various cancers, including breast cancer [130], bladder cancer [131], ovarian cancer [132], cervical cancer [? ]olecules-2562947, and other malignancies [134][135][136].…”

Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

“…High expression of PLK1 is reported to be associated with histological grade and clinical stage [ 143 ]. Elevated levels of PLK1 /PLK1 mRNA and protein account for ovarian cancer cell lines and tissue and promote growth and migration of cancer cells and diminish apoptosis [ 270 ]. Overexpression of PLK1 correlates positively with mitotic activity and is a prognostic factor in ovarian carcinoma linked to worse patient prognosis as judged from immunohistochemistry of several malignant epithelial subtypes [ 130 ].…”

“…miRNAs play important anti-oncogenic as well as oncogenic roles in the pathogenesis of ovarian cancer (for reviews see [ 280 , 281 ]). MiR-545 directly targets PLK1 mRNA and inhibits PLK1 expression in ovarian cancer thereby acting as a tumor suppressor as demonstrated in vitro and in vivo in a xenograft mouse model [ 270 ]. MiR-545 functions as a tumor suppressor and is lowly expressed in epithelial ovarian tissue whereas overexpression leads to inhibition of growth and increase in apoptosis [ 282 ].…”