MicroRNA-150 Predicts a Favorable Prognosis in Patients with Epithelial Ovarian Cancer, and Inhibits Cell Invasion and Metastasis by Suppressing Transcriptional Repressor ZEB1

Abstract

MicroRNA (miR)-150 has been reported to be dramatically downregulated in human epithelial ovarian cancer (EOC) tissues and patients’ serum compared to normal controls. This study aimed to investigate clinical significance and molecular mechanisms of miR-150 in EOC. In the current study, quantitative real-time PCR analysis showed that miR-150 was significantly downregulated in human EOC tissues compared to normal tissue samples. Then, we demonstrated the significant associations of miR-150 downregulation with aggressive clinicopathological features of EOC patients, including high clinical stage and pathological grade, and shorter overall and progression-free survivals. More importantly, the multivariate analysis identified miR-150 expression as an independent prognostic biomarker in EOC. After that, luciferase reporter assays demonstrated that Zinc Finger E-Box Binding Homeobox 1 (ZEB1), a crucial regulator of epithelial-to-mesenchymal transition (EMT), was a direct target of miR-150 in EOC cells. Moreover, we found that the ectopic expression of miR-150 could efficiently inhibit cell proliferation, invasion and metastasis by suppressing the expression of ZEB1. Furthermore, we also observed a significantly negative correlation between miR-150 and ZEB1 mRNA expression in EOC tissues (rs = –0.45, P<0.001). In conclusion, these findings offer the convincing evidence that aberrant expression of miR-150 may play a role in tumor progression and prognosis in patients with EOC. Moreover, our data reveal that miR-150 may function as a tumor suppressor and modulate EOC cell proliferation, and invasion by directly and negatively regulating ZEB1, implying the re-expression of miR-150 might be a potential therapeutic strategy for EOC.

ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2

“…Downregulation of ZEB1 has been found to inhibit EMT of ovarian cancer cells [12]. ZEB1 also acts as the target of miRs, mediating the inhibitory effect on EMT of ovarian cancer cells [8, 10, 14]. Dysregulation of ZEB1 is also involved in emodin-induced inhibition of EMT in epithelial ovarian cancer cells [13].…”

MicroRNA-150 functions as an antioncogenic regulator in osteosarcoma

“…Several studies have indicated that miRNAs contribute to various physiological and pathological processes, and participate in the initiation and progression of cancer (20,21). Numerous studies have demonstrated that miR-150 is downregulated in certain types of human cancer, including pancreatic cancer (22), esophageal squamous cell carcinoma (23), colorectal cancer (24), hepatocellular carcinoma (25), ovarian cancer (26) and malignant lymphoma (27). However, miR-150 was also reported to be upregulated in prostate (28), non-small cell lung (29), breast (30) and gastric cancer (31).…”

MiR-205 promotes motility of ovarian cancer cells via targeting ZEB1

“…Since elucidating the underlying mechanisms of metastasis occurred during the progression of EOC will make significant contributions toward combating this disease, a number of studies have identified several crucial regulators in the EMT, such as miR-125a, the miR-200 family of microRNAs (miR-141, miR-200a, b, c, and miR-429), miR-34, miR-205, zinc finger E-box binding homeobox 1 (ZEB1) and zinc finger E-box binding homeobox 2 (ZEB2) [11][12][13][14][15]. Especially, the plasma miR-205 has been indicated as a biomarker for ovarian cancer detection that complement CA-125, and the upregulation of miR-205 has also been reported to promote the invasion and proliferation of ovarian cancer cells [16]; ZEB1 has been identified as an activator of EMT in EOC cells [17], and the regulatory effect of miR-205 on ZEB1 expression has been confirmed based on various cancer cells, including breast cancer cells and papillary urothelial tumors of the urinary bladder [18,19]. In the current study, to investigate the clinical significance of miR-205 and ZEB1 in human EOC and to clarify the underlying mechanisms by which they are involved into tumorigenic processes of this disease, quantitative real-time PCR was performed to detect the expression levels of miR-205 and ZEB1 mRNA in human EOC tissues, and statistical analysis was used to evaluate their associations with clinicopathological features of EOC patients; Then, luciferase reporter assay was used to confirm target associations between miR-205 and ZEB1; After that, the functions of miR-205-ZEB1 axis on cell migration and invasion were further determined by transwell assay in vitro.…”