miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN

Abstract

Abstract. MicroRNAs (miRNAs) are small non-coding RNAs, 8-23 nucleotides in length, which regulate gene expression at the post-transcriptional level. The present study was performed to analyze the association between microRNA-21 and cisplatin resistance in epithelial ovarian cancer (EOC) SKOV3 and SKOV3/DDP cells. In this experiment, the resistance of SKOV3 and SKOV3/DDP cells to cisplatin was evaluated using the MTT assay. Reverse transcription-quantitative polymerase chain reaction analysis was used to assess miRNA-21 levels and phosphatase and tensin homolog (PTEN) mRNA levels. Western blotting was used to assess PTEN protein levels. miRNA-21 mimics or inhibitors were transfected into SKOV3 and SKOV3/DDP cells. Prior to transfection, higher expression levels of miRNA-21 were observed in SKOV3/DDP cells compared with SKOV3 cells. Following transfection with miRNA-21 mimics, SKOV3 cells demonstrated increased sensitivity to cisplatin compared with negative control cells. Following transfection with the miRNA-21 inhibitor, SKOV3/DDP cells demonstrated decreased sensitivity to cisplatin compared with negative control cells. Furthermore, PTEN mRNA expression levels in SKOV3 cells transfected with miRNA-21 mimics was significantly lower compared with negative control cells. These results suggested that miRNA-21 may regulate cisplatin resistance by negatively targeting PTEN in EOC. IntroductionEpithelial ovarian cancer (EOC) is one of the most common malignant gynecologic tumors. Debulking surgery followed by a combination of platinum and taxane based chemotherapy are widely used treatments for EOC at present. Although overall survival rates have increased slightly over the past 25 years, 5-year survival remains <50% (1). The high mortality rate of ovarian cancer is due to late-stage diagnosis and resistance to platinum-based chemotherapy. However, the mechanisms underlying cisplatin resistance in EOC remain to be fully understood.MicroRNAs (miRNAs) are small non-coding RNAs of 8-23 nucleotides that post-transcriptionally regulate gene expression. Multiple previous reports have indicated that dysregulation of miRNA target genes promotes drug resistance, and inhibition of miRNAs may reverse drug resistance (2,3). miRNA-21 is overexpressed in multiple types of cancer, and promotes the initiation of cancer, progression and drug-resistance (4-9). miRNA-21 impacts tumorigenesis by negatively regulating several targets. Phosphatase and tensin homolog (PTEN) is a tumor suppressor molecule. Inactivating mutations and deletions of the PTEN gene have been observed in multiple types of cancer. Notably, bioinformatics tools have demonstrated that the 3'-untranslated region of the PTEN gene harbors a putative binding site for miRNA-21 (10). miRNA-21 expression has been revealed to be markedly increased in ovarian cancer compared with benign ovarian tumor tissues (11). miRNA-21 expression was also demonstrated to be increased in drug-resistant ovarian cancer compared with drug-sensitive ovarian cancer serum. In the present study,...

Exosome mediated miR-155 delivery confers cisplatin chemoresistance in oral cancer cells via epithelial-mesenchymal transition

“…For example, miR-34a has been shown to be downregulated in 5-fluorouracil (5-FU) resistant colorectal cancer, and its restoration caused regaining of 5-FU sensitivity via its direct target, lactate dehydrogenase A [20]. In contrast, miR-21 was found to be overexpressed in multiple cancers and its overexpression mediated cisplatin resistance particularly, in ovarian cancer via PTEN down-regulation [21]. Likewise, overexpression of miR-140 in colorectal cancer has been associated with chemoresistance to methotrexate and 5-FU, an effect mediated in part due to HDAC4 suppression [22].…”

Role of MiR-205/PTEN in cisplatin-resistant esophageal squamous cell carcinoma

“…PTEN may also be the important anti-tumor factor in this cancer type. The cisplatin resistance-related effect of PTEN has been shown in previous studies in which PTEN inhibited the chemoresistance to cisplatin in epithelial ovarian cancer [17]. MiRNA-205mediated PTEN downregulation is the key factor in chemoresistance of non-small cell lung cancer [18].…”

Anticancer Activities of the Quinone-Methide Triterpenes Maytenin and 22-β-hydroxymaytenin Obtained from Cultivated Maytenus ilicifolia Roots Associated with Down-Regulation of miRNA-27a and miR-20a/miR-17-5p

“…Noteworthily, the most down regulated miRNA following treatment with QMTs in the cancer cell line was miR-21-5p. This miRNA is overexpressed in many human malignancies and it has been shown to enhance chemoresistance to cisplatin [32][33][34]. The effect of QMTs on this miRNA could be explored as a therapeutic target.…”