miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells

Abstract

Epithelial ovarian cancer is the most lethal gynecological malignancy in the Western world. A major impediment for the successful treatment is the development of drug resistance. The molecular processes that contribute to resistance have been extensively studied; however, there is not much known about regulation by microRNAs (miRNAs). We compared miRNA expression profiles of an isogenic cisplatin-sensitive and -resistant ovarian cancer cell line pair (A2780/A2780 DDP) and found 27 miRNAs to be differentially expressed (2-fold). Five of these, including the family members miR-141/200c, showed a correlation with cisplatin sensitivity in the NCI-60 panel. Overexpression of miR-141 resulted in enhanced resistance to cisplatin in ovarian cancer cell lines. We next correlated the expression level of miR-141 in 132 primary ovarian tumors (108 serous and 24 non-serous) with response to platinum-based chemotherapy. Although no differences were observed in the serous tumors, miR-141 levels were higher in non-serous ovarian tumors that did not respond well to therapy (platinum-free interval <6 months). We demonstrate that miR-141 directly targets KEAP1, and that downregulation of KEAP1 induces cisplatin resistance. Conversely, overexpression of KEAP1 significantly enhanced cisplatin sensitivity. Expression of KEAP1 with its 3'-UTR, and a 3'-UTR in which the miR-141 target site has been mutated, revealed that miR-141 regulates KEAP1 upon exposure to cisplatin. Finally, we show that the NF-κB pathway, which can be regulated by KEAP1, is activated upon miR-141 overexpression, and that inhibition of this pathway partially reverses miR-141-mediated cisplatin resistance. These findings demonstrate that the miR-141-mediated regulation of KEAP1 has a crucial role in the cellular response to cisplatin.

Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer

“…Recently, miRNAs have been identified as oncogenes or tumor suppressors and play a role in drug resistance. 12,13 For instance, miR-141 enhances cisplatin resistance through repressing KEAP1 in ovarian cancer cells, 14 and miR-106a induces multidrug resistance by targeting RUNX3 in gastric cancer. 15 On the contrary, miR-200b and miR-15b reverse chemotherapy induced epithelial-mesenchymal transition (EMT) in human tongue cancer cells by targeting BMI1.…”

miR-141 confers docetaxel chemoresistance of breast cancer cells via regulation of EIF4E expression

“…Recently, a study showed that downregulated miR-141 may confer cisplatin resistance in esophageal squamous cell carcinoma (19). Moreover, miR-141 modulates cisplatin sensivitity in ovarian cancer cells (20 The present study is the first to report that increased miR-141 expression was associated with acquired docetaxel resistance in vitro and changes in miR-141 expression modulated response to docetaxel in BC cells, at least in part by targeting the eukaryotic translation initiation factor 4E (EIF4E). Furthermore, we showed that suppression of miR-141 or EIF4E significantly promoted or reduced docetaxel induced apoptosis, respectively.…”

“…Equally important, Imanaka et al highlighted an important regulatory role for miR-141 in the development of cisplatin resistance in esophageal squamous cell carcinoma (19). Furthermore, the miR-141-mediated regulation of kEAP1 has a crucial role in the cellular response to cisplatin in ovarian cancer cells (20). Moreover, the downregulated miR-141 was involved in Helicobacter pylori-modulated cisplatin sensitivity in gastric cancer (29).…”

“…van Jaarsveld et al, stressed that miR-141 is an oncogene that can enhance anoikis resistance in ovarian cancer cells through downregulation of kLF12. Indeed, the known targets of miR-141, kEAP1 and kLF12 played an important role in regulating drug-resistance and cancer development (20).…”

Non-Coding RNAs Mediate Chemotherapy Resistance in Ovarian Cancer

“…High ALDH1 expression was associated with chemoresistance in in vitro and ex vivo samples [26]. Besides, miR-200 family [27][28][29][30], miR-199/214 cluster [31][32][33][34][35], miR-31 [36] et al, are also reported to be connected with chemotherapy resistance, including cisplatin and pactitaxel (Table 1). [25] miR-591 ZEB1 Paclitaxel resistance [25] miR-23b ALDH1 Chemoresistance [26] miR-27a ALDH1 Chemoresistance [26] miR-27b ALDH1 Chemoresistance [26] miR-346 ALDH1 Chemoresistance [26] miR-424 ALDH1 Chemoresistance [26] miR-503 ALDH1 Chemoresistance [26] miR-200 family…”