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.

• Authors: M T M van Jaarsveld, J Helleman, A W M Boersma, P F van Kuijk, W F van Ijcken, E Despierre, I Vergote, R H J Mathijssen, E M J J Berns, J Verweij, J Pothof, E A C Wiemer
• Journal: Oncogene (Oncogene) Vol. 32 Issue 36 Pg. 4284-93 (Sep 05 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 23045278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Intracellular Signaling Peptides and Proteins
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• MIRN141 microRNA, human
• MIRN200 microRNA, human
• MicroRNAs
• NF-kappa B
• Cisplatin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Cluster Analysis
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Kelch-Like ECH-Associated Protein 1
• MicroRNAs (genetics)
• Middle Aged
• NF-kappa B (metabolism)
• Neoplasm Grading
• Neoplasm Staging
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Signal Transduction