microRNA-200a-3p increases 5-fluorouracil resistance by regulating dual specificity phosphatase 6 expression

• Published in: Experimental & molecular medicine 2017-05, Vol.49 (5), p.e327-e327
• Main Authors: Lee, Heejin, Kim, Chongtae, Kang, Hoin, Tak, Hyosun, Ahn, Sojin, Yoon, Sungjoo Kim, Kuh, Hyo-Jeong, Kim, Wook, Lee, Eun Kyung
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 38/1; 38/77; 38/90; 5-Fluorouracil; 631/337/384/331; 96/31; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer; Cell Line, Tumor; Cell survival; Cisplatin; Cisplatin - pharmacology; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 6 - genetics; Dual Specificity Phosphatase 6 - metabolism; Ectopic expression; Fluorouracil - pharmacology; Growth rate; Hepatocellular carcinoma; Humans; Lentivirus; Liver cancer; Medical Biochemistry; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular Medicine; Original; original-article; Phosphatase; Retroviridae; Stem Cells; Survival
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/emm.2017.33

Acquisition of resistance to anti-cancer drugs is a significant obstacle to effective cancer treatment. Although several efforts have been made to overcome drug resistance in cancer cells, the detailed mechanisms have not been fully elucidated. Here, we investigated whether microRNAs (miRNAs) function as pivotal regulators in the acquisition of anti-cancer drug resistance to 5-fluorouracil (5-FU). A survey using a lentivirus library containing 572 precursor miRNAs revealed that five miRNAs promoted cell survival after 5-FU treatment in human hepatocellular carcinoma Hep3B cells. Among the five different clones, the clone expressing miR-200a-3p (Hep3B-miR-200a-3p) was further characterized as a 5-FU-resistant cell line. The cell viability and growth rate of Hep3B-miR-200a-3p cells were higher than those of control cells after 5-FU treatment. Ectopic expression of a miR-200a-3p mimic increased, while inhibition of miR-200a-3p downregulated, cell viability in response to 5-FU, doxorubicin, and CDDP (cisplatin). We also showed that dual-specificity phosphatase 6 (DUSP6) is a novel target of miR-200a-3p and regulates resistance to 5-FU. Ectopic expression of DUSP6 mitigated the pro-survival effects of miR-200a-3p. Taken together, these results lead us to propose that miR-200a-3p enhances anti-cancer drug resistance by decreasing DUSP6 expression. Cancer therapy: A mechanism of drug resistance A small RNA molecule that increases resistance to a key anti-cancer drug may be a viable target for tackling drug resistance. Multi-drug resistance is becoming a major barrier to successful chemotherapy, but the precise mechanisms involved are unclear. Eun Kyung Lee at the Catholic University of Korea in Seoul and co-workers investigated whether small non-coding molecules called microRNAs play a role enhancing resistance to 5-fluorouracil (5-FU), a leading anti-cancer drug. The team added 572 different microRNAs to human liver cancer cells and found that one in particular, miR-200a-3p, increased cancer cell survival following treatment with 5-FU. Further study showed that miR-200a-3p achieved this by reducing the levels of a protein known to play a key role in regulating cancer development. The discovery could lead to novel therapies to combat drug resistance.