MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2) (PNAS, 2010, 107:21098-21103)

報告日期: 2011/03/04
報告時間: 17:10/18:00
報告學生: 吳長霖 (英文報告)
講評老師: 陳玉玲

Full Text: http://basicmed.med.ncku.edu.tw/admin/up_img/0304-3.pdf

MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)
Nicola Valeri, Pierluigi Gasparini, Chiara Braconib, Alessio Paone, Francesca Lovat, Muller Fabbri, Khlea M. Sumani, Hansjuerg Alder, Dino Amadorie, Tushar Patel, Gerard J. Nuovo, Richard Fishel, and Carlo M. Croce
Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21098-103.
Speaker: Wu, Chang-Lin
Commentator: Chen, Yuh-Ling, Ph.D.
Date: 2011/03/04
Place: Room 602, College of medicine
Background  In the U.S., colorectal cancer (CRC) is the most common cancer type, and about 51,370 was estimated to have died from colorectal cancer in 2010 according to the American Cancer Society. 5-fluorouracil (5-FU) is a pyrimidine analog and has been utilized in cancer chemotherapy for CRC treatment both in the adjuvant and metastatic setting. However,primary or acquired resistance to pyrimidine analog treatment is still a common problem during 5-FU-base chemotherapy.
        MicroRNA 21 (miR-21) has been found to overexpress in various cancers including CRC. It is also known that miR-21 can regulate the expression of tumor suppressor genes including p21, and TGFβ receptor II. A recent report shown that overexpression of miR-21 is associated with poor benefit from 5-FU adjuvant chemotherapy in stage-II and -III CRC. In addition to miR-21, it has been report DNA mismatch repair (MMR) system status can affect the benefit of 5-FU in CRC patient during chemotherapy. 5-FU metabolites can incorporate into DNA and MMR can recognize and bind DNA containing 5-FU cause cell cycle G2/M phase arrest, further lead to apoptosis. Indicating that defects in MMR is also associated with 5-FU-resistance during chemotherapy. No evidence had defined whether miR-21 can regulate MMR components expression. In this article, authors suggested that miR-21-linked 5-FU resistance is affect by regulate MMR components expression in CRC.
Objective To demonstrate that miR-21 targets and down-regulates the core mismatch repair (MMR) recognition protein complex, human mutS homolog2 (hMSH2) and 6 (hMSH6).
ResultsFirst, the authors predict miR-21 target in MMR components via in silico analysis. They found bothhMSH2 and hMSH6 mRNA 3’ UTR have miR-21 binding sequences. Based on western blotting and 3’ UTR regulation analysis, they suggested miR-21 exerts a direct effect on the hMSH2 and hMSH6 3’ UTR that ultimately regulates hMSH2 and hMSH6 protein expression. Moreover, authors found miR-21 is inversely correlated with hMSH2 expression in CRC tissue sample. Compare to normal tissue, CRC tissue have higher miR-21 and lower hMSH2 expressions.
        Then, the authors demonstrated that miR-21 overexpression decreased the percentage of sub-G1 (apoptosis) and G2/M cells following treatment with 5-FU. Cells transfected with miR-21 displayed reduced G2/M arrest and apoptosis, similar to cells transfected with siRNA to hMSH2. Not only in vitro, but in xenograft model, miR-21 overexpression tumor is resistant to 5-FU and similar to hMSH2 knock down tumor.
Conclusion Theauthors have correlated 5-FU drug resistance in colorectal tumors to the overexpression of miR-21 that directly down-regulates the core MMR proteins hMSH2 and hMSH6, ultimately leading to a defect in damage-induced G2/M arrest and apoptosis.
Valeri N, et al. (2010) Modulation of mismatch repair and genomic stability by miR-155. PNAS USA107:6982–6987.