MiR-297 modulate multidrug resistance in human colorectal carcinoma by down-regulating MRP-2
State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, PR China. Biochemical Journal
(Impact Factor: 4.4).
06/2012; 446(2):291-300. DOI: 10.1042/BJ20120386
Colorectal carcinoma is a frequent cause of cancer-related death in men and women. miRNAs (microRNAs) are endogenous small non-coding RNAs that regulate gene expression negatively at the post-transcriptional level. In the present study we investigated the possible role of microRNAs in the development of MDR (multidrug resistance) in colorectal carcinoma cells. We analysed miRNA expression levels between MDR colorectal carcinoma cell line HCT116/L-OHP cells and their parent cell line HCT116 using a miRNA microarray. miR-297 showed lower expression in HCT116/L-OHP cells compared with its parental cells. MRP-2 (MDR-associated protein 2) is an important MDR protein in platinum-drug-resistance cells and is a predicted target of miR-297. Additionally miR-297 was down-regulated in a panel of human colorectal carcinoma tissues and negatively correlated with expression levels of MRP-2. Furthermore, we found that ectopic expression of miR-297 in MDR colorectal carcinoma cells reduced MRP-2 protein level and sensitized these cells to anti-cancer drugs in vitro and in vivo. Taken together, our findings suggest that miR-297 could play a role in the development of MDR in colorectal carcinoma cells, at least in part by modulation of MRP-2.
Available from: PubMed Central
- "ABCC2 can recognize GSH-conjugated form of Pt drugs and effectively pump them out of the cells to confer resistance. To date, only miR-297 has been reported to be down-regulated in a oxaliplatin-resistant colon cancer cell model (HCT116/L-OHP) to cause ABCC2 overexpression and Pt drug resistance . A complementary binding site for miR-297 was identified on ABCC2 3′UTR to mediate the specific gene repression. "
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ABSTRACT: Multidrug resistance (MDR) is a major obstacle to successful cancer treatment. It is often associated with an increased efflux of a variety of structurally unrelated anticancer drugs by ATP-binding cassette (ABC) transporters including P-gp, ABCG2 and MRP1. MicroRNAs (miRNAs) are small non-coding RNAs that govern posttranscriptional regulation of target genes by interacting with specific sequences in their 3[prime] untranslated region (3[prime]UTR), thereby promoting mRNA degradation or suppressing translation. Accumulating evidence suggests that alterations in miRNAs contribute to resistance to anticancer drugs. While miRNAs are well-known to be dysregulated in cancer, recent literature revealed that miRNA levels in biological samples may be correlated with chemotherapy response. This review summarized the coordinated network by which miRNA regulated MDR transporters. The usefulness of miRNAs as prognostic biomarkers for predicting chemotherapeutic outcome is discussed. MiRNAs may also represent druggable targets for circumvention of MDR.
Journal of Biomedical Science 12/2013; 20(1):99. DOI:10.1186/1423-0127-20-99 · 2.76 Impact Factor
Available from: Nuzhat Ahmed
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ABSTRACT: Chemotherapy with platinum and taxanes is the first line of treatment for all epithelial ovarian cancer (EOC) patients after debulking surgery. Even though the treatment is initially effective in 80% of patients, recurrent cancer is inevitable in the vast majority of cases. Emerging evidence suggests that some tumor cells can survive chemotherapy by activating the self-renewal pathways resulting in tumor progression and clinical recurrence. These defined population of cells commonly termed as 'cancer stem cells' (CSC) may generate the bulk of the tumor by using differentiating pathways. These cells have been shown to be resistant to chemotherapy and, to have enhanced tumor initiating abilities, suggesting CSCs as potential targets for treatment. Recent studies have introduced a new paradigm in ovarian carcinogenesis which proposes in situ carcinoma at the fimbrial end of the fallopian tube to generate high-grade serous ovarian carcinomas, in contrast to ovarian cortical inclusion cysts (CIC) which produce borderline and low grade serous, mucinous, endometrioid and clear cell carcinomas. This review summarizes recent advances in our understanding of the cellular origin of EOC and the molecular mechanisms defining the basis of CSC in EOC progression and chemoresistance. Using a model ovarian cancer cell line we highlight the role of CSC in response to chemotherapy, and relate how CSCs may impact on chemoresistance and ultimately recurrence. We also propose the molecular targeting of CSCs and suggest ways that may improve the efficacy of current chemotherapeutic regimens needed for the management of this disease. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry 01/2013; 114(1). DOI:10.1002/jcb.24317 · 3.26 Impact Factor
Available from: sciencedirect.com
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ABSTRACT: Multidrug resistance (MDR) is the main barrier to the success of chemotherapy for gastric cancer (GC). miR-106a, which is highly expressed in GC, influences a variety of aspects of GC. However, the function of miR-106a in MDR of GC still remains unclear. In the present study, we found that miR-106a is elevated in MDR cell lines. miR-106a promotes chemo-resistance of GC cells, accelerates ADR efflux, and suppresses drug-induced apoptosis. Finally, we show that runt-related trans factor 3 (RUNX3) is the functional target of miR-106a. Collectively, these findings demonstrate that miR-106a may promote MDR in GC cells by targeting RUNX3.
FEBS letters 08/2013; 587(18). DOI:10.1016/j.febslet.2013.06.058 · 3.17 Impact Factor
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