Alterations of microRNAs and their targets are associated with acquired resistance of MCF‐7 breast cancer cells to cisplatin

Abstract

Cancer cells that develop resistance to chemotherapeutic agents are a major clinical obstacle in the successful treatment of breast cancer. Acquired cancer chemoresistance is a multifactorial phenomenon, involving various mechanisms and processes. Recent studies suggest that chemoresistance may be linked to drug-induced dysregulation of microRNA function. Furthermore, mounting evidence indicates the existence of similarities between drug-resistant and metastatic cancer cells in terms of resistance to apoptosis and enhanced invasiveness. We studied the role of miRNA alterations in the acquisition of cisplatin-resistant phenotype in MCF-7 human breast adenocarcinoma cells. We identified a total of 103 miRNAs that were overexpressed or underexpressed (46 upregulated and 57 downregulated) in MCF-7 cells resistant to cisplatin. These differentially expressed miRNAs are involved in the control of cell signaling, cell survival, DNA methylation and invasiveness. The most significantly dysregulated miRNAs were miR146a, miR-10a, miR-221/222, miR-345, miR-200b and miR-200c. Furthermore, we demonstrated that miR-345 and miR-7 target the human multidrug resistance-associated protein 1. These results suggest that dysregulated miRNA expression may underlie the abnormal functioning of critical cellular processes associated with the cisplatin-resistant phenotype.Breast cancer is the most common malignancy in women. In the United States, the incidence of invasive breast cancer, the most serious form of breast cancer, was estimated as 182,460 new cases and 40,480 deaths in 2008.1

miR-181a modulates acute myeloid leukemia susceptibility to natural killer cells

“…Our findings further indicate that inhibition of miR-181a in leukemia cells impacted their susceptibility to NKmediated lysis. Although emerging studies indicate the potential involvement of miR-146a in cell proliferation and drug resistance, 44,45 blocking miR-146a in our experimental model had no effect on NK-cell mediated lysis. Therefore, we hypothesized that miR-146a is involved in the molecular mechanisms that contribute to drug resistance but not to resistance to NK-mediated lysis.…”

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

“…The exact role for the FOXP3-induced miRs identified in our study in normal and cancerous epithelial cells is yet to be determined, as each miR can potentially target multiple transcripts (Farazi et al, 2010). However, experimentally validated miR-7 targets including growth factor receptors and signalling molecules such as EGFR, PAK1, RAF-1, IRS1 and IRS2 are frequently upregulated in cancers (Kefas et al, 2008;Reddy et al, 2008;Pogribny et al, 2010), supporting a role for miR-7 in FOXP3 tumoursuppressor function. We have also observed the reduced mRNA levels for the miR-7 targets EGFR, PAK1 and RAF-1 in FOXP3-transduced BT549 cells correlating with the increased miR-7 levels (Supplementary Figure S8), suggesting that, in addition to suppressing SATB1, miR-7 may also suppress other important oncogenes.…”

Human anti-nucleolin recombinant immunoagent for cancer therapy

“…Recently, we reported that NCL has a critical protumorigenic function regulating the biogenesis of selected microRNAs (miRNAs), a class of noncoding single-stranded RNAs 19-22 nt in length (17) that regulate gene expression at the posttranscriptional level by targeting mRNAs in a sequence-specific manner (18). In fact, NCL enhances the maturation of specific miRNAs (including miR-21, miR-221, and miR-222) causally involved in cancer pathogenesis and resistance to several antineoplastic treatments (19)(20)(21)(22)(23). Our findings demonstrated that NCL modulates the biogenesis of these miRNAs at the posttranscriptional level, enhancing their maturation from pri-to premiRNAs, identifying a novel NCL-dependent oncogenic mechanism (19).…”