MicroRNAs modulate the chemosensitivity of tumor cells

Abstract

MicroRNAs are strongly implicated in such processes as development, carcinogenesis, cell survival, and apoptosis. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. In the experimental system, we increased the expression of individual microRNAs by transfecting their precursors (which are active) or suppressed the expression by transfection of antisense oligomers. In three NCI-60 human cancer cell lines, a panel of 60 lines used for anticancer drug discovery, we assessed the growthinhibitory potencies of 14 structurally diverse compounds with known anticancer activities. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growthinhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that f30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Ten of those microRNAs have already been implicated in cancer biology. Our results support a substantial role for microRNAs in anticancer drug response, suggesting novel potential approaches to the improvement of chemotherapy. [Mol Cancer Ther 2008;7(1):1 -9]

MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma

“…24 In addition, inhibition of miR-21 has been shown to increase the sensitivity of NCI60 and cholangiocarcinoma cell lines to chemotherapeutic agents. 17,25 miR-20b is highly overexpressed in ESCC and gastric cancer, 26,27 and its high-expression level is associated with a lower probability of survival. 28 The expression of miR-205 is highly specific for squamous epithelium, 29 and it has been shown to be downregulated in both esophageal adenocarcinoma and ESCC.…”

“…[10][11][12][13] Altered expression of miRNAs in primary human cancers has been used for tumor diagnosis, classification, staging and prognosis. 14 Furthermore, the involvement of miRNAs in the response of tumor cells to chemotherapeutic agents has also been confirmed, [15][16][17] which suggests that miRNAs could have a broad effect on the response of cancer cells to chemotherapy.…”

Multidrug Resistance Transporters – Roles in maintaining Cancer Stem-Like Cells

“…The regulation of the other two major multidrug resistance transporters, Pglycoprotein/MDR1 and MRP1, by miR-451, -27a and -326, respectively, have also been reported (Kovalchuk et al, 2008;Liang et al, 2010). More importantly, modulation of miRNA expression or function can alter sensitivity of cancer cells to anticancer drugs (Zhu et al, 2008;Pan et al, 2009;Blower et al, 2008). This could be achieved by inhibiting the function of up-regulated miRNAs or restoring the expression of down-regulated miRNAs.…”

“…First, miRNA expression is largely dysregulated in drug-resistant cancer cells (Zhu et al, 2008;Pan et al, 2009). Second, the miRNA expression patterns in the NCI-60 drug screen cell lines are significantly correlated to the sensitivity patterns of the cancer cells for a large set of anticancer agents (Blower et al, 2008). Third, numerous miRNAs have been found to regulate drug resistance genes such as DHFR (Mishra et al, 2007) and BCL2 (Xia et al, 2008).…”

Marine fungal metabolite 1386A alters the microRNA profile in MCF-7 breast cancer cells

“…Thus, miRNAs were confirmed to modulate breast cancer initiation, invasion and metastasis (24)(25)(26). At present, several studies have suggested the importance of miRNAs in modulating the chemosensitivity and chemoresistance of tumor cells (27)(28)(29). Si et al reported that suppression of miR-21 sensitized MCF-7 cells to topotecan (30) and enhanced chemosensitivity of leukemic HL60 cells to arabinosylcytosine (31).…”