MicroRNA expression profiles associated with development of drug resistance in Ehrlich ascites tumor cells

TY - JOUR

T1 - MicroRNA expression profiles associated with development of drug resistance in Ehrlich ascites tumor cells

AU - Husted, Susanne

AU - Søkilde, Rolf

AU - Rask, Lene

AU - Cirera, Susanna

AU - Busk, Peter Kamp

AU - Eriksen, Jens

AU - Litman, Thomas

PY - 2011/12/5

Y1 - 2011/12/5

N2 - Multidrug resistance (MDR) poses a major obstacle to successful chemotherapeutic treatment of cancer, and often involves multiple genes, which may be regulated post-transcriptionally by microRNAs (miRNAs). The purpose of the present study was therefore to identify any resistance-associated changes in miRNA expression in a sensitive and five increasingly drug-resistant Ehrlich ascites tumor (EAT) cell lines, representing different steps in the development of resistance. We used an LNA-enhanced microarray platform to study the global miRNA expression profiles in the six murine EAT cell lines, and identified growth-, hypoxia-, and resistance-specific miRNA patterns. Among the differentially expressed miRNAs, we found the two clusters miR-183∼miR-96∼miR-182 and miR-200b∼miR-200a∼miR-429 as well as miR-141 to be consistently upregulated in the MDR cell lines, while miR-125b-5p and the two clusters miR-30d∼miR-30b and miR-23b∼miR-27b∼miR-24-1 were downregulated in most of the resistant EAT cells. Several of the target genes for these miRNAs-including Zeb1/Zeb2 and members of the Fox gene family-could contribute to the drug-resistant phenotype, although we did not find that the degree of resistance was directly correlated to any specific changes in miRNA expression. Probably, the observed miRNA expression patterns reflect the underlying genomic instability of the tumor cells, and further studies are needed to explore how the highly complex regulatory miRNA networks contribute to the development of MDR.

AB - Multidrug resistance (MDR) poses a major obstacle to successful chemotherapeutic treatment of cancer, and often involves multiple genes, which may be regulated post-transcriptionally by microRNAs (miRNAs). The purpose of the present study was therefore to identify any resistance-associated changes in miRNA expression in a sensitive and five increasingly drug-resistant Ehrlich ascites tumor (EAT) cell lines, representing different steps in the development of resistance. We used an LNA-enhanced microarray platform to study the global miRNA expression profiles in the six murine EAT cell lines, and identified growth-, hypoxia-, and resistance-specific miRNA patterns. Among the differentially expressed miRNAs, we found the two clusters miR-183∼miR-96∼miR-182 and miR-200b∼miR-200a∼miR-429 as well as miR-141 to be consistently upregulated in the MDR cell lines, while miR-125b-5p and the two clusters miR-30d∼miR-30b and miR-23b∼miR-27b∼miR-24-1 were downregulated in most of the resistant EAT cells. Several of the target genes for these miRNAs-including Zeb1/Zeb2 and members of the Fox gene family-could contribute to the drug-resistant phenotype, although we did not find that the degree of resistance was directly correlated to any specific changes in miRNA expression. Probably, the observed miRNA expression patterns reflect the underlying genomic instability of the tumor cells, and further studies are needed to explore how the highly complex regulatory miRNA networks contribute to the development of MDR.

KW - Animals

KW - Antineoplastic Agents

KW - Carcinoma, Ehrlich Tumor

KW - Cell Line, Tumor

KW - Cisplatin

KW - Doxorubicin

KW - Drug Resistance, Neoplasm

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Mice

KW - MicroRNAs

KW - Reverse Transcriptase Polymerase Chain Reaction

U2 - 10.1021/mp200255d

DO - 10.1021/mp200255d

M3 - Journal article

C2 - 21899346

SN - 1543-8384

VL - 8

SP - 2055

EP - 2062

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 6

ER -