Abstract
Multidrug resistance (MDR) is usually correlated with the poor prognosis of gastric cancer. In this study, we revealed a total of 11 microRNAs (miRNA) that regulated MDR of gastric cancer via high-throughput functional screening, and miR-508-5p reversed MDR most efficiently among these candidate miRNAs. The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1. These findings suggest that a miR-508-5p/ZNRD1/ABCB1 regulatory loop has a critical role in MDR in gastric cancer. In addition, miR-508-5p could be used as a prognostic factor for overall survival in gastric cancer. These data reveal an important role for miR-508-5p in the regulation of MDR in gastric cancer, and suggest the potential application of miR-508-5p in drug resistance prediction and treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cisplatin / pharmacology
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Doxorubicin / pharmacology
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Drug Resistance, Multiple
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Drug Screening Assays, Antitumor
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Fluorouracil / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mice
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Mice, Nude
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MicroRNAs / biosynthesis
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MicroRNAs / genetics*
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RNA, Messenger / genetics
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / genetics*
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Stomach Neoplasms / metabolism
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Transfection
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Vincristine / pharmacology
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Xenograft Model Antitumor Assays
Substances
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3' Untranslated Regions
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents
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DNA-Binding Proteins
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MIRN508 microRNA, human
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MicroRNAs
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POLR1H protein, human
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RNA, Messenger
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Vincristine
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Doxorubicin
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Cisplatin
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Fluorouracil