title: The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer.
abstract: Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among gastric cancer (GC) patients. In a previous study using high-throughput functional screening, we identified 11 microRNAs (miRNAs) that regulate MDR in GC and found that miR-508-5p reversed MDR by targeting ABCB1 and ZNRD1. However, the mechanism by which miR-508-5p was decreased in chemo-resistant GC cells was unclear. In this study, we found that ectopic miR-27b is sufficient to sensitize tumors to chemotherapy in vitro and in vivo. Moreover, miR-27b directly targets the 3' untranslated regions (3'-UTRs) of CCNG1, a well-known negative regulator of P53 stability. Interestingly, miR-27b up-regulation leads to increased miR-508-5p expression, and this phenomenon is mediated by CCNG1 and P53. Further investigation indicated that miR-508-5p is directly regulated by P53. Thus, the miR-27b/CCNG1/P53/miR-508-5p axis plays important roles in GC-associated MDR. In addition, miR-27b and miR-508-5p expression was detected in GC tissues with different chemo-sensitivities, and we found that tissues in which miR-27b and miR-508-5p are up-regulated are more sensitive to chemotherapy. Together, these data suggest that the combination of miR-27b and miR-508-5p represents a potential marker of MDR. Restoring the miR-27b and miR-508-5p levels might contribute to MDR reversion in future clinical practice.
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Shang
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: The 88th Hospital of PLA, Tai'an 271001, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Gui
authors.initials: G
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Guanhong
authors.initials: G
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056766:Cyclin G1 / Q000235:genetics* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C534702:CCNG1 protein, human; D056766:Cyclin G1; C531388:MIRN27 microRNA, human; C571981:MIRN508 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D002945:Cisplatin; D005472:Fluorouracil
keywords: CCNG1; gastric cancer; miR-27b; miR-508-5p; multidrug resistance