title: miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer.
abstract: GRP78, a major endoplasmic reticulum chaperone and signaling regulator, is commonly overexpressed in cancer. Moreover, induction of GRP78 by a variety of anti-cancer drugs, including histone deacetylase inhibitors, confers chemoresistance to cancer, thereby contributing to tumorigenesis. Thus, therapies aimed at decreasing GRP78 levels, which results in the inhibition of tumor cell proliferation and resensitization of tumor cells to chemotherapeutic drugs may hold promise for cancer treatment. Despite advances in our understanding of GRP78 actions, little is known about endogenous inhibitors controlling its expression. As endogenous regulators, microRNAs (miRNAs) play important roles in modulating gene expression; therefore, we sought to identify miRNA(s) that target GRP78, under the hypothesis that these miRNAs may serve as therapeutic agents. Here, we report that three miRNAs (miR-30d, miR-181a, miR-199a-5p) predicted to target GRP78 are down-regulated in prostate, colon and bladder tumors, and human cancer cell lines. We show that in C42B prostate cancer cells, these miRNAs down-regulate GRP78 and induce apoptosis by directly targeting its 3' untranslated region. Importantly, we demonstrate that the three miRNAs act cooperatively to decrease GRP78 levels, suggesting that multiple miRNAs may be required to efficiently control the expression of some genes. In addition, delivery of multiple miRNAs by either transient transfection or lentivirus transduction increased the sensitivity of cancer cells to the histone deacetylase inhibitor, trichostatin A, in C42B, HCT116 and HL-60 cells. Together, our results indicate that the delivery of co-transcribed miRNAs can efficiently suppress GRP78 levels and GRP78-mediated chemoresistance, and suggest that this strategy holds therapeutic potential.
authors.affiliation: 1] Department of Urology, Los Angeles, CA, USA [2] Program in Genetic, Molecular, and Cellular Biology, Los Angeles, CA, USA.
authors.forename: S-F
authors.initials: SF
authors.lastname: Su
authors.forename: Y-W
authors.initials: YW
authors.lastname: Chang
authors.forename: C
authors.initials: C
authors.lastname: Andreu-Vieyra
authors.forename: J Y
authors.initials: JY
authors.lastname: Fang
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: B
authors.initials: B
authors.lastname: Han
authors.forename: A S
authors.initials: AS
authors.lastname: Lee
authors.forename: G
authors.initials: G
authors.lastname: Liang
mesh_terms: D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005822:Genetic Vectors; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D012313:RNA / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014410:Tumor Stem Cell Assay; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C000717248:Hspa5 protein, mouse; D006877:Hydroxamic Acids; C546086:MIRN30b microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C039919:RNA, recombinant; C531408:mirn199 microRNA, human; C012589:trichostatin A; D012313:RNA; D019284:Thapsigargin