title: miR-217 and CAGE form feedback loop and regulates the response to anti-cancer drugs through EGFR and HER2.
abstract: MicroRNA array analysis revealed that miR-217 expression was decreased in anti-cancer drug-resistant Malme3MR cancer cells. CAGE, a cancer/testis antigen, was predicted as a target of miR-217. Luciferase activity and ChIP assays revealed a negative feedback relationship between CAGE and miR-217. miR-217 and CAGE oppositely regulated the response to anti-cancer drugs such as taxol, gefitinib and trastuzumab, an inhibitor of HER2. miR-217 negatively regulated the tumorigenic, metastatic, angiogenic, migration and invasion potential of cancer cells. The xenograft of Malme3MR cells showed an increased expression of pEGFRY845. CAGE and miR-217 inhibitor regulated the expression of pEGFRY845. CAGE showed interactions with EGFR and HER2 and regulated the in vivo sensitivity to trastuzumab. The down-regulation of EGFR or HER2 enhanced the sensitivity to anti-cancer drugs. CAGE showed direct regulation of HER2 and was necessary for the interaction between EGFR and HER2 in Malme3MR cells. miR-217 inhibitor induced interactions of CAGE with EGFR and HER2 in Malme3M cells. The inhibition of EGFR by CAGE-binding GTGKT peptide enhanced the sensitivity to gefitinib and trastuzumab and prevented interactions of EGFR with CAGE and HER2. Our results show that miR-217-CAGE feedback loop serves as a target for overcoming resistance to various anti-cancer drugs, including EGFR and HER2 inhibitors.
authors: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors: Youngmi
authors: Y
authors: Kim
authors: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors: Hyuna
authors: H
authors: Kim
authors: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors: Deokbum
authors: D
authors: Park
authors: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors: Minho
authors: M
authors: Han
authors: Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors: Hansoo
authors: H
authors: Lee
authors: College of Pharmacy, Ewha Womans University, Seoul 03760, Korea.
authors: Yun Sil
authors: YS
authors: Lee
authors: Graduate School of Medicine, Kangwon National University, Chunchon 200-701, Korea.
authors: Jongseon
authors: J
authors: Choe
authors: Graduate School of Medicine, Kangwon National University, Chunchon 200-701, Korea.
authors: Young Myeong
authors: YM
authors: Kim
authors: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors: Dooil
authors: D
authors: Jeoung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053487:DEAD-box RNA Helicases; D066246:ErbB Receptors; D000077156:Gefitinib; D035683:MicroRNAs; D017239:Paclitaxel; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C553315:MIRN217 microRNA, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C454199:DDX53 protein, human
keywords: CAGE; EGFR; HER2; anti-cancer drug-resistance; miR-217