title: Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance.
abstract: Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Man Kit
authors.initials: MK
authors.lastname: Siu
authors.forename: Wassim
authors.initials: W
authors.lastname: Abou-Kheir
authors.forename: Juan Juan
authors.initials: JJ
authors.lastname: Yin
authors.forename: Yung-Sheng
authors.initials: YS
authors.lastname: Chang
authors.forename: Ben
authors.initials: B
authors.lastname: Barrett
authors.forename: Florent
authors.initials: F
authors.lastname: Suau
authors.forename: Orla
authors.initials: O
authors.lastname: Casey
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Paul
authors.initials: P
authors.lastname: Hynes
authors.forename: Yao-Yu
authors.initials: YY
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Center of Excellence for Cancer Research, Wan Fang Hospital, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yen-Nien
authors.initials: YN
authors.lastname: Liu
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kelly
mesh_terms: D020413:3' Untranslated Regions; D066258:Amphiregulin; D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D066255:EGF Family of Proteins / Q000235:genetics / Q000378:metabolism; D066260:Epiregulin / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; C117307:KRAS protein, human; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C587886:TGFA protein, human; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins