Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance
| Autor: | Yen Nien Liu, Paul G. Hynes, Wei Yu Chen, Ben Barrett, Jiaoti Huang, Lei Fang, Wassim Abou-Kheir, Orla Casey, Florent Suau, Man Kit Siu, Yao Yu Hsieh, Juan Juan Yin, Yung Sheng Chang, Kathleen Kelly |
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| Rok vydání: | 2014 |
| Předmět: |
Oncology
Male medicine.disease_cause Epiregulin Metastasis Prostate cancer Mice 0302 clinical medicine Bone metastasis/Epidermal growth factor receptor (EGFR)/Prostate cancer/miR-203/KRAS/Tyrosine kinase inhibitors (TKIs) resistance Epidermal growth factor receptor Neoplasm Metastasis 3' Untranslated Regions Hematology 05 social sciences Bone metastasis ErbB Receptors Heterografts KRAS miR-203 Tyrosine kinase Research Paper Signal Transduction medicine.medical_specialty EGF Family of Proteins Molecular Sequence Data Down-Regulation Mice Nude Bone Neoplasms Biology Amphiregulin Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Internal medicine Cell Line Tumor Proto-Oncogene Proteins 0502 economics and business medicine Animals Humans Egfr signaling Protein Kinase Inhibitors Base Sequence business.industry Cancer Prostatic Neoplasms Correction Gene signature Transforming Growth Factor alpha medicine.disease MicroRNAs Cancer research biology.protein ras Proteins 050211 marketing business 030217 neurology & neurosurgery |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Man Kit Siu 1,2,* , Wassim Abou-Kheir 3,* , Juan Juan Yin 4,* , Yung-Sheng Chang 1 , Ben Barrett 4 , Florent Suau 4 , Orla Casey 4 , Wei-Yu Chen 5 , Lei Fang 4 , Paul Hynes 4 , Yao-Yu Hsieh 1,6 ,Yen-Nien Liu 1,7 , Jiaoti Huang 8 and Kathleen Kelly 4 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 2 Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 3 Department of Anatomy, Cell Biology and Physiological Sciences Faculty of Medicine, American University of Beirut, Beirut, Lebanon 4 Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 5 Department of Pathology, Wan Fang Hospital, College of Medicine, Taipei Medical University, Taipei, Taiwan 6 Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 7 Center of Excellence for Cancer Research, Wan Fang Hospital, College of Medicine, Taipei Medical University, Taipei, Taiwan 8 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA * These authors contributed equally to this work. Correspondence: Yen-Nien Liu, email: // Keywords : Bone metastasis/Epidermal growth factor receptor (EGFR)/Prostate cancer/miR-203 /KRAS/Tyrosine kinase inhibitors (TKIs) resistance Received : February 20, 2014 Accepted : May 18, 2014 Published : May 20, 2014 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. |
| Databáze: | OpenAIRE |
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