title: XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell.
abstract: The X-linked inhibitor of apoptosis protein (XIAP) is a well-known potent apoptosis suppressor and also participates in cancer cell biological behaviors, therefore attracting great attentions as a potential antineoplastic therapeutic target for past years. Anti-IAP therapy is reported to be closely related to epidermal growth factor receptor (EGFR) expression level. However, whether and how XIAP modulates EGFR expression remains largely unknown.
  
  
  
  Human XIAP was knockdown with short-hairpin RNA in two different bladder cancer cell lines, T24T and UMUC3. Two XIAP mutants, XIAP ∆BIR (deletion of N-terminal three BIR domains) and XIAP ∆RING (deletion of C-terminal RING domain and keeping the function of BIR domains), were generated to determine which domain is involved in regulating EGFR.
  
  
  
  We found here that lacking of XIAP expression resulted in a remarkable suppression of EGFR expression, consequently leading to the deficiency of anchorage-independent cell growth. Further study demonstrated that BIR domain of XIAP was crucial for regulating the EGFR translation by suppressing the transcription and expression of miR-200a. Mechanistic studies indicated that BIR domain activated the protein phosphatase 2 (PP2A) activity by decreasing the phosphorylation of PP2A at Tyr307 in its catalytic subunit, PP2A-C. Such activated PP2A prevented the deviant phosphorylation and activation of MAPK kinases/MAPKs, their downstream effector c-Jun, and in turn inhibiting transcription of c-Jun-regulated the miR-200a.
  
  
  
  Our study uncovered a novel function of BIR domain of XIAP in regulating the EGFR translation, providing significant insight into the understanding of the XIAP overexpression in the cancer development and progression, further offering a new theoretical support for using XIAP BIR domain and EGFR as targets for cancer therapy.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.
authors.forename: Xingruo
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.
authors.forename: Guosong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Liao
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Liu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.|Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China, 325035.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.|Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China, 325035.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Departments of Urology and Pathology, New York University School of Medicine, New York, NY, 10016, USA.|VA Medical Center in Manhattan, New York, NY, 10010, USA.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, USA. chuanshu.huang@nyumc.org.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D009154:Mutation; D014176:Protein Biosynthesis; D000072417:Protein Domains / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D054648:Protein Phosphatase 2
keywords: Bladder cancer; EGFR; Rac1; XIAP BIR domain; miRNA