title: SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer.
abstract: The epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Two ZEB family members, ZEB1 and ZEB2(SIP1), inhibit transcription of the E-cadherin gene and induce EMT in vitro. However, their relevance to human cancer is insufficiently studied. Here, we performed a comparative study of SIP1 and ZEB1 proteins in cancer cell lines and in one form of human malignancy, carcinoma of the bladder. Whereas ZEB1 protein was expressed in all E-cadherin-negative carcinoma cell lines, being in part responsible for the high motility of bladder cancer cells, SIP1 was hardly ever detectable in carcinoma cells in culture. However, SIP1 represented an independent factor of poor prognosis (P = 0.005) in a series of bladder cancer specimens obtained from patients treated with radiotherapy. In contrast, ZEB1 was rarely expressed in tumor tissues; and E-cadherin status did not correlate with the patients' survival. SIP1 protected cells from UV- and cisplatin-induced apoptosis in vitro but had no effect on the level of DNA damage. The anti-apoptotic effect of SIP1 was independent of either cell cycle arrest or loss of cell-cell adhesion and was associated with reduced phosphorylation of ATM/ATR targets in UV-treated cells. The prognostic value of SIP1 and its role in DNA damage response establish a link between genetic instability and metastasis and suggest a potential importance for this protein as a therapeutic target. In addition, we conclude that the nature of an EMT pathway rather than the deregulation of E-cadherin per se is critical for the progression of the disease and patients' survival.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7XL, United Kingdom.
authors.forename: A Emre
authors.initials: AE
authors.lastname: Sayan
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Griffiths
authors.forename: Raj
authors.initials: R
authors.lastname: Pal
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Browne
authors.forename: Andrew
authors.initials: A
authors.lastname: Ruddick
authors.forename: Tamer
authors.initials: T
authors.lastname: Yagci
authors.forename: Richard
authors.initials: R
authors.lastname: Edwards
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Mayer
authors.forename: Hasan
authors.initials: H
authors.lastname: Qazi
authors.forename: Sandeep
authors.initials: S
authors.lastname: Goyal
authors.forename: Serena
authors.initials: S
authors.lastname: Fernandez
authors.forename: Kees
authors.initials: K
authors.lastname: Straatman
authors.forename: George D D
authors.initials: GD
authors.lastname: Jones
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Bowman
authors.forename: Alexandra
authors.initials: A
authors.lastname: Colquhoun
authors.forename: J Kilian
authors.initials: JK
authors.lastname: Mellon
authors.forename: Marina
authors.initials: M
authors.lastname: Kriajevska
authors.forename: Eugene
authors.initials: E
authors.lastname: Tulchinsky
mesh_terms: D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
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