SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer.
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.
Sayan
A Emre
AE
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7XL, United Kingdom.
Griffiths
Thomas R
TR
Pal
Raj
R
Browne
Gareth J
GJ
Ruddick
Andrew
A
Yagci
Tamer
T
Edwards
Richard
R
Mayer
Nick J
NJ
Qazi
Hasan
H
Goyal
Sandeep
S
Fernandez
Serena
S
Straatman
Kees
K
Jones
George D D
GD
Bowman
Karen J
KJ
Colquhoun
Alexandra
A
Mellon
J Kilian
JK
Kriajevska
Marina
M
Tulchinsky
Eugene
E
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
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
Cancer Res. 2008 Apr 1;68(7):2479-88
18381457
J Pathol. 2007 Apr;211(5):507-515
17299729
Genes Dev. 2004 May 15;18(10):1131-43
15155580
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9891-6
16788066
Mol Cell Biol. 2004 Sep;24(17):7559-66
15314165
Oncogene. 2007 Dec 10;26(56):7773-9
18066090
Cell Cycle. 2008 Oct;7(20):3112-8
18927505
Int J Clin Oncol. 2008 Aug;13(4):287-97
18704628
Clin Cancer Res. 2007 Mar 15;13(6):1685-94
17363521
Development. 2008 Feb;135(3):579-88
18192284
PLoS One. 2008 May 14;3(5):e2153
18478055
Oncogene. 2007 Oct 25;26(49):6979-88
17486063
J Cell Biol. 1998 Aug 10;142(3):837-46
9700170
Cell Signal. 2005 May;17(5):535-47
15683729
J Cell Biol. 1997 Dec 29;139(7):1861-72
9412478
Oncogene. 2005 Mar 31;24(14):2375-85
15674322
Cell. 2008 May 16;133(4):704-15
18485877
Nat Rev Cancer. 2008 Dec;8(12):957-67
19005492
Nat Rev Cancer. 2007 Jun;7(6):415-28
17508028
Mol Cell Biol. 2008 Mar;28(5):1528-40
18172008
Apoptosis. 2002 Jun;7(3):247-60
11997669
Nucleic Acids Res. 2005 Nov 24;33(20):6566-78
16314317
Gastroenterology. 2006 Sep;131(3):830-40
16952552
Cancer Res. 2006 Apr 1;66(7):3893-902
16585218
Dev Cell. 2008 Jun;14(6):818-29
18539112
EMBO J. 2003 May 15;22(10):2453-62
12743039
Cancer Lett. 1996 Mar 19;101(1):43-51
8625281
Mol Biol Cell. 2007 Nov;18(11):4615-24
17855508
Clin Cancer Res. 2007 Apr 1;13(7):2046-53
17404085
Am J Pathol. 2002 Nov;161(5):1881-91
12414534
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2178-83
16461895
Mol Cell Biol. 2005 Oct;25(20):9138-50
16199889
Cancer Res. 2006 May 15;66(10):5338-45
16707460