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[Cancer Research 58, 5071-5074, November 15, 1998]
© 1998 American Association for Cancer Research
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Inhibition of Apoptosis by Survivin Predicts Shorter Survival Rates in Colorectal Cancer

Hiroshi Kawasaki, Dario C. Altieri, Cai-De Lu1, Masao Toyoda, Toshiyuki Tenjo and Nobuhiko Tanigawa2

Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Osaka 569-8686, Japan [H. K., C-D. L. M. T., T. T., N. T.], and Boyer Center for Molecular Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06536 [D. C. A.]

Deregulated inhibition of apoptosis (programmed cell death) may facilitate the insurgence of neoplasia, but whether it also influences the outcome of common cancers has remained controversial. In this study, we investigated the expression of a novel inhibitor of apoptosis, survivin, in colorectal cancer and its relationship with tumor cell apoptosis and overall prognosis. By immunohistochemistry, survivin was expressed in 91 of 171 (53.2%) cases of colorectal carcinomas of histological stages 0 to IV. In contrast, normal colon epithelium did not express survivin. Although survivin expression did not correlate with p53 abnormalities (46.5% versus 58.0%; P = 0.18), survivin-positive cases were strongly associated with bcl-2 expression (72.5% versus 27.4%; P < 0.0001) and reduced apoptotic index (0.76% ± 0.39% versus 1.17% ± 0.62%; P < 0.0001). Expression of survivin alone in bcl-2-negative (disordant) cases also resulted in reduced apoptotic index (0.82% ± 0.57% versus 1.16% ± 0.66%; P = 0.0046). When analyzed for prognostic significance, patients with low apoptotic index (<0.97%) had worse survival rates than the group with high apoptosis (P < 0.001), and a multivariate Cox proportional hazard model identified reduced apoptosis as an independent predictive factor for overall survival (P < 0.0001). These data demonstrate that apoptosis inhibition by survivin, alone or in cooperation with bcl-2, is an important predictive/prognostic parameter of poor outcome in colorectal carcinoma and identify survivin as a new diagnostic/therapeutic target in cancer.

1 Visiting scholar from Zhejiang Medical University, Hangzhou, China.

2 To whom requests for reprints should be addressed, at Department of General and Gastroenterological Surgery, Osaka Medical College, 2-7 Daigaku-Machi, Takatsuki City, Osaka 569-8686, Japan. Phone: 81 726 84 6441; Fax: 81 726 84 6541; E-mail: sur001@poh.osaka-med.ac.jp.

Received 8/17/98. Accepted 9/30/98.




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A I Sarela, R C A Macadam, S M Farmery, A F Markham, and P J Guillou
Expression of the antiapoptosis gene, Survivin, predicts death from recurrent colorectal carcinoma
Gut, May 1, 2000; 46(5): 645 - 650.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
I. Tamm, S. M. Kornblau, H. Segall, S. Krajewski, K. Welsh, S. Kitada, D. A. Scudiero, G. Tudor, Y. H. Qui, A. Monks, et al.
Expression and Prognostic Significance of IAP-Family Genes in Human Cancers and Myeloid Leukemias
Clin. Cancer Res., May 1, 2000; 6(5): 1796 - 1803.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
J. Rohayem, P. Diestelkoetter, B. Weigle, A. Oehmichen, M. Schmitz, J. Mehlhorn, K. Conrad, and E. P. Rieber
Antibody Response to the Tumor-associated Inhibitor of Apoptosis Protein Survivin in Cancer Patients
Cancer Res., April 1, 2000; 60(7): 1815 - 1817.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
R. R. Hozak, G. A. Manji, and P. D. Friesen
The BIR Motifs Mediate Dominant Interference and Oligomerization of Inhibitor of Apoptosis Op-IAP
Mol. Cell. Biol., March 1, 2000; 20(5): 1877 - 1885.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
S. Whitman, X. Wang, R. Shalaby, and E. Shtivelman
Alternatively Spliced Products CC3 and TC3 Have Opposing Effects on Apoptosis
Mol. Cell. Biol., January 15, 2000; 20(2): 583 - 593.
[Abstract] [Full Text]

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 J. Cell Sci.Home page
J Zhao, T Tenev, L. Martins, J Downward, and N. Lemoine
The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner
J. Cell Sci., January 12, 2000; 113(23): 4363 - 4371.
[Abstract] [PDF]

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 Clin. Cancer Res.Home page
K. Tanaka, S. Iwamoto, G. Gon, T. Nohara, M. Iwamoto, and N. Tanigawa
Expression of survivin and Its Relationship to Loss of Apoptosis in Breast Carcinomas
Clin. Cancer Res., January 1, 2000; 6(1): 127 - 134.
[Abstract] [Full Text]

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 Cancer Res.Home page
C. Mahotka, M. Wenzel, E. Springer, H. E. Gabbert, and C. D. Gerharz
Survivin-{{Delta}}Ex3 and Survivin-2B: Two Novel Splice Variants of the Apoptosis Inhibitor Survivin with Different Antiapoptotic Properties
Cancer Res., December 1, 1999; 59(24): 6097 - 6102.
[Abstract] [Full Text] [PDF]

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 JCOHome page
M. Monzo, R. Rosell, E. Felip, J. Astudillo, J. J. Sanchez, J. Maestre, C. Martin, A. Font, A. Barnadas, and A. Abad
A Novel Anti-Apoptosis Gene: Re-expression of Survivin Messenger RNA as a Prognosis Marker in Non-Small-Cell Lung Cancers
J. Clin. Oncol., July 1, 1999; 17(7): 2100 - 2100.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
F. Li and D. C. Altieri
The Cancer Antiapoptosis Mouse Survivin Gene: Characterization of Locus and Transcriptional Requirements of Basal and Cell Cycle-dependent Expression
Cancer Res., July 1, 1999; 59(13): 3143 - 3151.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
G. M. Kasof and B. C. Gomes
Livin, a Novel Inhibitor of Apoptosis Protein Family Member
J. Biol. Chem., January 26, 2001; 276(5): 3238 - 3246.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
W. H. Hoffman, S. Biade, J. T. Zilfou, J. Chen, and M. Murphy
Transcriptional Repression of the Anti-apoptotic survivin Gene by Wild Type p53
J. Biol. Chem., January 25, 2002; 277(5): 3247 - 3257.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
D. Grossman, P. J. Kim, J. S. Schechner, and D. C. Altieri
Inhibition of melanoma tumor growth in vivo by survivin targeting
PNAS, January 16, 2001; 98(2): 635 - 640.
[Abstract] [Full Text] [PDF]


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