XAF1 as a prognostic biomarker and therapeutic target in pancreatic cancer

被引:51
作者
Huang, Jia [1 ]
Yao, Wei-yan [1 ]
Zhu, Qi [1 ]
Tu, Shui-ping [1 ]
Yuan, Fei [2 ]
Wang, Hua-feng [2 ]
Zhang, Yong-ping [1 ]
Yuan, Yao-zong [1 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Dept Gastroenterol, Rui Jin Hosp, Shanghai 200030, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Dept Pathol, Rui Jin Hosp, Shanghai 200030, Peoples R China
关键词
X-LINKED INHIBITOR; XIAP-ASSOCIATED FACTOR-1; INDUCED APOPTOSIS; EXPRESSION; RESISTANCE; SURVIVIN; PROTEIN; GENE; IAP; METHYLATION;
D O I
10.1111/j.1349-7006.2009.01396.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
XAF1 (X chromosome-linked inhibitor of apoptosis [XIAP]-associated factor 1) is a novel XIAP modulator that negatively regulates the anti-apoptotic effects of XIAP and sensitizes cells to other cell death triggers. It has been reported to be downregulated in a variety of human cancer cell lines. However, the role of XAF1 in pancreatic carcinogenesis remains unclear. In the present study, we investigated the prognostic values of XAF1 expression and its regulation in cancer cell growth and apoptosis both in vitro and in vivo. From the immunohistochemistry staining of tissue microarray, 40 of 89 (44.9%) pancreatic specimens showed low levels of XAF1 expression. Statistical analysis suggested the downregulation of XAF1 was significantly correlated with tumor staging (P = 0.047) and those patients with low XAF1 levels had shorter survival times (P = 0.0162). Multivariate analysis indicated that XAF1 expression was an independent prognostic indicator of the survival of patients with pancreatic cancer (P = 0.007). Furthermore, we found that restoration of XAF1 expression mediated by Ad5/F35 virus suppressed cell proliferation and induced cell cycle arrest and apoptosis, accompanied by the activation of caspases 3, 8, and 9 and poly(ADP-ribose) polymerase as well as increased level of cytochrome c and Bid cleavage. Notably, XAF1 restoration robustly decreased survivin expression rather than XIAP. In addition, in vivo s.c. xenografts from Ad5/F35-XAF1 treatment, which showed less cellular proliferation and enhanced apoptosis, were significantly smaller than those from control groups. Our findings document that XAF1 is a valuable prognostic marker in pancreatic cancer and could be a potential candidate for cancer gene therapy. (Cancer Sci 2010; 101: 559-567)
引用
收藏
页码:559 / 567
页数:9
相关论文
共 45 条
[1]   Validating survivin as a cancer therapeutic target [J].
Altieri, DC .
NATURE REVIEWS CANCER, 2003, 3 (01) :46-54
[2]   Survivin, versatile modulation of cell division and apoptosis in cancer [J].
Altieri, DC .
ONCOGENE, 2003, 22 (53) :8581-8589
[3]   Degradation of survivin by the x-linked inhibitor of apoptosis (XIAP)-XAF1 complex [J].
Arora, Vinay ;
Cheung, Herman H. ;
Plenchette, Stephanie ;
Micali, O. Cristina ;
Liston, Peter ;
Korneluk, Robert G. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (36) :26202-26209
[4]   Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial [J].
Burris, HA ;
Moore, MJ ;
Andersen, J ;
Green, MR ;
Rothenberg, ML ;
Madiano, MR ;
Cripps, MC ;
Portenoy, RK ;
Storniolo, AM ;
Tarassoff, P ;
Nelson, R ;
Dorr, FA ;
Stephens, CD ;
VanHoff, DD .
JOURNAL OF CLINICAL ONCOLOGY, 1997, 15 (06) :2403-2413
[5]  
Byun DS, 2003, CANCER RES, V63, P7068
[6]   Frequent alteration of XAF1 in human colorectal cancers:: Implication for tumor cell resistance to apoptotic stresses [J].
Chung, Sun-Ku ;
Lee, Min-Goo ;
Ryu, Byung-Kyu ;
Lee, Jin-Hee ;
Han, Jikhyon ;
Byun, Do-Sun ;
Chae, Kwon-Seok ;
Lee, Kil Yeon ;
Jang, Jae-Young ;
Kim, Hyo-Jong ;
Chi, Sung-Gil .
GASTROENTEROLOGY, 2007, 132 (07) :2459-2477
[7]   X-linked IAP is a direct inhibitor of cell-death proteases [J].
Deveraux, QL ;
Takahashi, R ;
Salvesen, GS ;
Reed, JC .
NATURE, 1997, 388 (6639) :300-304
[8]   IAP family proteins - suppressors of apoptosis [J].
Deveraux, QL ;
Reed, TC .
GENES & DEVELOPMENT, 1999, 13 (03) :239-252
[9]   Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition [J].
Du, CY ;
Fang, M ;
Li, YC ;
Li, L ;
Wang, XD .
CELL, 2000, 102 (01) :33-42
[10]   Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor [J].
Fang, XL ;
Liu, ZX ;
Fan, YD ;
Zheng, CY ;
Nilson, S ;
Egevad, L ;
Ekman, P ;
Xu, DW .
INTERNATIONAL JOURNAL OF CANCER, 2006, 118 (10) :2485-2489