Expression and biological significance of c-FLIP in human hepatocellular carcinomas

被引:34
作者
Du, Xilin [1 ]
Bao, Guoqiang [1 ]
He, Xianli [1 ]
Zhao, Huadong [1 ]
Yu, Fang [2 ]
Qiao, Qing [1 ]
Lu, Jianguo [1 ]
Ma, Qingjiu [1 ]
机构
[1] Fourth Mil Med Univ, Tangdu Hosp, Dept Gen Surg, Xian 710038, Peoples R China
[2] Fourth Mil Med Univ, Dept Biochem, Xian 710032, Peoples R China
来源
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH | 2009年 / 28卷
关键词
FAS-MEDIATED APOPTOSIS; CANCER CELL-DEATH; RECEPTOR-INDUCED APOPTOSIS; NF-KAPPA-B; PROTEIN; CHEMOTHERAPY; INHIBITION; RESISTANCE; LEVEL; REGULATOR;
D O I
10.1186/1756-9966-28-24
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: c-FLIP can be considered as a tumor-progression factor in regard to its antiapoptotic functions. In the present study, we intended to investigate the expression of c-FLIP in human HCC tissues, and its relation with drug-induced cell apoptosis through the specific inhibition of c-FLIP expression by siRNA in 7721 cells. Methods: c-FLIP expression was quantified immunohistochemically in HCC tissues(eighty-six cases), and corresponding noncancerous tissues (fifty-seven cases). Patients with HCC were followed up for cancer recurrence. Then, the c-FLIP gene was silenced with specific siRNA in 7721 HCC cells. c-FLIP expression was detected by RT-PCR, Western Blot and immunocytochemical staining. The cellular viability and cell apoptosis were assayed in vitro with cells treated with doxorubicin. Results: Positive immunostaining was detected for c-FLIP in 83.72% (72/86) human HCC tissues, 14.81% (4/27) hepatic cirrhosis, 11.11% (2/18) hepatic hemangioma tissues, and absent in normal hepatic tissues. The overexpression(more than 50%) of c-FLIP in HCC adversely affected the recurrence-free survival. Through c-FLIP gene silencing with siRNA, the expressions of c-FLIP mRNA and protein were remarkably down-regulated in 7721 HCC cells. And doxorubicin showed apparent inhibition on cell proliferations, and induced more apoptosis. Conclusion: These results indicate that c-FLIP is frequently expressed in human HCCs, and its overexpression implied a lesser probability of recurrence-free survival. The specific silencing of c-FLIP gene can apparently up-regulate drug-induced HCC cell apoptosis, and may have therapeutic potential for the treatment of human HCC.
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页数:8
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共 27 条
  • [1] Differential sensitivity of endothelial cells of various species to apoptosis induced by gene transfer of Fas ligand:: Role of flip levels
    Bouchet, D
    Tesson, L
    Ménoret, S
    Charreau, B
    Mathieu, P
    Yagita, H
    Duisit, G
    Anegon, I
    [J]. MOLECULAR MEDICINE, 2002, 8 (10) : 612 - 623
  • [2] A system for stable expression of short interfering RNAs in mammalian cells
    Brummelkamp, TR
    Bernards, R
    Agami, R
    [J]. SCIENCE, 2002, 296 (5567) : 550 - 553
  • [3] Persistent inhibition of FLIPL expression by lentiviral small hairpin RNA delivery restores death-receptor-induced apoptosis in neuroblastoma cells
    Flahaut, M
    Mühlethaler-Mottet, A
    Auderset, K
    Bourloud, KB
    Meier, R
    Popovic, MB
    Joseph, JM
    Gross, N
    [J]. APOPTOSIS, 2006, 11 (02) : 255 - 263
  • [4] Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP
    Galligan, L
    Longley, DB
    McEwan, M
    Wilson, TR
    McLaughlin, K
    Johnston, PG
    [J]. MOLECULAR CANCER THERAPEUTICS, 2005, 4 (12) : 2026 - 2036
  • [5] PRIMARY LIVER NEOPLASMS - EVALUATION OF PROLIFERATIVE INDEX USING MOAB KI-67
    GRIGIONI, WF
    DERRICO, A
    BACCI, F
    GAUDIO, M
    MAZZIOTTI, A
    GOZZETTI, G
    MANCINI, AM
    [J]. JOURNAL OF PATHOLOGY, 1989, 158 (01) : 23 - 29
  • [6] Downregulation of c-FLIP sensitizes DU145 prostate cancer cells to Fas-mediated apoptosis
    Hyer, ML
    Sudarshan, S
    Kim, Y
    Reed, JC
    Dong, JY
    Schwartz, DA
    Norris, JS
    [J]. CANCER BIOLOGY & THERAPY, 2002, 1 (04) : 401 - 406
  • [7] Death and anti-death: Tumour resistance to apoptosis
    Igney, FH
    Krammer, PH
    [J]. NATURE REVIEWS CANCER, 2002, 2 (04) : 277 - 288
  • [8] Inhibition of death receptor signals by cellular FLIP
    Irmler, M
    Thome, M
    Hahne, M
    Schneider, P
    Hofmann, B
    Steiner, V
    Bodmer, JL
    Schroter, M
    Burns, K
    Mattmann, C
    Rimoldi, D
    French, LE
    Tschopp, J
    [J]. NATURE, 1997, 388 (6638) : 190 - 195
  • [9] Impairment of the ubiquitin-proteasome system by cellular FLIP
    Ishioka, Toshiyasu
    Katayama, Ryohei
    Kikuchi, Ryo
    Nishimoto, Michie
    Takada, Shinji
    Takada, Ritsuko
    Matsuzawa, Shu-ichi
    Reed, John C.
    Tsuruo, Takashi
    Naito, Mikihiko
    [J]. GENES TO CELLS, 2007, 12 (06) : 735 - 744
  • [10] Jackel MC, 1998, HNO, V46, P614, DOI 10.1007/s001060050283