Hepatic oval cell response to the choline-deficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxygenase 2 inhibitor
Hepatic oval cell response to the choline-deficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxygenase 2 inhibitor
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DOI：
10.1093/carcin/bgi365
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发表时间：
2006-08-01
期刊：
影响因子：
4.7
通讯作者：
Olynyk, John K.
中科院分区：
文献类型：
--
作者：
Davies, Richard A.;Knight, Belinda;Olynyk, John K.
在许多肝细胞癌的啮齿动物模型中，卵圆细胞的增殖先于肿瘤发生，阻止这种增殖反应可以降低继发癌症的风险。本研究旨在确定选择性环氧合酶-2(COX-2)抑制剂SC-236是否影响(I)小鼠肝癌发生模型中卵圆细胞对肝损伤的反应和(Ii)卵圆细胞系。四周龄的小鼠在有或没有SC-236的情况下，接受正常饮食或胆碱缺乏、乙硫氨酸补充(CDE)饮食的喂养。治疗2周、4周、12周、52周后分别检测肝组织学改变和卵圆细胞数。对卵圆细胞进行形态评分和M-2-丙酮酸激酶同工酶(M2PK)或A6免疫组化染色。以永生化的卵圆细胞系(PIL-2)为研究对象，研究SC-236对卵圆细胞增殖、凋亡及Akt磷酸化的影响。与未服用SC-236的CDE喂养的小鼠相比，服用SC-236的CDE喂养的小鼠的M2PK阳性卵圆细胞和COX-2阳性细胞的百分比分别减少了80%和45%。部分M2PK阳性卵圆细胞也呈COX-2阳性。SC-236对CDE喂养小鼠的A6阳性细胞百分率无影响。服用SC-236的小鼠在2周时TUNEL阳性细胞数增加了73%，证明了这一点。原代卵圆细胞和PIL-2细胞表达COX-2。在体外，SC-236处理PIL-2细胞可导致A6阴性细胞呈剂量依赖性的优先死亡。25和50亩前列腺素E-2可部分抑制SC-236诱导的细胞死亡25%。在体外，卵圆细胞死亡与细胞凋亡和Akt磷酸化降低70%相关。这些结果提示，SC-236诱导的M2PK阳性卵圆细胞数量减少可能与COX-2依赖抑制Akt磷酸化和诱导细胞凋亡有关。
Oval cell proliferation precedes neoplasia in many rodent models of hepatocellular carcinoma and prevention of this proliferative response can reduce the risk of subsequent carcinoma. This study aimed to determine whether a selective cyclo-oxygenase-2 (COX-2) inhibitor, SC-236, affects (i) the oval cell response to liver injury in a mouse model of hepatocarcinogenesis and (ii) an oval cell line. Four-week-old mice were fed either normal chow or a choline deficient, ethionine supplemented (CDE) diet in the presence or absence of SC-236. Liver histology and oval cell numbers were determined after 2, 4, 12 and 52 weeks of treatment. Oval cells were scored using morphological criteria and positive immuno-staining for the M-2-isozyme of pyruvate kinase (M2PK) or A6. An immortalized oval cell line (PIL-2) was used to study the in vitro effects of SC-236 on oval cell proliferation, apoptosis and Akt phosphorylation. The percentage of M2PK-positive oval cells and COX-2-positive cells was reduced by 80% and 45%, respectively, in CDE-fed mice receiving SC-236 compared with CDE-fed animals not receiving SC-236. Some M2PK-positive oval cells were also COX-2 positive. The percentage of A6-positive cells was not affected by SC-236 administration to CDE-fed mice. Administration of SC-236 increased apoptosis as evidenced by a 73% increase in the number of TUNEL-positive cells at 2 weeks in CDE-fed mice. Primary oval cells and PIL-2 cells expressed COX-2. In vitro treatment of PIL-2 cells with SC-236 resulted in a dose-dependent preferential death of A6-negative cells. Administration of 25 and 50 mu M Prostaglandin E-2 partially attenuated SC-236 induced cell death by 25%. In vitro oval cell death was associated with apoptosis and a 70% reduction in Akt phosphorylation. These results suggest that the SC-236 induced reduction of M2PK-positive oval cell numbers may be due to COX-2 dependent inhibition of Akt phosphorylation and induction of apoptosis.