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FHIT Suppresses Prostaglandin E_2 in the Carcinogenic Activity by Inflammation in Colorectal Cancer.

FHIT 通过结直肠癌炎症抑制前列腺素 E_2 的致癌活性。

基本信息

批准号：
15390379
负责人：
KOSHI Mimori
金额：
$ 9.41万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The FHIT gene is considered to be susceptible to environmental carcinogens, such as tobacco and alcohols. The inflammation in the cmicrocircumstances were defined by arachidonic cascade which is mediated through cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) may influence the malignant phenotype of colorectal cancer (CRC) by acting as mediators in carcinogen affected epithelial tissues. In the present study, immunohistochemical analysis of 62 CRCs showed that a subset of CRC cases with COX-2 overexpression but no FHIT expression exhibited more advanced clinicopathological features (depth of tumor invasion, p < 0.007 ; Dukes stage, p < 0.007), compared to cases with undetectable COX-2 but positive FHIT expression. In vitro experiments using induced FHIT expressing cells showed a diminished COX-2 expression by western blotting compared with control cells. Moreover, after stimulation by COX-2 inducers (lipopolysaccharide, phorbol 12-myristate 13-acetate or interleukin 1 beta), PGE2 … More production and cell proliferation were repressed (0.75-fold and 0.87-fold) in FHIT expressing cells compared to control cells, as determined by ELISA and MTT assays, respectively. On the other hand, we established FHIT siRNA clones and repressed FHIT expression in colorectal cancer cell line, CCK81. As a result, PGE2 production by ELISA and the cellular proliferation by MTT assay was diminished in the FHIT inhibited cell by RNAi comparing with the control FHIT. In conclusion, loss of FHIT expression with overexpression of COX-2 in CRC may predict a higher malignant potential. Conversely, FHIT protein induction repressed cell proliferation by inhibiting prostaglandin E2 production in colorectal cancer.Moreover, the current comprehensive gene analysis after adenoviral-FHIT (Ad-FHIT) treatment is therefore considered to shed some light on the following two points. One is to clarify the mechanism of apoptotic activity by Ad-FHIT and the other is to identify the candidate cancer associated targets affected by Ad-FHIT treatment. Those molecules may consider to be a fine target under the inflammation mediated carcinogenic activity in CRC cases. Less

FHIT基因被认为易受环境致癌物的影响，如烟草和酒精。微环境中的炎症反应是由环氧合酶-2（考克斯-2）介导的花生四烯酸级联反应引起的，前列腺素E2（PGE 2）可能通过在致癌物影响的上皮组织中起介导作用而影响结直肠癌（CRC）的恶性表型。在本研究中，62例CRC的免疫组化分析显示，与检测不到考克斯-2但FHIT表达阳性的病例相比，考克斯-2过表达但FHIT表达阴性的CRC病例亚组表现出更晚期的临床病理特征（肿瘤浸润深度，p <0.007 ; Dukes分期，p < 0.007）。使用诱导的FHIT表达细胞的体外实验显示，与对照细胞相比，通过蛋白质印迹法，考克斯-2表达减少。此外，在用考克斯-2诱导剂（脂多糖、佛波醇12-肉豆蔻酸酯13-乙酸酯或白细胞介素1 β）刺激后， ...更多信息与对照细胞相比，FHIT表达细胞中FHIT的产生和细胞增殖被抑制（0.75倍和0.87倍），这分别通过ELISA和MTT测定来确定。另一方面，我们建立了FHIT siRNA克隆，并在大肠癌细胞系CCK 81中抑制FHIT表达。结果表明，与对照组相比，RNAi抑制FHIT细胞PGE 2的产生和MTT法细胞增殖均明显降低。总之，FHIT表达缺失伴考克斯-2过表达的结直肠癌可能预示着更高的恶性潜能。相反，FHIT蛋白的诱导通过抑制前列腺素E2的产生而抑制结直肠癌细胞的增殖。此外，目前对腺病毒-FHIT（Ad-FHIT）治疗后的全面基因分析因此被认为在以下两点上提供了一些线索。一是阐明Ad-FHIT的凋亡作用机制，二是鉴定Ad-FHIT治疗影响的候选肿瘤相关靶点。这些分子可能被认为是CRC病例中炎症介导的致癌活性的良好靶点。少