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

FHIT基因被认为对烟草和酒精等环境致癌物质敏感。微环境中的炎症由环氧合酶-2(COX-2)介导的花生四烯酸串联反应来定义，前列腺素E_2(PGE_2)可能通过在致癌物影响的上皮组织中起中介作用而影响结直肠癌(CRC)的恶性表型。在本研究中，62例大肠癌的免疫组织化学分析显示，与COX-2过表达但FHIT阳性的病例相比，COX-2过表达但无FHIT表达的结直肠癌表现出更高级的临床病理特征(肿瘤侵袭深度，p&lt；0.007；Dukes分期，p&lt；0.007)。用诱导的FHIT表达细胞进行的体外实验显示，与对照细胞相比，Western blotting显示COX-2的表达降低。此外，在COX-2诱导剂(脂多糖、佛波酯13-乙酸酯或白介素1β)刺激后，前列腺素E_2…酶联免疫吸附试验和四甲基偶氮唑盐比色法分别检测到FHIT表达细胞的产量和细胞增殖受到抑制(分别是对照细胞的0.75倍和0.87倍)。另一方面，我们建立了FHIT siRNA克隆，并在结直肠癌细胞系CCK81中抑制了FHIT的表达。结果表明，与对照组相比，RNAi抑制的FHIT抑制细胞产生PGE2的能力和细胞增殖能力的降低。综上所述，在结直肠癌中，FHIT表达缺失和COX-2过表达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的产生抑制了结直肠癌细胞的增殖。此外，目前在腺病毒-FHIT(Ad-FHIT)治疗后的全面基因分析被认为揭示了以下两点。其一是阐明Ad-FHIT诱导细胞凋亡的机制，其二是确定受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炎症介导的结直肠癌致癌活性下的一个很好的靶点。较少

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