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

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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