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There is limited information on the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC). The Fragile Histidine Triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumor suppressor gene in a variety of human malignancies. Recent studies have suggested that Fhit inactivation can be a consequence of defects in mismatch repair proteins. We analyzed Fhit and Mlh1 protein expressions using immunohistochemical methods in 20 GBCs and three gallbladder adenomas (GBAs) to elucidate the role of Fhit protein in gallbladder carcinogenesis. In addition, we examined whether Fhit and Mlh1 protein expressions correlated with P53 expression and clinicopathological findings. Significant loss or reduction in Fhit expression was noted in nine (45%) of the GBCs and one of the GBAs. Loss of Mlh1 protein expression was detected in six (30%) of the GBCs and one of the GBAs. Reduced Fhit expression was significantly associated with the absence of Mlh1 protein expression in the GBCs and the GBAs (p=0.0186). P53 overexpression was present in 11 (55%) of the GBCs, but none of the GBAs. Fhit and Mlh1 protein expressions were not significantly associated with P53 expression and clinicopathological findings. These results suggested that reduced Fhit expression might be involved in the development of GBC and be correlated with Mlh1 expression. [Copyright &y& Elsevier]

Expression of the hMLH1 gene, one of the DNA mismatch repair genes, is frequently repressed in various cancers such as colorectal, ovarian, gastric, and endometrial origins with a microsatellite instable phenotype. In this study, we investigated details of the relationship between the transcriptional activity and the protein-binding sites in the 5′-flanking region of the hMLH1 gene. Luciferase reporter gene analysis with a series of deletion mutants revealed that a region containing −301 to −76 relative to a translation start site is essential for maximal expression. Eight protein-binding sites in this region were identified by in vivo methylation footprinting analysis and homology search. A presence of binding proteins to CCAAT-box at −145 to −139 was confirmed by the electrophoresis mobility shift assay. Partial involvement of NF-Y was seen by the super gel shift assay. Three reporter plasmids having a single site-directed mutation at −163 to −158, −145 to −139, or −96 to −93 showed 14–30% less activities to that of having the wild-type. Dual or triple mutations were no greater effect than the single mutation on the activity. These results indicate that three cis-elements are essential for full expression of the hMLH1 gene and may work co-operatively. [Copyright &y& Elsevier]

During the past few decades, many studies have been conducted to evaluate the effects of n-6 and n-3 polyunsaturated fatty acids (PUFAs) on colorectal carcinogenesis. This report provides a brief overview of the recent studies that have been performed in cultured colon cells, animal models as well as of the population-based and short-term biomarker studies with humans. No differential effect between n-6 and n-3 PUFAs has been observed in vitro. Results from animal models indicate that n-6 PUFAs have a tumor enhancing effect, predominantly during the post-initiation phase. n-3 PUFAs may protect against colorectal carcinogenesis during both the initiation and post-initiation phase. Population-based human studies show little or no associations between n-6 or n-3 PUFA intake and colorectal cancer. Short-term biomarker studies in humans suggest though that fish oil (FO) supplementation with high amounts of n-3 PUFAs may protect against colorectal carcinogenesis and that n-6 PUFA supplementation may increase the risk. [Copyright &y& Elsevier]