Fhit gene alterations in hepatocarcinogenesis induced by a choline‐deficient L‐amino acid–defined diet in rats

Abstract

Alterations of the fragile histidine triad (Fhit) gene were investigated in rat hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined (CDAA) diet. Males of the F344 strain, 6 wk of age, were fed a CDAA diet, and subgroups were killed at 2, 4, 12, 20, and 75 wk after the beginning of the experiment. Fifteen hepatocellular carcinomas (HCCs) were noted in rats by the last time point; they were dissected free from the surrounding tissue. Normal control liver specimens were obtained from 6-wk-old rats. Total RNAs were extracted from whole livers of animals fed the CDAA diet for 2, 4, 12, and 20 wk and from HCCs, for assessment of aberrant transcription of the Fhit gene by reverse transcription-polymerase chain reaction. Aberrant transcripts were detected in livers of rats fed the CDAA diet for 4, 12, and 20 wk, but not 2 wk, as well as in 11 of 15 HCCs (73.3%). Southern blot analysis showed a genomic DNA abnormality in one of seven informative HCCs (14.3%), while Western blot analysis showed reduction of Fhit protein expression in seven of nine HCCs (77.8%). No abnormal expression was evident in the livers after exposure to the CDAA diet for 2-20 wk. These results suggest that Fhit alterations may play important roles in hepatocarcinogenesis due to choline deficiency in rats.

Effect of fragile histidine triad gene transduction on proliferation and apoptosis of human hepatocellular carcinoma cells

“…No abnormal FHIT transcripts were found in normal livers. It was recently reported that many other factors can also induce liver carcinogenesis in rats [25][26][27][28][29] .…”

Dissection of Signal Transduction Pathways as a Tool for the Development of Targeted Therapies of Hepatocellular Carcinoma

“…Disjunctive abnormalities of chromosome division during cell replication have been induced by the demethylating agent 5-aza-cytidine [106], and pericentromeric rearrangement may be induced by 5-aza-cytidine and 5-aza-2-deoxycytidine [107,108]. The existence of a profound genomic deregulation induced by methyl deficiency is proved by its association with upregulation of c-myc, c-fos, Ras family genes, Odc, Tgf-1, and Hgf, and downregulation of Egf gene [96,109,110] in liver of rats fed CCD or MDD, and the presence of aberrant transcript of Fhit gene, in 73% of HCCs developing in rats fed CDD [111], whereas the presence of p53 mutations in HCC induced by methyl deficiency is controversial [112][113][114]. Methionine or choline administration often reverses the alteration in liver gene expression and inhibits the development of preneoplastic lesions [96].…”