The existence of a pathological vicious cycle (a positive nevertheless feedback loop) involving ��-catenin, as we postulate, would serve to enhance the survival and continued growth of CRC cells by selectively upregulating various oncogenic factors. A recent study has suggested the existence of another pathological vicious cycle involving ��-catenin in CRC. In addition to its effects on gastrin and on the expression of other target genes, Hovanes et al (2001) reported that LEF-1, one of the transcriptional partners of ��-catenin, is likewise a target gene of ��-catenin/TCF-dependent transcription. The upregulation of ��-catenin expression by gastrin was also associated with the enhancement of the critical cell cycle regulator, cyclin D1.

Consistent with our current findings, we have previously reported that gastrin enhanced cyclin D1 protein and cyclin D1 promoter activity in the human gastric adenocarcinoma cell line AGS-B (Song et al, 2003b). However, in contrast to the present study, we did not observe an increase in ��-catenin protein expression in AGS-B cells incubated in the presence of gastrin. Several possibilities may explain these disparate results, including interspecies variations. Another possibility is the fact that AGS-B cells have been engineered to overexpress the gastrin receptor, which could potentially favour a direct increase in cyclin D1 by gastrin rather than utilising ��-catenin as a mediator of transcription. Furthermore, overexpression of the receptor may have modulated other components that could affect ��-catenin stability.

Despite our observation in the present study that both ��-catenin and cyclin D1 expression were enhanced by gastrin, it is nevertheless possible that the increase in cyclin D1 may have occurred independently of ��-catenin-dependent transcription. Along these lines, gastrin has been previously shown to stimulate the expression of c-myc, another target of ��-catenin, in intestinal epithelial cells (IEC-6) (Wang et al, 1995). Although we did not examine c-myc levels in this study, it is certainly possible that gastrin may involve not only c-myc and cyclin D1, but also multiple ��-catenin target genes and pathways in exerting its growth potential, whether directly or indirectly. Another possibility is simply the fact that every immortal cell line possesses slightly different characteristics that produce disparate results.

For example, unlike AGS-B cells (Song et al, 2003b), in AGS-E cells, a related human gastric adenocarcinoma cell line overexpressing the gastrin receptor, G-17 induction of cyclin D1 transcription was mediated through both ��-catenin and CREB pathways (Pradeep et al, 2004). Entinostat In conclusion, the results of the present studies demonstrate for the first time that gastrin enhances ��-catenin protein by prolonging its half-life.