Opposite expression patterns of Sonic hedgehog and Indian hedgehog are associated with aberrant methylation status of their promoters in colorectal cancers.

AIMS

Activation of the Hedgehog (Hh) signalling pathway in colorectal cancers (CRCs) is controversial, and its regulation mechanism remains to be elucidated. In the present study we attempted to clarify the regulatory mechanism of the expression of Hh ligands during colorectal carcinogenesis.

METHODS

Reverse transcriptase polymerase chain reaction and immunohistochemistry were used to characterise expressions of the SHH, IHH and GLI1 genes in 36 CRCs, and the findings compared to 21 hyperplastic polyps and 32 colorectal adenomas. In addition, the methylation status of the SHH and IHH promoters in these samples were investigated.

RESULTS

Expressions of SHH and GLI1 proteins were increased significantly in CRCs compared with those in hyperplastic polyps and colorectal adenomas (p<0.01 for both). In contrast, IHH was almost lost in both colorectal adenomas and CRCs. Furthermore, DNA methylation analysis revealed that the frequency of SHH methylation in CRCs (20.6%) was significantly lower than that in colorectal adenomas (72.4%, p<0.001) and hyperplastic polyps (64.7%, p = 0.002). IHH promoter methylation was frequently observed in colorectal adenomas (55.2%, p = 0.004) and CRCs (70.6%, p<0.001) compared with that in hyperplastic polyps (11.8%).

CONCLUSION

SHH hypomethylation could lead to the SHH dependent activation of Hh pathway in CRCs. On the other hand, down-regulation of IHH expression as a result of hypermethylation, may be an early event in colorectal carcinogenesis.