The role of folate status and methylenetetrahydrofolate reductase gene C677T polymorphism in sonic hedgehog signal and its altered methylation pattern in human colorectal carcinoma

Abstract

Aberrant activation of the hedgehog (Hh) signaling pathway plays a critical role in human colorectal carcinomas (CRC) with unclear mechanisms. The objectives of the study was to determine the expression of sonic hedgehog (Shh), Gli effector and hedgehog interacting protein (HIP), the altered methylation of the promoter regions, tissue folate status as well as the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in a total of 70 CRC tissues and the counter‐paired non‐cancerous tissues. The methylation status of Shh and HIP was determined by methylation‐specific PCR by bisulfate treatment of DNA from tissues followed by amplification using specific designed primer pairs. Among the detectable CRC (38 pairs), 63% and 44.7% of CRC tissues had increased expressions of Shh and Gli transcripts, whereas 60.5% exhibited reduced the HIP expressions (P < 0.05) as compared with the counterpart paired non‐cancerous tissues. Compared with the MTHFR 677 CT/TT variants, CRC with 677CC genotype compared appears to be associated with increased Shh expression and reduced HIP expressions, yet without reaching a statistical significance. Folate status did not differ among the C677T variants or among the cancerous vs noncancerous tissues. For several CRC tissues, altered methylation of Shh and HIP promoter region corresponds with their gene expression pattern. Taken together, CRC has increased expressions of Shh signaling molecules, which may be differentially related to their promoter methylation pattern and MTHFR 677CT genotype.Grant Funding Source: national science council