Functional STR within PTPN11: a novel potential risk factor for colorectal cancer

PTPN11 was previously regarded as a proto-oncogene, but recent reports have found that it acts as a tumor repressor in hepatocellular carcinogenesis and a prognostic predictor for colorectal carcinoma (CRC), although, its role in colorectal carcinogenesis is still unclear. This hospital-based case-control study with 830 CRC cases and 878 controls was carried out to determine the effect of the short tandem repeat (STR) polymorphism, located in the 3'UTR, on CRC risk in the study population of Chinese adults. Distribution of the genotypic frequency between CRC cases and controls in the Xuzhou study center revealed that the risk of CRC decreased as the repeat numbers increased. Compared with the 11/12 genotype, those with the 13/14 genotype were conferred reduced risk of CRC (OR=0.74, 95% CI=0.59-0.95, P=0.02), while carriers with the 15/16 genotype showed a marked reduction in CRC risk (OR=0.50, 95% CI=0.34-0.74, P=0.0004). A similar trend in genotype and allelic frequency was also observed in the Suining study center as well as in the pooled results. Using RT-qPCR analysis, longer alleles were found to upregulate the expression of PTPN11 in both tumor tissues and adjacent non-tumor tissues, with the expression of PTPN11 in non-CRC tissues observed to be 2.5-fold higher than those of CRC tissues. In the gain-of-function in vitro studies, it was found that constructs with allele 14 had the highest luciferase expression, while the allele 12 constructs had much lower expression, indicating that the STR polymorphism could influence the transcriptional activity and therefore was able to modulate PTPN11 expression. In conclusion, these findings indicate that the STR polymorphism located in PTPN11 modulates colorectal carcinogenesis probably through a motif change in the 3'UTR. Further studies with more study centers and the inclusion of other ethnic Chinese populations would have to be carried in the future so as to substantiate this observation.