Discussion In this study, we found that pri-miR-34b/c rs4938723 variant genotypes in dominant genetic model significantly increased HCC risk PD173955? in women as compared with the female subjects without HCC. Furthermore, the interaction of rs4938723 in dominant genetic model with female gender was significantly associated with HCC risk. HCC is more common in men than in women, especially in the HBV-infected population [2], [3]. This gender disparity might be caused by sex hormone signaling, genetic predisposition such as polysomy of chromosome 7, and increased exposure to environmental risk factors in men [40]�C[42]. Heavy alcohol consumption has been reported to increase HCC risk in male HBsAg carriers [43]. In China, heavy alcohol consumption is more common in men than in women.

Thus, the rs4938723 effect on genetic susceptibility to HBV-HCC might be overwhelmed by strong effects of these risk factors in men. The effect in women might reflect a less biased association of rs4938723 with HBV-HCC. rs4938723 (chr.111382565) is located at the putative promoter region of pre-miR-34b/c. Since miR-34b/c has tumor suppression function, the mutation genotypes (TC and CC) of rs4938723 should be associated with the down-regulation of miR-34b/c in liver. To evaluate if rs4938723 with a base T-to-C change might alter the binding sites of transcriptional factors, we carried out an in silico assay by downloading a 50 bp genomic sequence covering rs4938723 (chr.111382539-chr.111382588) to predict transcriptional factors binding sites online (http://www.cbrc.jp/research/db/TFSEARCH.html).

It was found that the T-to-C change at rs4938723 introduced binding sites of GATA-1, GATA-2, GATA-3, GATA-X, and AP-4 in the 50bp genomic sequence (Figure S1). GATA transcriptional factors can be regulated by gonadotropin and other sexual hormones and control gonadal development and sex differentiation in mammals [44]. GATA-2 plays an important role in activating androgen receptor signaling in prostate cancer [45]. GATA-3, in association with estrogen receptor, can regulate genes critical to the hormone-responsive breast cancer phenotype and play a crucial role for the response of estrogen receptor alpha-positive breast cancers to estradiol [46], [47]. Thus, we speculate that sexual hormones and their receptors might affect the function of GATA transcriptional factors binding to the putative promoter sequence with the T-to-C change at rs4938723, and regulate the expression of pri-miR-34b/c.

This speculation needs to be confirmed by biological assays in future studies. Infection and nonresolving inflammation contribute to about a quarter of all cancer cases. Inflammation modulates Cilengitide the expressions of miRNAs that influence the production of tumor-related proteins [24], [48]. miRNAs possibly link nonresolving inflammation and cancers.