In the present study, we demonstrated that the G allele of mTOR promoter polymorphism rs2295080 was associated with a significantly decreased risk of GC. We found that the T to G change in rs2295080 substantially altered transcriptional activity of mTOR gene via influencing the binding of some transcriptional factor. We also observed that mTOR rs2295080 T allele was associated with higher mTOR mRNA expression levels in vivo.
Mammalian target of rapamycin (mTOR), also known as FRAP1, is one necessary member of PI3K/Akt/mTOR pathway and central to metabolic signaling 
. It can be activated by insulin, insulin-like growth factors and other growth factors, and inactivated during cellular starvation. mTOR exists two different kinds of complex, named mTORC1 and mTORC2, respectively 
. The mTORC1 complex phosphorylates its downstream effecter p70S6k, which could induce the degradation of insulin receptor substrate and further increase the insulin-driven Akt activity. The mTORC2 complex phosphorylates the C-terminus of Akt at ser473, which could lead to the entire activation of Akt 
. As a therapeutic target in other cancers 
, mTOR could also emerged as a potential target for treatment of gastric cancer, spontaneously. Sirolimus 
and everolimus 
, the mTOR inhibitors, were identified to result in G1 cell cycle arrest and inhibited the proliferation of gastric cell lines. Recently, a novel potential mTOR
promoter polymorphism rs2295080 has been described in several studies 
. However, insufficient functional studies were performed to evaluate the role of this genetic variant in regulating the mTOR
expression. In GC, our findings provided the evidence that rs2295080 T allele could enhance the transcription activity of mTOR
to some extent in GES-1 cell line after transfected in vitro
. And further luciferase assay in three gastric cancer cell lines (i.e., BGC-823, MGC-803, and SGC-7901) further confirmed this effect of rs2295080 polymorphism. These results in our present study were in accordance with the outcomes in renal cancer cell line and cervix cancer cell line 
. In EMSA assay, rs2295080 was predicted to locate on the potential binding site, whose polymorphic variants could influence the recruit of transcription factors (using the p-MATCH program, which uses binding sites in TRANSFAC; www.gene-regulation.com
). Taken these results together, it is plausible that mTOR
rs2295080 polymorphism could influence the expression level of mTOR
and individual susceptibility to various cancers.
The SNP rs2295080, as well as another intron SNP rs11121704, was first reported by Hildebrandt et al.
to locate in mTOR
potential promoter region 
. As described in esophageal cancer, rs2295080 seemed no association or function with survival after chemoradiotherapy and surgery. But until now, several studies have identified the effect of this polymorphism in mTOR
for cancer risk 
, all of which considered rs2295080 T allele as a risk factor. In the current study, the association between rs2295080 T allele and GC risk was consistent with the results of previous three studies 
. In addition, our results also suggested that this polymorphism might be a biological crux in the development of GC. Because of different populations and different mechanisms among occurrence, development, and survival, we speculated the ethnicity differences and mechanistic distinctions might explain these discordances.
Another novel result comes from the association between genders and mTOR
rs2295080 polymorphism in stratified analysis. This rs2295080 polymorphism revealed more strong significance in men than women. Additionally, Hartgrink et al
. (2009) has reported the ratio of men to women infected by gastric cancer is about 2
1 per annum 
. Further explanation for connections of these results needs to be sought, and different sorts of hormones expression in males and females become the best consideration, rationally. In a study of breast cancer, Galoian et al.
has given the data that prolinerich polypeptide-1 exerts antiproliferative effect via inhibiting mTOR kinase activity in ER-negative MDA-231, but no inhibitory effect exists in luminal T47-D cell which performs as an ER-positive cell line 
. However, for studies of androgen, it was believed that androgen might stimulate mTOR activity in PTEN-deficient prostate cancer cells. A recent study on androgen receptor improved the role of androgen in up-regulating mTORC2 activity 
. It is likely that androgen, instead of estrogen, may increase the mTOR
expression; androgen may lead to the high incidence of gastric cancer in men and the strong significance of mTOR
rs2295080 in male group in our study.
Some limitations of our present study should be pointed out as follows. First, rs2295080 was not the only polymorphism significantly existing on mTOR
, and the importance of combining SNPs was neglected in our study. Second, as crucial factors in gastric carcinogenesis, the lacks of Helicobacter pylori
information, smoking information, and drinking information were also insufficient in our study, it is untoward for us for further investigation of the effects of this polymorphism. In addition, because of the relative small sample size in our study, no significant results seemed to be found in particular strata (age subgroups, female subgroup, and other clinico-pathological subgroups) of stratified analyses (Table S3
). Further larger study with more information was expected to verify our findings.
In conclusion, our study illuminated the mTOR rs2295080 locating in the promoter region of mTOR gene was significantly associated with risk of gastric cancer in a Chinese population.