Consistent with the physiological and pathological roles of glutamate in cancer development, we found marked differences in the expression of SLC38A1 in gastric cancer relative to adjacent non-cancerous tissue. The uncontrolled proliferation of neoplastic cells requires dramatic changes in energy metabolism
, in which the primary metabolic fuel and nitrogen source for tumor cells in glutamine
[19–21]. Glutamine is known to exert influence on a number of signaling pathways that contribute to tumor growth
, and is additionally correlated with maintaining the TCA cycle and supporting NADPH production when glucose supply is limited
While glutamine is not an essential amino acid, it plays an important role in maintaining the intestinal barrier structure and immune function. Within the three mammalian system A amino acid transporters, SLC38A1 has the highest affinity for glutamine, and is strongly expressed in glutamatergic neurons
Low blood glutamine concentration has been found in patients with gastric carcinoma and conversely increased in the mucous membrane adjacent to the malignant tissue
. It is possible that ectopic activation of SLC38A1 may reflect a compensatory mechanism that confers a survival advantage.
SLC38A1 expression in gastric cancer and other malignancies
In the present study, we found an increased expression of SLC38A1 in gastric carcinomas, relative to adjacent non-cancerous gastric mucosa, suggesting that SLC38A1 might play an important part in gastric cancer malignant transformation. Enhanced SLC38A1 expression has been observed in several other types of malignancies, including liver cancer
, Hilar cholangiocarcinoma
 and C6 glioma
. An elevated expression of SLC38A1 has been found to be closely linked to differentiation status, lymph node metastasis and TNM staging, and is thus implicated in the growth, invasion, metastasis and progression of gastric carcinomas.
Potential mechanism of the action
Consistent with the observation in HepG2 liver cancer cell lines
, our study showed that inhibiting SLC38A1 expression with siRNA decreased the growth of cultured SH-10-TC cells, thus indicating an overexpression of SLC38A1 contributes to oncogenesis of gastric cancer through promoting cell proliferation. Inhibiting SLC38A1 expression also reduced cell migration, providing evidence for increased cell migration as a mechanism for enhanced metastatic potential, and local invasiveness of SLC38A1-expressing tumor cells.
In breast cancer, scientists discovered that 17 beta-estradiol specifically increased System A activity by two to four-fold in estrogen receptor positive cell lines, with a maximum stimulation observed 48 h after estrogen-treatment. In estrogen receptor negative cell lines, however, no stimulation was observed, which provided evidence that estrogen receptors play a role in the activation of system A by estrogen
. In liver cancer, System A amino acid transporters produced a different kind of inactivation and substrate protection in membrane vesicles and reconstituted proteoliposomes, supporting the hypothesis that there were inherent differences presented in System A carriers in normal and transformed liver tissue
. In the current study, we found enhanced SCL38A1 expression in gastric cancer, which supported the implication of glutamine metabolism in tumors
[29–31]. Interestingly, certain cancer cell lines are dependent on glutamine despite the fact that glutamine is a nonessential amino acid
. To be utilized by tumor cells, glutamine must be transported into tumor cell mitochondria. This implies that SLC38A1 could transport glutamine, and thus play an important role in neoplastic progression/development.
Association of SLC38A1 expression with clinicopathological characteristics as well as prognosis in patients with GC
Upon further investigation of the relationship between SLC38A1 and clinicopathological factors, we found that overexpression of SLC38A1 was strongly associated with patient age, differentiation status, lymph node metastasis, TNM stage and the expression of PCNA, whereas no significant association was found in patient gender, tumor size, tumor location, operation manner, lymphovascular invasion, depth of tumor invasion, and p53 expression. These results indicated that SLC38A1 plays a central role in the malignant progression of gastric carcinomas.
Risk factors for gastric cancers have been reported in a number of studies, including differentiation,
 nerve invasion
, lymphovascular invasion
[13, 34], TNM stage
, and some molecular markers
. Our study confirmed that differentiation, lymphovascular invasion and the TNM stage were independent predictors for gastric cancer. We additionally found that SLC38A1 expression alone was a prognostic factor, with its prognostic value in multivariate survival analysis for patients who underwent gastrectomy. Therefore, we supposed that overexpression of SLC38A1 is a significant factor associated with a poor prognosis, and might be a marker to forecast gastric cancer patients’ recurrence and survival. Secondly, patients with poorer prognosis should be monitored more closely and/or undergo more positive treatment.