Gastric cancer is one of the most common cancers worldwide and it poses one of the most serious public health problem [1
]. Recurrence and metastasis are still the major issues for the poor survival of advanced gastric cancer patients [30
]. Although previous studies have found that many aberrant expressed genes in gastric tumor can help classify the risk of patient outcome [5
], more novel molecular markers that can identify tumor progression and predict the prognosis individually are still urgently needed. The 14-3-3 family proteins have gained much attention over the past years due to their involvement in cancers by regulation of diverse cellular processes [14
]. Among the seven isoforms, 14-3-3σ is up-regulated by p53 in response to DNA damage, and sequesters the essential mitotic initiation complex, cdc2-cyclin B1, from entering the nucleus, thus preventing the initiation of mitosis [31
]. As a result, 14-3-3σ induces G2 arrest and allows DNA damage repair. Thus, different from other members of the family, 14-3-3σ is defined as a negative regulator of cell cycle checkpoints and a potential tumor-suppressor protein [12
]. However, the biological role of 14-3-3ơ in tumorigenesis and progression of various types of human tumors remains controversial. Here, to further reveal the biological function of 14-3-3ơ in gastric cancer, we studied 14-3-3ơ expression dynamics and analyzed their clinicopathological/prognostic significances in 152 tumor specimens.
In this study, to develop an objective 14-3-3σ cutoff point for survival analysis, we used the ROC curve analysis to generate a cutoff score in the training set. 14-3-3σ expression, which was classified as high and low level by the ROC-derived cutoff point, was mainly found to be higher in more advanced tumor stages (stage III and IV), indicating that 14-3-3σ might be involved in gastric cancer progression. Correlation analysis further demonstrated that high 14-3-3σ expression was associated with clinical stage and tumor invasion in gastric cancer (Table ). Furthermore, in the testing set and overall patients, high 14-3-3ơ expression predicted a significant OS and PFS disadvantage over low 14-3-3ơ expression subgroup (Figure ). Importantly, worse prognostic impact of increased 14-3-3σ expression was demonstrated in patients with stage III and IV tumors (Figure ), indicating that 14-3-3ơ might be a novel factor for risk definition in gastric cancer. In addition, multivariate analyses in the testing set and overall patients revealed that 14-3-3ơ expression was an independent prognostic parameter. Taken together, our findings in this study provided evidence that elevated expression of 14-3-3σ in gastric cancer might facilitate an increased malignant and worse prognostic phenotype of this tumor.
With regard to the prognostic impact of 14-3-3σ in different human cancers, some of the reported data are totally contradictory. It was documented that loss expression of 14-3-3σ was linked to a poor prognosis of patients with breast and nasopharyngeal cancers [23
]. However, consistent with the results found in pancreatic and colorectal carcinomas [26
], our finding in this study showed that high expression of 14-3-3σ was positively associated with clinic stage and poor survival. The underlying mechanism(s) of 14-3-3σ to impact cancer prognosis might be depended on intrinsic properties of the tumor type. Moreover, different co-expression of 14-3-3σ and other molecules [24
], as well as the nature of the therapeutic regimen in various types of human cancers [32
], which further make us to understand that the function of 14-3-3σ and its underlying mechanism(s) to impact cancer prognosis may be tumor-type specific. Recently, studies have showed that overexpression of 14-3-3σ is correlated with tumor metastasis and progression in pancreatic [25
], breast [33
] and ovarian cancer cells [34
], which may further explain our findings that higher 14-3-3σ expression is mainly detected in more advanced tumor stages and also identified as a poor prognosis indicator in late-stage gastric cancer patients. Hence, our study demonstrated that 14-3-3σ was an independent prognostic biomarker for OS and PFS in gastric cancer. Especially, overexpression of 14-3-3σ was relevant with tumor progression. The findings reported here could have clinical value in predicting the prognosis of gastric cancer and identifying gastric cancer patients that are at high risk of progression and recurrence.