The Expression And Clinical Significance Of Suppressor Of Cytokine Signaling3(SOCS-3)in Gastric Cancer

Objective:To investigate the expression of SOCS-3, STAT-3and pSTAT-3mRNA and protein in human gastric carcinoma tissues; To explore the relationship between the expression of SOCS-3, STAT-3and pSTAT-3and clinicopathological features and to estimate the value in the prognosis of gastric cancer (GC).Methods:SOCS-3, STAT-3, and pSTAT-3were evaluated in GC tissues and adjacent nontumor tissues of107patients who underwent curative surgery by immunohistochemistry. Further, SOCS-3and STAT-3mRNA levels were also detected simultaneously. In addition, survival analysis was performed between clinicopathologic variables and prognosis of GC patients. Finally, correlative analysis was adopted for demonstration the best predictor of the survival independent factor.Results:1. There were significant differences of SOCS-3(χ2=7.35,P<0.001), STAT-3(χ2=3.29,P=0.014), and pSTAT3(χ2.16,P=0.008) protein expression between GC and non-tumor adjacent tissues. Thirty-one of107patients (29%) showed high-grade expression of SOCS-3protein in tumor tissues, while68of107patients (63.6%) showed high-grade expression in non-tumor adjacent tissues. For STAT-3and pSTAT-3, they were62.6%vs21.5and42.1%vs0. SOCS-3protein expression was negatively correlated with the expression of STAT-3and pSTAT-3proteins (p<0.05).2. The relative mRNA expression value of SOCS-3in GC tissues were significantly much lower than those in non-tumor adjacent tissues (0.37±0.14VS1.02±0.27, fold change0.36, p=0.025). Conversely, the relative mRNA expression value of STAT-3in GC tissues were significantly much higher than those in non-tumor adjacent tissues (3.15±1.32vs1.13±0.64, fold change2.79,P=0.004). To precisely assess the relevance of various clinicopathologic variables to SOCS-3mRNA expression, we conducted quantitative real-time PCR in the frozen paired normal and tumor samples from107GC patients. SOCS-3mRNA expression was significantly higher in high-grade expression of SOCS-3protein cases than low-grade expression of SOCS-3protein cases (2-(ΔΔCt) Fold change1.41,P=0.028), which was consistent with protein expression evaluated by immunohistochemistry.3. SOCS-3protein expression was significantly associated with several clinicopathologic variables in GC tissues as follows:gender, number of metastatic lymph nodes, extent of metastatic lymph nodes, STAT-3protein expression, and pSTAT-3protein expression (p<0.05). However, only STAT-3protein expression and number of metastatic lymph nodes were identified as the independent indicators of SOCS-3protein expression in GC tissues after curative surgery with the binary logistic regression multivariate analysis (p<0.05). Furtermore, N stage was eventually identified as the most relative variable to SOCS-3protein expression with the multinomial logistic regression analysis (p<0.05). STAT-3protein expression was significantly associated with extent of metastatic lymph nodes and N stage (p<0.05). However, only N stage was identified as the independent indicators of STAT-3protein expression in GC tissues after curative surgery with the binary logistic regression multivariate analysis (p<0.05). pSTAT-3protein expression was significantly associated with extent of metastatic lymph nodes and N stage (p<0.05). However, only extent of metastatic lymph nodes was identified as the independent indicators of STAT-3protein expression in GC tissues after curative surgery (p<0.05).4. Univariate analysis showed significant relationships between OS and SOCS-3protein expression, STAT protein expression, N stage, and extent of metastatic lymph nodes (p<0.05), but not with age at surgery, gender, size of tumor, location of tumor, depth of tumor invasion (T stage, according to the7th edition TNM classification for GC), and Lauren’s classification of tumor. Furthermore, SOCS-3protein expression (HR=3.673;P<0.001), and N stage (HR=1,569;P<0.001) were identified as the independent factors of OS in all enrolled GC patients following the multivariate analysis (Cox proportional hazards model, forward:LR).Conclusion:1. The SOCS-3gene mRNA and protein expression in gastric tumor tissues were significantly lower than those in adjacent non-tumor tissues. It suggested that SOCS-3may be a tumor suppressor gene.2. SOCS-3was the best predicator of lymph node metastasis from GC identified with the norminal regression analysis. Therefore, SOCS-3should be considered as a potential indicator for predication the lymph node metastasis from GC.