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The Prognostic Role of SOCS3 and A20 in Human Cholangiocarcinoma.

Wang Y, Wan M, Zhou Q, Wang H, Wang Z, Zhong X, Zhang L, Tai S, Cui Y - PLoS ONE (2015)

Bottom Line: Although tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) can decrease SOCS3 expression and is involved in the regulation of tumorigenesis in certain malignancies, its role in CCA remains unknown.These proteins were both associated with CCA lymph node metastasis, postoperative recurrence and overall survival rate.Thus, our study demonstrated that SOCS3 and A20 represent novel prognostic factors for human CCA.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P. R. China; Key Laboratory of Myocardial Ischemia Mechanism and Treatment Ministry of Education, Harbin, Heilongjiang, P. R. China.

ABSTRACT
As an antagonist of the JAK/STAT pathway, suppressor of cytokine signaling 3 (SOCS3) plays an integral role in shaping the inflammatory environment, tumorigenesis and disease progression in cholangiocarcinoma (CCA); however, its prognostic significance remains unclear. Although tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) can decrease SOCS3 expression and is involved in the regulation of tumorigenesis in certain malignancies, its role in CCA remains unknown. In this study, we investigated the expression of SOCS3 and A20 in human CCA tissues to assess the prognostic significance of these proteins. The expression of SOCS3 and A20 was initially detected by western blot in 22 cases of freshly frozen CCA tumors with corresponding peritumoral tissues and 22 control normal bile duct tissues. Then, these proteins were investigated in 86 CCA patients by immunohistochemistry (IHC) and were evaluated for their association with clinicopathological parameters in human CCA. The results indicated that SOCS3 expression was significantly lower in CCA tumor tissues than in corresponding peritumoral biliary tissues and normal bile duct tissues. Conversely, A20 was overexpressed in CCA tissues. Thus, an inverse correlation between the expression of SOCS3 and A20 was discovered. Furthermore, patients with low SOCS3 expression or high A20 expression showed a dramatically lower overall survival rate. These proteins were both associated with CCA lymph node metastasis, postoperative recurrence and overall survival rate. However, only A20 showed a significant association with the tumor node metastasis (TNM) stage, while SOCS3 showed a significant association with tumor differentiation. Multivariate Cox analysis revealed that SOCS3 and A20 were independent prognostic indicators for overall survival in CCA. Thus, our study demonstrated that SOCS3 and A20 represent novel prognostic factors for human CCA.

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A20 and SOCS3 expression in CCA tissues.A. Western blot analysis of A20 and SOCS3 in CCA tumor tissues and normal biliary duct tissues. T, tumor tissue; P, peritumoral biliary tissue; N, normal biliary duct tissue. B. Expression index of SOCS3 protein. The SOCS3 protein expression level in T was significantly lower than that in P (P < 0.0001). C. Expression index of A20 protein. The A20 protein expression level in CCA was significantly higher than that in P (P < 0.0001). D. Linear regression analysis of A20 and SOCS3 expression in CCA tumor tissue and normal biliary duct tissues. Each point represents a tissue sample, with n = 66 cases (22 tumor, 22 paratumor, and 22 normal biliary duct tissues). The A20 level was inversely correlated with SOCS3 expression. A20 and SOCS3 protein levels were measured by expression index (the ratio of protein of interest to β-actin expression). ***: T compared with P or N, P < 0.05.
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pone.0141165.g001: A20 and SOCS3 expression in CCA tissues.A. Western blot analysis of A20 and SOCS3 in CCA tumor tissues and normal biliary duct tissues. T, tumor tissue; P, peritumoral biliary tissue; N, normal biliary duct tissue. B. Expression index of SOCS3 protein. The SOCS3 protein expression level in T was significantly lower than that in P (P < 0.0001). C. Expression index of A20 protein. The A20 protein expression level in CCA was significantly higher than that in P (P < 0.0001). D. Linear regression analysis of A20 and SOCS3 expression in CCA tumor tissue and normal biliary duct tissues. Each point represents a tissue sample, with n = 66 cases (22 tumor, 22 paratumor, and 22 normal biliary duct tissues). The A20 level was inversely correlated with SOCS3 expression. A20 and SOCS3 protein levels were measured by expression index (the ratio of protein of interest to β-actin expression). ***: T compared with P or N, P < 0.05.

Mentions: The protein expression levels of SOCS3 and A20 were first detected by western blot analysis in freshly frozen tumors and the corresponding peritumoral biliary tissues from 22 CCA cases. The SOCS3 signal was positive in only 27.27% (6 cases) of the tumor tissues, while it was positive in all corresponding peritumoral biliary tissues. Conversely, the A20 signal was positive in all tumor tissues and in 68.75% (15 cases) of the corresponding peritumoral biliary tissues (Fig 1A). The quantitative analysis of each protein band was standardized against β-actin expression in each sample, and the ratio of the protein of interest to β-actin expression was defined as the expression index. The protein expression level of SOCS3 in CCA tumor tissues was conspicuously lower than that in the corresponding peritumoral biliary tissues (7.56-fold on average, P < 0.0001), and it was also lower than that in normal biliary duct tissues (Fig 1B). In contrast, the protein expression level of A20 in CCA tumor tissues was conspicuously higher than that in the corresponding peritumoral biliary tissues (2.23-fold on average, P < 0.0001), and it was also significantly higher than the protein expression level of A20 in normal biliary duct tissues (Fig 1C). Linear regression analysis further revealed that the A20 level was inversely correlated with SOCS3 expression in CCA tumor tissues and normal biliary duct tissues (R2 = 0.8232, P < 0.0001; Fig 1D).


The Prognostic Role of SOCS3 and A20 in Human Cholangiocarcinoma.

Wang Y, Wan M, Zhou Q, Wang H, Wang Z, Zhong X, Zhang L, Tai S, Cui Y - PLoS ONE (2015)

A20 and SOCS3 expression in CCA tissues.A. Western blot analysis of A20 and SOCS3 in CCA tumor tissues and normal biliary duct tissues. T, tumor tissue; P, peritumoral biliary tissue; N, normal biliary duct tissue. B. Expression index of SOCS3 protein. The SOCS3 protein expression level in T was significantly lower than that in P (P < 0.0001). C. Expression index of A20 protein. The A20 protein expression level in CCA was significantly higher than that in P (P < 0.0001). D. Linear regression analysis of A20 and SOCS3 expression in CCA tumor tissue and normal biliary duct tissues. Each point represents a tissue sample, with n = 66 cases (22 tumor, 22 paratumor, and 22 normal biliary duct tissues). The A20 level was inversely correlated with SOCS3 expression. A20 and SOCS3 protein levels were measured by expression index (the ratio of protein of interest to β-actin expression). ***: T compared with P or N, P < 0.05.
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pone.0141165.g001: A20 and SOCS3 expression in CCA tissues.A. Western blot analysis of A20 and SOCS3 in CCA tumor tissues and normal biliary duct tissues. T, tumor tissue; P, peritumoral biliary tissue; N, normal biliary duct tissue. B. Expression index of SOCS3 protein. The SOCS3 protein expression level in T was significantly lower than that in P (P < 0.0001). C. Expression index of A20 protein. The A20 protein expression level in CCA was significantly higher than that in P (P < 0.0001). D. Linear regression analysis of A20 and SOCS3 expression in CCA tumor tissue and normal biliary duct tissues. Each point represents a tissue sample, with n = 66 cases (22 tumor, 22 paratumor, and 22 normal biliary duct tissues). The A20 level was inversely correlated with SOCS3 expression. A20 and SOCS3 protein levels were measured by expression index (the ratio of protein of interest to β-actin expression). ***: T compared with P or N, P < 0.05.
Mentions: The protein expression levels of SOCS3 and A20 were first detected by western blot analysis in freshly frozen tumors and the corresponding peritumoral biliary tissues from 22 CCA cases. The SOCS3 signal was positive in only 27.27% (6 cases) of the tumor tissues, while it was positive in all corresponding peritumoral biliary tissues. Conversely, the A20 signal was positive in all tumor tissues and in 68.75% (15 cases) of the corresponding peritumoral biliary tissues (Fig 1A). The quantitative analysis of each protein band was standardized against β-actin expression in each sample, and the ratio of the protein of interest to β-actin expression was defined as the expression index. The protein expression level of SOCS3 in CCA tumor tissues was conspicuously lower than that in the corresponding peritumoral biliary tissues (7.56-fold on average, P < 0.0001), and it was also lower than that in normal biliary duct tissues (Fig 1B). In contrast, the protein expression level of A20 in CCA tumor tissues was conspicuously higher than that in the corresponding peritumoral biliary tissues (2.23-fold on average, P < 0.0001), and it was also significantly higher than the protein expression level of A20 in normal biliary duct tissues (Fig 1C). Linear regression analysis further revealed that the A20 level was inversely correlated with SOCS3 expression in CCA tumor tissues and normal biliary duct tissues (R2 = 0.8232, P < 0.0001; Fig 1D).

Bottom Line: Although tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) can decrease SOCS3 expression and is involved in the regulation of tumorigenesis in certain malignancies, its role in CCA remains unknown.These proteins were both associated with CCA lymph node metastasis, postoperative recurrence and overall survival rate.Thus, our study demonstrated that SOCS3 and A20 represent novel prognostic factors for human CCA.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P. R. China; Key Laboratory of Myocardial Ischemia Mechanism and Treatment Ministry of Education, Harbin, Heilongjiang, P. R. China.

ABSTRACT
As an antagonist of the JAK/STAT pathway, suppressor of cytokine signaling 3 (SOCS3) plays an integral role in shaping the inflammatory environment, tumorigenesis and disease progression in cholangiocarcinoma (CCA); however, its prognostic significance remains unclear. Although tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) can decrease SOCS3 expression and is involved in the regulation of tumorigenesis in certain malignancies, its role in CCA remains unknown. In this study, we investigated the expression of SOCS3 and A20 in human CCA tissues to assess the prognostic significance of these proteins. The expression of SOCS3 and A20 was initially detected by western blot in 22 cases of freshly frozen CCA tumors with corresponding peritumoral tissues and 22 control normal bile duct tissues. Then, these proteins were investigated in 86 CCA patients by immunohistochemistry (IHC) and were evaluated for their association with clinicopathological parameters in human CCA. The results indicated that SOCS3 expression was significantly lower in CCA tumor tissues than in corresponding peritumoral biliary tissues and normal bile duct tissues. Conversely, A20 was overexpressed in CCA tissues. Thus, an inverse correlation between the expression of SOCS3 and A20 was discovered. Furthermore, patients with low SOCS3 expression or high A20 expression showed a dramatically lower overall survival rate. These proteins were both associated with CCA lymph node metastasis, postoperative recurrence and overall survival rate. However, only A20 showed a significant association with the tumor node metastasis (TNM) stage, while SOCS3 showed a significant association with tumor differentiation. Multivariate Cox analysis revealed that SOCS3 and A20 were independent prognostic indicators for overall survival in CCA. Thus, our study demonstrated that SOCS3 and A20 represent novel prognostic factors for human CCA.

No MeSH data available.


Related in: MedlinePlus