The Prognostic Role of SOCS3 and A20 in Human Cholangiocarcinoma

<div><p>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.</p></div

Univariate log-rank test of clinicopathological features of 86 patients with cholangiocarcinoma.

<p>Univariate log-rank test of clinicopathological features of 86 patients with cholangiocarcinoma.</p

Inverse correlation between SFRP1 expression and β-catenin expression in human biliary tract cancer^*.

<p>*<i>r</i> = 0.636, <i>P</i> = 0.001.</p

Multivariate Cox regression analysis of prognostic markers in 78 patients with biliary tract cancer.

<p>*HR hazard ratio, CI confidence interval.</p

IHC staining for SOCS3 and A20 in human CCA.

<p>Original magnification 200×, scale bar = 100 μm. A. High SOCS3 expression was found predominately in the cytoplasm and cytomembrane in CCA tissues. B. Low SOCS3 expression in CCA tissues. C. High A20 expression was found in the nucleus. D. Low A20 expression in CCA tissues.</p

Multivariate Cox regression analysis of clinicopathological features of 86 patients with cholangiocarcinoma.

<p>HR, hazard ratio; CI, confidence interval.</p><p>Multivariate Cox regression analysis of clinicopathological features of 86 patients with cholangiocarcinoma.</p

Immunological staining for SFRP1 and β-catenin in human biliary tract carcinoma.

<p>Immunological staining for SFRP1 and β-catenin in human biliary tract carcinoma.</p

Relationships between the expression of SFRP1, β-catenin and clinicopathologic features in human biliary tract cancer.

<p>Relationships between the expression of SFRP1, β-catenin and clinicopathologic features in human biliary tract cancer.</p

Kaplan-Meier curves of overall survival in CCA patients.

<p>A. The correlation with SOCS3 level. B. The correlation with A20 level.</p

The inverse correlation between SOCS3 and A20.

<p>From left to right, the expression of SOCS3 is compared to that of A20 (n = 86) for high to high (n = 6), high to low (n = 18), low to high (n = 53) and low to low expression (n = 9) (r = -0.585, <i>P <</i> 0.0001).</p