Expression of claudins-1, -4, -5, -7 and occludin in hepatocellular carcinoma and their relation with classic clinicopathological features and patients' survival

Abstract

Background: Occludin and claudins are integral constituents of tight junction proteins and are de-regulated in various malignancies, including hepatocellular carcinoma (HCC). This study investigated whether expression of claudins 1, 4, 5, 7 and occludin may be used as prognostic markers for overall and disease-free survival in patients with HCC after hepatectomy.

Patients and methods: The study included 67 hepatectomy specimens obtained from an equal number of patients with HCC who underwent partial hepatectomy at the Patras University Hospital for therapeutic reasons. Ten normal liver tissues were used as controls. Expression of claudins 1, 4, 5, 7 and occludin in liver tissues was assessed by immunochemistry. Clinicopathological features were also available for each case.

Results: Expression of claudins 1, 4, 5, 7 and occludin was significantly increased in HCC specimens compared to non-neoplastic liver tissues and normal controls (p<0.001 in each case) Moreover, there was a statistically significant association between low level of claudin-4 and advanced tumor grade (p=0.03). Down-regulation of claudin-1 was associated with low overall survival in univariate survival analysis (p=0.049) and Kaplan-Meier analysis (p=0.04). Multivariate analysis showed that the claudin-4 level was an independent factor for survival prognosis (p=0.01). In addition, down-regulation of claudin-4 expression was associated with increased recurrence rate and low disease-free survival rate in univariate analysis (p=0.038), Kaplan-Meier plot (p=0.013) and multivariate analysis (p=0.013). A low level of claudin-5 and high level of claudin-7 levels were independent negative prognostic factors according to multivariate analysis (p=0.015 and 0.009, respectively).

Conclusion: The present study demonstrates that high expression of claudins 1, 4, 5 and down-regulation of claudin-7 are positive prognostic markers and are associated with good outcome and increased survival rates. Moreover, an increase in claudin-4 expression may serve as an independent positive prognostic factor for low recurrence rate after hepatectomy.

Keywords: Claudins; hepatocellular carcinoma; occludin; tight junction proteins.