Clinicopathological and Prognostic Significance of Klotho and Estrogen Receptors Expression in Human Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is male-predominant cancer, but the underlying mechanism remains unclear. This study aimed to investigate the expression of the age-suppressing gene klotho and estrogen receptors (ERs) in HCC patients and analyze their association with clinicopathological variables and their effects on prognosis. Methods: The expression patterns of klotho, ER alpha, and ER beta were determined by tissue microarray and immunohistochemical technique, and their correlations with clinicopathological characteristics were investigated using univariate and multivariate analysis. Results: Klotho expression was significantly lower in HCC than in the adjacent noncancerous tissues (52.7% (49/93) vs. 90.8% (79/87), P =.000), and its protein level in HCC tissue was negatively correlated with clinical staging, histological grade, and stage of the primary tumor (T) (P <.05). Whereas the expression of nuclear ER alpha and ER beta was higher in HCC than their corresponding non-neoplastic tissues (55.9% (52/93) vs. 35.6% (31/87), P =.006; 59.1% (55/93) vs. 43.7% (38/87), P =.038), and the level of nuclear ER alpha and ER beta in HCC tissue was inversely correlated with T stage, tumor size, and clinical staging (P <.05). Correlation analysis showed the expression level of klotho, which is positively correlated with that of nuclear ERa (r = 0.243, P =.019). Patients with klotho-positive tumors had longer survival than those with klotho-negative tumors (P =.002). Cox proportional hazards model analysis demonstrated that positive expression of klotho was an important factor indicating good prognosis (P =.003). Conclusion: Klotho, partially regulated by ER alpha-mediated estrogen pathway, acts as a tumor suppressor and might be a novel biomarker candidate for predicting progression and prognosis in HCC patients.