Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. An excess of iron in liver tissue causes oxidative stress, leading to hepatocellular carcinogenesis. Iron metabolism, which is regulated by a complex mechanism, is important for cancer cell survival. The aim of this study is to clarify the role of iron regulatory protein in the progression of HCC and in patient outcome. We first investigated the mRNA level of iron metabolism-related genes, including hepcidin, ferroportin 1 (FPN-1) and transferrin receptor (TFR)-1/2. TFR-1/2 protein expression was then evaluated in surgical specimens from 210 cases using immunohistochemistry, and we compared clinicopathological factors with TFR-1/2 expression. The mRNA expression levels of TFR-1 were significantly increased in HCC tissues compared with adjacent non-cancerous tissues (P = 0.0013), but there were no differences in other genes. High expression of TFR-1 in HCC was associated with the absence of alcohol abuse (P = 0.0467), liver cirrhosis (P < 0.0001), higher alpha-fetoprotein (AFP; P < 0.0001), smaller tumour size (P = 0.0022), poor histological differentiation (P < 0.0001) and morphological features (P < 0.0001). In contrast, high expression of TFR-2 in HCC was associated with lower AFP (P < 0.0001), well-differentiated histological grade (P < 0.0001) and morphological features (P = 0.0010). Multivariate analysis for both overall survival and recurrence-free survival indicated that high TFR-1 expression was a significant prognostic factor for poor outcome. We found an inverse correlation of TFR-1 and TFR-2 expression in AFP and tumour differentiation. TFR-1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection.