Transferrin receptor 1 overexpression is associated with tumor dedifferentiation and acts as a potential prognostic indicator of hepatocellular carcinoma

Abstract

Aim

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.

Materials

We first investigated the mRNA level of iron‐metabolism‐related genes including hepcidin, ferroportin 1 (FPN1), and transferrin receptor (TFR)‐1/‐2. Then TFR1/2 protein expression was evaluated in surgical specimens from 210 cases using immunohistochemistry, and we compared clinicopathologic factors with TFR1/2 expression.

Results

The mRNA expression levels of TFR1 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 TFR1 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 tumor size (p=0.0022), poor histological differentiation (p<0.0001) and morphological features (p<0.0001). In contrast, high expression of TFR2 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 TFR1 expression was a significant prognostic factor for poor outcome.

Conclusion

We found an inverse correlation of TFR1 and TFR2 expression in AFP and tumor differentiation. TFR1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection

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