Expression of Iron-Regulatory Genes in Hepatocellular Carcinoma and Its Pathologic, Clinical, and Epidemiologic Significance
Date Issued
2009
Date
2009
Author(s)
Tseng, Hsi-Huang
Abstract
Recent advance in the discovery of iron-regulatory genes (IRGs) has greatly renewed our view of iron metabolism, and established the importance of the liver for it secretes the iron hormone hepcidin. The study aimed to answer the long-term pathologic curiosity as to why hepatoma cells are iron-negative, and the almost never explored question about iron nutrition in patients with hepatocellular carcinoma (HCC). e began the experiments in October 2005, measuring iron stores with Perls’ Prussian blue stain and 16 IRGs’ expression with real-time polymerase chain reaction (PCR) in HCCs and adjacent nontumor specimens of 50 HCC patients, who received surgery in Changhua Christian Hospital between 2000 and 2003. We found iron was depleted and five IRGs—hepcidin, ceruloplasmin, transferrin, transferrin receptor 1 and 2—were dysregulated in HCC, with hepcidin particularly showing a dramatic reduction. o search for the cause of hepcidin reduction, we performed methylaiton-specific PCR but found hepcidin promoter not hypermethylated in HCC. However, immunohistochemistry shows a reduced expression of the transcription factor CEBPA, and real-time PCR shows another transcription factor HNF4A3 was upregulated.ecause CEBPA is also a tumor suppressor, and its reduction was found associated with advanced tumor stage in our study, we further performed Kaplan–Meier survival analysis and Cox proportional hazards analysis and found an association between reduced CEBPA expression and shortened patient survival. Further methylation-specific PCR did not reveal an increase of CEBPA methylation in HCC.everal implications may be drawn from the study. First, loss of CEBPA and hepcidin may play role in causing the iron-negative phenomenon in hepatoma cells. Second, the altered expression of IRGs in HCC may lead the body toward paradoxical directions of iron imbalance, with iron accumulated in tissues but deficient in erythroid cells, thus further damaging the liver and contributing to patient anemia. Third, targeting CEBPA downregulation for HCC treatment may inhibit tumor growth and restore much of hepcidin expression and liver functions, thus improving patient survival and quality of life. Finally, nontumor part of the liver may increase hepcidin to defend the body against HCC—the malignancy in the very same organ.
Subjects
Hepatocellular carcinoma
iron-regulatory genes
DNA methylation
iron
hepcidin
anemia
survival
Type
thesis
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