High α‐fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: Significance of hepatitis virus infection, age, p53 and β‐catenin mutations

Abstract

Key words: ␣-fetoprotein; hepatocellular carcinoma; p53; ␤-catenin; tumor stage; prognosis ␣-Fetoprotein (AFP), a member of the albuminoid multigene family located at chromosome 4q11-q13, 1 is abundantly expressed in the fetal yolk sac and liver, 2,3 but not in normal adult tissues. Chromosome 4q is one of the most frequent chromosomal region exhibiting allelic losses in hepatocellular carcinoma (HCC), 4 -7 whereas AFP expression resurges during liver regeneration 8 and in HCC. 2,8 -10 The AFP elevation in HCC has been shown to correlate with poor tumor differentiation, 9,10 tumor burden, 11 early recurrence after tumor resection 12,13 and unfavorable prognosis. 11 Serum AFP elevation concurrent with aberrant growth is usually regarded as coincidental, and its role in HCC progression receives little attention. However, cumulative evidence has shown that AFP plays an important role in the regulation of tumor growth and cell differentiation 14 -17 and can stimulate proliferation of human hepatoma cells, probably through the AFP receptors. 17-19 AFP-producing gastric cancer is more aggressive with higher malignant potential, high frequency of liver metastasis and a poor prognosis than AFP-negative gastric cancers. 20,21 HCC clones derived from the same parent cell line exhibited higher serum AFP levels in nude mice bearing tumor implants with high metastatic potential than in those with low metastatic tumor implants. 22 These findings indicate the potential role of AFP in progression and metastasis of HCC.Regulation of AFP gene expression is a complex process mediated by a number of transcriptional activators and repressors binding to a complex of promoter and enhancer(s) within the AFP gene. 23,24 Clinically, AFP elevation in sera or AFP mRNA expression in HCC occurs more often in HCC patients of younger age 9 and positive for serum HBsAg. 10,11 But the molecular mechanism is not fully understood. The tumor suppressor p53 acts through its binding within the AFP repressor region, displacing bound HNF-3 and altering the chromatin structure at the core promoter, to repress AFP gene expression. 25,26 Recently, it is shown that mutant ␤-catenin can induce p53 expression via the induction of p14(ARF), 27 which in turn leads to suppression of AFP expression through site-specific DNA binding within the AFP repressor domain, and the repression is abolished by mutation within the DNA binding domain of p53 protein. 25 The p53 and ␤-catenin genes are the 2 most commonly mutated genes in HCC, 28 -33 but their potential interplay in AFP elevation remains to be elucidated.In this study, we aimed to examine the AFP levels in HCC with special emphases on their relations to the tumor progression, the related factors including mutations of p53 and ␤-catenin and the usefulness of AFP mRNA detection in the liver for the prediction of early tumor recurrence. MATERIAL AND METHODS PatientsFrom 1987 to 1997, 909 surgically resected primary HCCs were pathologically assessed at the National Taiwan University Hospital. Among them, 781 unif...

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

“…In contrast, overexpression of p110 CUX1 was able to accelerate S phase entry and to stimulate proliferation, migration and invasion 35,48 . Moreover, CUX1 was shown to promote genomic instability following cytokinesis failure 30 Regulation of AFP gene expression is a complex process mediated by a number of transcriptional activators and repressors that bind the AFP gene 7,8 . ZBTB20 was recently identified as a potent repressor of AFP transcription in knockout mouse studies 9 .…”

“…3f). As mutation of β-catenin has also been reported to be involved in upregulation of AFP expression 8 , we next analysed β-catenin activity in miR122-silenced cells. Similar to p53, no change in β-catenin activity was evident in miR122-silenced cells compared with control cells (Fig.…”

DEP Domain Containing 1 is a Novel Diagnostic Marker and Prognostic Predictor for Hepatocellular Carcinoma

“…High AFP as an indicator of poor survival was reported previously (Peng et al, 2004;Cheng et al, 2011). A systematic review of 72 studies revealed that PVTT, large tumor size, tumor number are robust indicators of poor prognosis (Tandon and Garcia-Tsao, 2009).…”

Distinctions Between Clinicopathological Factors and Prognosis of Alpha-fetoprotein Negative and Positive Hepatocelluar Carcinoma Patients

“…If there is an abnormal increase, it implies the occurrence of some certain disease, such as hepatocellular carcinoma and embryonal cell carcinoma. Nowadays, AFP is generally used not only in screening and diagnosing HCC, but also in evaluating the prognosis of HCC patients who undergo the hepatectomy (Peng et al, 2004). Although AFP has occasionally been reported in some other primary tumor e.g.…”