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...

BACKGROUNDIntrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression.METHODSOPN mRNA levels, which were increased preferentially in HCC in a DD assay and verified with Northern blotting, were measured in 240 surgically removed, unifocal, primary HCCs using the reverse transcription–polymerase chain reaction at the exponential phase. OPN mRNA expression was correlated with clinicopathologic features, particularly portal vein invasion, early tumor recurrence, and prognosis.RESULTSOsteopontin mRNA was overexpressed in 133 tumors (55%). The OPN overexpression was associated closely with α‐fetoprotein elevation (P = 0.001), p53 mutation (P = 0.021), larger tumors (P = 0.002), high‐grade HCC (P < 0.001), late‐stage HCC (P < 0.001), early tumor recurrence and/or metastasis (P = 0.003), and a lower 10‐year survival rate (P = 0.00013). Multivariate analysis revealed that tumor stage and early tumor recurrence were crucial prognostic factors. In early‐stage HCC, which has no vascular invasion and a lower early tumor recurrence than late‐stage HCC, OPN mRNA overexpression predicted a higher early recurrence rate (P = 0.003).CONCLUSIONSOPN mRNA overexpression was correlated closely with high‐grade, late‐stage, and early tumor recurrence, which lead to poorer prognosis. Osteopontin overexpression might serve as an unfavorable prognostic factor and a useful marker for predicting early recurrence in early‐stage HCC. Cancer 2003;98:119–27. © 2003 American Cancer Society.DOI 10.1002/cncr.11487

SUMMARY (De)acetylation of histone and non-histone proteins is an important post-translational modification affecting many cellular processes. Here we report that NuA4 acetylation of Sip2, one of three regulatory β subunits of Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. We used mutations at four acetylation sites, K12, 16, 17 and 256, to study acetyl-Sip2 function. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), ultimately leads to slower growth but extends replicative lifespan. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a novel protein acetylation- phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging and extends replicative lifespan in yeast.

Etiological variations in hepatocellular carcinoma (HCC) exist across different geographic areas. To gain better control of HCC, we retrospectively studied the secular trends and geographic variations in hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related HCCs in Taiwan. A total of 18,423 HCC cases enrolled in 8 medical centers from 1981 to 2001 were reviewed. Overall, 67% of male HCC in Taiwan was related to HBV infection whereas 55.2% of female HCC in Taiwan was related to HCV infection. The mean age of patients with HBV-related HCC was 53.2 6 13.6 years, while the mean age of patients with HCV-related HCC was 65.1 6 9.1 years (p < 0.001). The male/female ratio was 6.4 for HBV-related HCC, while it was 1.7 for the HCV-related HCC (p < 0.001). The percentage of HBV-related HCC progressively decreased from 81.5 to 66.2% in males, and from 66.7 to 41.4% in females over the study period. Our study demonstrates that the percentage of HBV-related HCC has progressively decreased over the last 20 years. The relative decrease in HBV-related HCC was not due to a decrease in HBV-related HCC death. Instead, it was caused by an increase in HCV-related HCC. Prevention of new HCV infection and the treatment of chronic hepatitis C should be the primary goals, which will result in better control of HCC in the future, even in an HBV-endemic area like Taiwan. ' 2006 Wiley-Liss, Inc.Key words: hepatocellular carcinoma; hepatitis B virus; hepatitis C virus; secular trend; geographic variation; Taiwan Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially in sub-Saharan Africa and Southeast Asia. Since 1984, it has been the leading cause of cancer death in Taiwan, 1 accounting for approximately 7,000 death annually. In addition, around 8,000 new HCC cases are diagnosed each year. 2 High-risk groups for HCC include patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), liver cirrhosis patients, and people with a family history of HCC. Chronic HBV and HCV infections are the 2 major etiologies of HCC in Taiwan. 3 About 15-20% of the general population in Taiwan are chronic carriers of hepatitis B surface antigen (HBsAg). 4 HBV carriers have a 20-to 98-fold increased risk of HCC, 5,6 especially among the hepatitis B e antigen (HBeAg)-positive group. 7 A recent prospective study has further confirmed that positivity for HBeAg is associated with an increased risk of HCC. 8 To combat HBV infection in Taiwan, a mass immunization program has been launched on July 1, 1984, aiming first at the prevention of perinatal mother-to-infant, chronic HBV infection. 9 This nationwide vaccination program has markedly decreased the HBV carrier rate 10 and childhood HBVrelated HCCs (B-HCCs). 11 An 80-85% decrease in HCC among Taiwanese adults up to 3-4 decades later is anticipated. 12 The prevalence of anti-HCV antibody (anti-HCV) is 2-4% among the general population of Taiwan, 13 while it ranges from 0.95 to 2.2% in Taiwanese blood donors. 13,14 The anti-HCV prevalen...

Percutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.