Opposite roles of human pancreatitis-associated protein and REGIA expression in hepatocellular carcinoma:: Association of pancreatitis-associated protein expression with low-stage hepatocellular carcinoma, β-catenin mutation, and favorable prognosis

Purpose: Pancreatitis-associated protein (PAP) and regenerating protein 1 alpha (Reg1A) are upregulated during the pancreas regeneration. This study is to investigate the clinicopathologic denotation of their expression in hepatocellular carcinoma (HCC). Experimental Design: PAP and REG1A m RNA levels were measured in 265 surgically removed unifocal primary HCCs using reverse transcription-PCR. Results: PAP and REG1A mRNAs were detected in 97 (36.6%) and 55 (20.8%) HCCs, respectively, including 46 with coexpression but in none of the 219 nontumorous livers. HCCs with PAP expression correlated with low-stage tumors without evidence of vascular invasion (P = 0.013) but the REG1A expression did not. By a combination analysis, HCCs with PAP expression alone showed the lowest frequency of p53 mutation (P < 0.036), the highest rates of grade 1 and low-stage tumors (P < 0.007 and P < 0,001, respectively), less frequent early tumor recurrence (P = 0.051), and hence a better 5-year survival (P = 0.044) than groups expressing PAP and REG1A, REG1A alone, and neither PAP or REG1A. Besides, PAP expressing HCCs had significantly frequent beta-catenin mutation, regardless of REG1A expression, P < 0.00001. In the subset of HCCs that has no mutations of p53 and beta-catenin but showed PAP expression, coexpression of REG1A and PAP was associated with more frequent vascular invasion than PAP expression alone (P < 0.005). Conclusions: These data suggest that PAP expression designate a subset of low-grade, low-stage HCC with frequent beta-catenin mutation and hence more favorable prognosis, whereas further genetic or epigenetic alterations, such as p53 mutation and REG1A expression, lead to more advanced HCCs.