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Opposite Roles of Human Pancreatitis-Associated Protein and REG1A Expression in Hepatocellular Carcinoma: Association of Pancreatitis-Associated Protein Expression with Low-Stage Hepatocellular Carcinoma, ß-Catenin Mutation, and Favorable Prognosis

Authors' Affiliations: Departments of ¹ Surgery and ² Pathology and ³ Hepatitis Research Center, National Taiwan University Hospital; Departments of ⁴ Surgery, ⁵ Graduate Institute of Pathology, and ⁶ Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan

Requests for reprints: Po-Huang Lee, Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. Phone: 886-2-23123456; Fax: 886-2-23934358; E-mail: pohuang{at}ha.mc.ntu.edu.tw.

Purpose: Pancreatitis-associated protein (PAP) and regenerating protein 1 (Reg1A) are up-regulated during the pancreas regeneration. This study is to investigate the clinicopathologic denotation of their expression in hepatocellular carcinoma (HCC).

Experimental Design: PAP and REG1A mRNA 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 ß-catenin mutation, regardless of REG1A expression, P < 0.00001. In the subset of HCCs that has no mutations of p53 and ß-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 ß-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.

Key Words: PAP • REG1A • ß-catenin • hepatocellular carcinoma

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