Opposite roles of human pancreatitis-associated protein and REG1A expression in hepatocellular carcinoma: association of pancreatitis-associated protein expression with low-stage hepatocellular carcinoma, beta-catenin mutation, and favorable prognosis.
OBJECTIVE
Pancreatitis-associated protein (PAP) and regenerating protein 1 alpha (Reg1A) are up-regulated during the pancreas regeneration. This study is to investigate the clinicopathologic denotation of their expression in hepatocellular carcinoma (HCC).


METHODS
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 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.
Yuan
Ray-Hwang
RH
Department of Surgery, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Jeng
Yung-Ming
YM
Chen
Hui-Ling
HL
Hsieh
Fon-Jou
FJ
Yang
Ching-Yao
CY
Lee
Po-Huang
PH
Hsu
Hey-Chi
HC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D051847:Lithostathine; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000073718:Pancreatitis-Associated Proteins; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; D037181:Lectins, C-Type; D051847:Lithostathine; D009419:Nerve Tissue Proteins; D000073718:Pancreatitis-Associated Proteins; C497617:REG1A protein, human; C000612141:REG3A protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin