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

Abstract

Purpose: Pancreatitis-associated protein (PAP) and regenerating protein 1 A (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 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 1and lowstage 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 h-catenin mutation, regardless of REG1A expression, P < 0.00001. In the subset of HCCs that has no mutations of p53 and h-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, lowstage HCC with frequent h-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.

Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with β-catenin mutations

“…Whether expression of REG1A and REG3A during hepatocarcinogenesis is a marker of poor prognosis is still unknown. However, a recent clinical data report their differential expression in HCC according to the tumor progression: REG3A would be correlated to a favorable prognosis, whereas expression of REG1A, alone or in combination with REG3A, is associated with a poor outcome (Yuan et al, 2005). This observation is close to that found in colorectal carcinogenesis where coexpression of these REG genes appears closely linked to the adverse outcome of the disease (Macadam et al, 2000).…”

“…However, we could not demonstrate that b-catenin directly regulates REG3A promoter activity: REG3A promoter constructs containing up to 2000 bp of regulatory sequences with several LEF/TCF sites showed no responsiveness to b-catenin signaling in transfection experiments (unpublished data). Albeit indirect, the regulation of REG genes expression by Wnt signaling is reinforced by a recent clinical study, which reports in a large series of 265 HCC a strong association between b-catenin mutation and overexpression of REG1A (P ¼ 0.00005) and REG3A (PAP) (Po0.00001) (Yuan et al, 2005).…”

Pancreatitis‐Associated Protein Is Related Closely to Neoplastic Proliferative Activity in Patients with Colorectal Carcinoma

“…patients with carcinoma (Christa et al, 1999;Rechreche et al, 1999;Cerwenka et al, 2001;Xie et al, 2003;Yonemura et al, 2003;Dhar et al, 2004;Yuan et al, 2005). PAP expression in carcinoma might be another characteristic of PAP (Rosty et al, 2002).…”

Expression of Reg Family Proteins in Embryonic Stem Cells and Its Modulation by Wnt/β-Catenin Signaling

“…Enhanced levels of the human Reg3A (also known as pancreatitis-associated protein (PAP)) and Reg1α were discovered in primary liver tumors with β-catenin mutations suggesting a possible regulation of these Reg genes by the canonical Wnt/β-catenin signaling pathway [ 17 ]. A strong association between β-catenin mutations and changes in the expression of Reg genes was also documented in a recent clinical study involving biopsy samples from patients with liver cancer [ 18 ]. Dysregulated activation of the canonical Wnt signaling has also been identifi ed in other cancer types (eg, seminoma [ 19 ], colon [ 20 ]) in which Reg proteins have been shown to be aberrantly overexpressed.…”

“…Reverse transcription was performed using the ImProm-II reverse transcriptase (Promega, Madison, WI) with 1 μg of total RNA and 250 ng random primers or oligo(dT) [12][13][14][15][16][17][18] primers at 42°C for 60 min. PCR runs were carried out with the resulting cDNA for 30-35 cycles at an annealing temperature of 58°C-60°C depending on the primer set.…”