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. 1999 Oct;45(4):605–612. doi: 10.1136/gut.45.4.605

Group II and IV phospholipase A2 are produced in human pancreatic cancer cells and influence prognosis

M Kashiwagi 1, H Friess 1, W Uhl 1, P Berberat 1, M Abou-Shady 1, M Martignoni 1, S Anghelacopoulos 1, A Zimmermann 1, M Buchler 1
PMCID: PMC1727671  PMID: 10486373

Abstract

BACKGROUND—Phospholipase A2 (PLA2) is involved in regulating biosynthesis of arachidonic acid and its metabolites. There are three major structurally different forms of PLA2: group I, also called pancreatic PLA2 (PLA2-I); group II, referred to as secretory non-pancreatic or synovial or platelet PLA2 (PLA2-II); group IV, referred to as cytosolic PLA2 (PLA2-IV).
AIMS—To examine PLA2-I, PLA2-II, and PLA2-IV in normal and pancreatic cancer tissues.
 Patients—PLA2 was studied in 58 pancreatic adenocarcinomas, obtained from 25 women and 33 men undergoing pancreatic resection. Normal organ donor pancreas served as control.
METHODS—The enzymes were analysed by northern blot, in situ hybridisation, and immunohistochemistry. The molecular findings were correlated with clinical variables of the patients.
RESULTS—Northern blot analysis of total RNA showed enhanced PLA2 group II and IV mRNA expression in 52% and 55% of the pancreatic cancer samples respectively compared with the normal controls (p = 0.0013 and p = 0.0025). On immunohistochemical analysis, intense PLA2-I immunoreactivity was seen in acinar cells, but not in ductal cells, in the normal pancreas. In pancreatic cancer cells, PLA2-I immunostaining was absent. PLA2-II immunostaining was visible only in some acinar and ductal cells in the normal pancreas, whereas in pancreatic cancer increased PLA2-II immunoreactivity was present in 65% of the cancer samples. On in situ hybridisation, weak PLA2-IV mRNA signals were detected in acinar and ductal cells of normal samples; these signals were present to a much greater extent in pancreatic cancer cells. The presence of PLA2-II in pancreatic cancer was associated with a higher degree of fibrosis (p<0.01). Furthermore, there was a significant correlation between the enhanced expression of PLA2-II and longer survival after surgery (p<0.03), but not of PLA2-IV and longer postoperative survival.
CONCLUSION—These data suggest that PLA2-II and PLA2-IV are upregulated in human pancreatic cancer, and that upregulation of PLA2-II in pancreatic cancer covariates negatively with cancer cell growth.


Keywords: pancreas; cancer; phospholipase A2; survival analysis

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Figure 1  .

Figure 1  

Northern blot analysis of phospholipase A2 (PLA2)-I, PLA2-II, and PLA2-IV mRNA in the normal pancreas (first four lanes) and in pancreatic tissues obtained from patients with pancreatic cancer (last nine lanes). In cancer samples, levels of PLA2-I mRNA were reduced compared with the normal controls. In contrast, enhanced levels of PLA2-II and PLA2-IV mRNA were found in many cancer samples, whereas low to undetectable PLA2-II and PLA2-IV mRNA expression was present in normal controls. 7S mRNA was used to assess equivalent RNA loading.

Figure 2  .

Figure 2  

In situ hybridisation of phospholipase A2 (PLA2)-IV in the normal pancreas (A) and in pancreatic cancer (B, antisense hybridisation, C, sense hybridisation). In the normal pancreas, faint PLA2-IV mRNA signals were present in some acinar cells (A). In contrast, intense PLA2-IV mRNA signals were found in the pancreatic cancer cells (B). (C) Sense hybridisation of a pancreatic cancer sample which exhibited high levels of PLA2-IV mRNA in northern blot hybridisation. Original magnifications: A, B × 200; C × 400. 

Figure 3  .

Figure 3  

Immunohistochemical analysis of phospholipase A2 (PLA2)-I (A, B) and PLA2-II (C, D) in the normal pancreas (A, C) and in pancreatic cancer (B, D). PLA2-I immunostaining was abundant in acinar cells of the normal pancreas (A). No PLA2-I immunostaining was present in the pancreatic cancer cells (B). In the normal pancreas, only a few acinar cells exhibited cytoplasmic PLA2-II immunoreactivity (black arrows, C), whereas PLA2-II immunostaining was often present in pancreatic cancer cells (D). The slides are counterstained with haematoxylin. Original magnifications × 200. 

Figure 4  .

Figure 4  

Survival curves. (A) Kaplan-Meier plots of the postoperative survival periods in patients whose tumours were defined as having weak or no phospholipase A2 (PLA2)-II mRNA expression versus patients with moderate to strong PLA2-II mRNA expression (broken line). Cox analysis of the postoperative survival periods showed that patients whose tumours exhibited weak or no PLA2-II mRNA expression lived a significantly shorter time (p<0.02) than those whose tumours exhibited moderate to strong PLA2-II mRNA levels. (B) Kaplan-Meier plots of the postoperative survival periods in patients whose tumours were defined as having a PLA2-II immunoreactivity score <100 versus patients with a PLA2-II immunoreactivity score ⩾100. Cox analysis of the postoperative survival periods showed that patients whose tumours exhibited a low PLA2-II immunoreactivity score lived a significantly shorter time (p<0.05) than those with a higher immunoreactivity score. (C) Kaplan-Meier plots of the postoperative survival periods in patients whose tumours were defined as having weak or no PLA2-IV mRNA expression versus patients with moderate to strong PLA2-IV mRNA expression. Cox analysis of the postoperative survival periods indicated no difference in survival between these two patient groups.

Selected References

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