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Expression of multiple forms of 3'-end variant CCK2 receptor mRNAs in human pancreatic adenocarcinomas
Anna Ryberg1, Kurt Borch, Hans-Jürg Monstein
1Division of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Clinical Microbiology, County Council of Östergötland, S-581 85 Linköping, Sweden. hans-jurg.monstein@liu.se.
Background:
Two main types of receptors for gastrin and cholecystokinin (CCK) have been cloned and identified. CCK1 (CCK-A) receptors are expressed in the pancreas, the gallbladder, and parts of the brain, while CCK2 (CCK-B/gastrin) receptors (CCK2R) are expressed in gastric glands and in most of the brain. A splice variant of the CCK2R designated CCKRi4sv (CCK-C), which is constitutively expressed in human pancreatic cancer cells, has also been described. The purpose of the present investigation was to study CCK2R, CCK2i4svR, and gastrin mRNA expression in human pancreatic adenocarcinoma on the assumption that co-expression of CCK2R and gastrin or constitutive CCK2i4svR mRNA expression plays a pivotal role in the progression of pancreatic cancer.
Findings:
PCR amplification using CCK2R specific primer-pairs, followed by ethidium-bromide stained agarose gel electrophoresis revealed the expression of wild-type CCK2R mRNA in 12 of 17 biopsy specimens. A CCK2R intron 4 specific nested PCR assay revealed that CCK2i4svR mRNA was expressed in only one of the biopsy specimen. The authenticity of PCR amplicons was confirmed by cloning of selected amplicons and DNA sequence analysis. Moreover, we found that hitherto undescribed multiple forms of 3'-end variant CCK2R mRNAs with various deletions in the retained intron 4 and exon 5, tentatively generating truncated proteins, were expressed in the pancreatic adenocarcinomas.
Conclusion:
Cloning and DNA sequencing of selected amplicons revealed that CCK2R and multiple CCK2i4svR-like mRNAs are expressed in human pancreatic adenocarcinoma. The originally described CCK2i4svR mRNA was only expressed in one of 17 tumours and appears to be rarely expressed in pancreatic adenocarcinoma. We report that CCK2R- and gastrin mRNA co-expression may play a role in a portion, but not in all of these tumours, and that aberrant splicing takes places in these tissues generating multiple forms of 3'-end variant CCK2R mRNAs.
Insights
Gastrin and cholecystokinin receptor 2 (CCK2R) mRNA, along with novel variants, are expressed in pancreatic cancer. Aberrant splicing generates multiple CCK2R mRNA forms, suggesting a role in tumor progression.
Area of Science:
- Molecular biology
- Oncology
- Gastroenterology
Background:
- Two main gastrin and cholecystokinin (CCK) receptors exist: CCK1 (CCK-A) and CCK2 (CCK-B/gastrin) receptors (CCK2R).
- CCK2R is found in gastric glands and the brain; a splice variant, CCKRi4sv (CCK-C), is in human pancreatic cancer cells.
- The role of CCK2R, CCK2i4svR, and gastrin mRNA in pancreatic cancer progression is under investigation.
Purpose of the Study:
- To investigate CCK2R, CCK2i4svR, and gastrin mRNA expression in human pancreatic adenocarcinoma.
- To determine if co-expression of CCK2R and gastrin or constitutive CCK2i4svR mRNA expression is pivotal in pancreatic cancer progression.
Main Methods:
- PCR amplification with CCK2R-specific primers.
- Ethidium-bromide stained agarose gel electrophoresis.
- Cloning and DNA sequence analysis of PCR amplicons.
Main Results:
- Wild-type CCK2R mRNA was expressed in 12 of 17 pancreatic adenocarcinoma biopsy specimens.
- CCK2i4svR mRNA was detected in only one specimen.
- Multiple 3'-end variant CCK2R mRNAs with deletions in intron 4 and exon 5 were identified, potentially generating truncated proteins.
Conclusions:
- CCK2R and multiple CCK2i4svR-like mRNAs are expressed in human pancreatic adenocarcinoma.
- The originally described CCK2i4svR mRNA is rarely expressed in these tumors.
- CCK2R and gastrin mRNA co-expression may contribute to the progression of a subset of pancreatic adenocarcinomas, with aberrant splicing generating variant CCK2R mRNAs.
