Dataset Information

A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort.

ABSTRACT:

Objectives

Variant c.811+32C>A in intron 4 of the cholecystokinin-B receptor gene (CCKBR) was reported to correlate with higher pancreatic cancer risk and poorer survival. The variant was suggested to induce retention of intron 4, resulting in a new splice form with enhanced receptor activity. Our objective was to validate the c.811+32C>A variant as an emerging biomarker for pancreatic cancer risk and prognosis.

Methods

We genotyped variant c.811+32C>A in 122 pancreatic adenocarcinoma case patients and 106 control subjects by sequencing and examined its association with cancer risk and patient survival. We tested the functional effect of variant c.811+32C>A on pre-messenger RNA splicing in human embryonic kidney 293T and Capan-1 cells transfected with CCKBR minigenes.

Results

The allele frequency of the variant was similar between patients and control subjects (18.4% and 17.9%, respectively). Survival analysis showed no significant difference between median survival of patients with the C/C genotype (266 days) and patients with the A/C or A/A genotypes (257 days). CCKBR minigenes with or without variant c.811+32C>A exhibited no difference in expression of the intron-retaining splice variant.

Conclusion

These data indicate that variant c.811+32C>A in CCKBR does not have a significant impact on pancreatic cancer risk or survival in a Hungarian cohort.

SUBMITTER: Balazs A

PROVIDER: S-EPMC4783207 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Publications

A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort.

Balázs Anita A Németh Balázs Csaba BC Ördög Balázs B Hegyi Eszter E Hritz István I Czakó László L Czimmer József J Gódi Szilárd S Csiszkó Adrienn A Rakonczay Zoltán Z Párniczky Andrea A Izbéki Ferenc F Halász Adrienn A Kahán Zsuzsanna Z Hegyi Péter P Sahin-Tóth Miklós M

Pancreas 20160401 4

<h4>Objectives</h4>Variant c.811+32C>A in intron 4 of the cholecystokinin-B receptor gene (CCKBR) was reported to correlate with higher pancreatic cancer risk and poorer survival. The variant was suggested to induce retention of intron 4, resulting in a new splice form with enhanced receptor activity. Our objective was to validate the c.811+32C>A variant as an emerging biomarker for pancreatic cancer risk and prognosis.<h4>Methods</h4>We genotyped variant c.811+32C>A in 122 pancreatic adenocarci ...[more]

PMID: 26646278

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis, as it is difficult to predict or circumvent, and it develops chemoresistance quickly. One cellular mechanism associated with chemoresistance is alternative splicing dysfunction, a process through which nascent mRNA is spliced into different isoforms. Survivin (Baculoviral IAP Repeat-Containing Protein 5 (BIRC5)), a member of the inhibitor of apoptosis (IAP) protein family and a cell cycle-associated oncoprotein, is overexpressed in most cancers and undergoes alternative splicing (AS) to generate six different splicing isoforms.MethodsTo determine if survivin splice variants (SSV) could be involved in PDAC chemoresistance, a Gemcitabine (Gem) resistant (GR) cell line, MIA PaCa-2 GR, was created and assessed for its SSV levels and their potential association with GR. Cross-resistance was assessed in MIA-PaCa-2 GR cells to FIRINOX (5-fluorouracil (5-FU), irinotecan, and oxaliplatin). Once chemoresistance was confirmed, RT-qPCR was used to assess the expression of survivin splice variants (SSVs) in PDAC cell lines. To confirm the effect of SSVs on chemoresistance, we used siRNA to knockdown all SSVs or SSV 2β.ResultsThe MIA PaCa-2 GR cell line was 40 times more resistant to Gem and revealed increased resistance to FIRINOX (5-fluorouracil (5-FU), irinotecan, and oxaliplatin); when compared to the parental MIA-PaCa-2 cells. RT-qPCR studies revealed an 8-fold relative expression increase in SSV 2β and a 2- to 8-fold increase in the other five SSVs in the GR cells. Knockdown of all SSV or SSV 2β only, using small inhibitory RNA (siRNA), sensitized the GR cells to Gem, indicating that these SSVs play a role in PDAC chemoresistance.ConclusionThese findings provide evidence for the potential role of SSV 2β and other SSVs in innate and acquired PDAC chemoresistance. We also show that the expression of SSVs is not affected by the type of chemoresistance, therefore targeting survivin splice variants in combination with chemotherapy could benefit a wide range of patients.

Dataset Information

A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort.

Objectives

Methods

Results

Conclusion

Publications

A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort.

Similar Datasets

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