Human P2X7 receptor variants Gly150Arg and Arg276His polymorphisms have differential effects on risk association and cellular functions in pancreatic cancer

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Abstract

Background

The purinergic P2X7 receptor (P2X7R) plays an important role in the crosstalk between pancreatic stellate cells (PSCs) and cancer cells, thus promoting progression of pancreatic ductal adenocarcinoma (PDAC). Single nucleotide polymorphisms (SNPs) in the P2X7R have been reported for several cancers, but have not been explored in PDAC.

Materials and methods

Blood samples from PDAC patients and controls were genotyped for 11 non-synonymous SNPs in P2X7R and a risk analysis was performed. Relevant P2X7R-SNP GFP variants were expressed in PSCs and cancer cells and their function was assayed in the following tests. Responses in Ca ²⁺ were studied with Fura-2 and dye uptake with YO-PRO-1. Cell migration was monitored by fluorescence microscopy. Released cytokines were measured with MSD assay.

Results

Risk analysis showed that two SNPs 474G>A and 853G>A (rs28360447, rs7958316), that lead to the Gly150Arg and Arg276His variants, had a significant but opposite risk association with PDAC development, protecting against and predisposing to the disease, respectively. In vitro experiments performed on cancer cells and PSCs expressing the Gly150Arg variant showed reduced intracellular Ca ²⁺ response, fluorescent dye uptake, and cell migration, while the Arg276His variant reduced dye uptake but displayed WT-like Ca ²⁺ responses. As predicted, P2X7R was involved in cytokine release (IL-6, IL-1β, IL-8, TNF-α), but the P2X7R inhibitors displayed varied effects.

Conclusion

In conclusion, we provide evidence for the P2X7R SNPs association with PDAC and propose that they could be considered as potential biomarkers.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12935-024-03339-9.

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Most cited references 50

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Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods

J Ferlay, M Colombet, I Soerjomataram … (2018)

Estimates of the worldwide incidence and mortality from 36 cancers and for all cancers combined for the year 2018 are now available in the GLOBOCAN 2018 database, compiled and disseminated by the International Agency for Research on Cancer (IARC). This paper reviews the sources and methods used in compiling the cancer statistics in 185 countries. The validity of the national estimates depends upon the representativeness of the source information, and to take into account possible sources of bias, uncertainty intervals are now provided for the estimated sex- and site-specific all-ages number of new cancer cases and cancer deaths. We briefly describe the key results globally and by world region. There were an estimated 18.1 million (95% UI: 17.5-18.7 million) new cases of cancer (17 million excluding non-melanoma skin cancer) and 9.6 million (95% UI: 9.3-9.8 million) deaths from cancer (9.5 million excluding non-melanoma skin cancer) worldwide in 2018.

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Pancreatic cancer

Jonathan Mizrahi, Rishi Surana, Juan W. Valle … (2020)

Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.

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Is Open Access

Estimated Projection of US Cancer Incidence and Death to 2040

Lola Rahib, Mackenzie R. Wehner, Lynn Matrisian … (2021)

Question How will the landscape of cancer incidences and deaths change in the next 2 decades? Findings In this cross-sectional study, the results estimate that leading cancer incidences and deaths in the US will be notably different in the year 2040 compared with current rankings. Estimates included increases in melanoma incidence, pancreatic cancer deaths, and liver cancer deaths, and decreases in prostate cancer incidence and breast cancer deaths. Meaning These estimates will be important to guide research, health care, and health policy efforts and emphasize the importance of cancer screening, early detection, and prevention. This cross-sectional study examines recent data from the Surveillance, Epidemiology, and End Results Program and US Census to estimate projections for US cancer incidence and deaths to 2040. Importance Coping with the current and future burden of cancer requires an in-depth understanding of trends in cancer incidences and deaths. Estimated projections of cancer incidences and deaths will be important to guide future research funding allocations, health care planning, and health policy efforts. Objective To estimate cancer incidences and deaths in the United States to the year 2040. Design and Setting This cross-sectional study’s estimated projection analysis used population growth projections and current population-based cancer incidence and death rates to calculate the changes in incidences and deaths to the year 2040. Cancer-specific incidences and deaths in the US were estimated for the most common cancer types. Demographic cancer-specific delay-adjusted incidence rates from the Surveillance, Epidemiology, and End Results Program were combined with US Census Bureau population growth projections (2016) and average annual percentage changes in incidence and death rates. Statistical analyses were performed from July 2020 to February 2021. Main Outcomes and Measures Total cancer incidences and deaths to the year 2040. Results This study estimated that the most common cancers in 2040 will be breast (364 000 cases) with melanoma (219 000 cases) becoming the second most common cancer; lung, third (208 000 cases); colorectal remaining fourth (147 000 cases); and prostate cancer dropping to the fourteenth most common cancer (66 000 cases). Lung cancer (63 000 deaths) was estimated to continue as the leading cause of cancer-related death in 2040, with pancreatic cancer (46 000 deaths) and liver and intrahepatic bile duct cancer (41 000 deaths) surpassing colorectal cancer (34 000 deaths) to become the second and third most common causes of cancer-related death, respectively. Breast cancer (30 000 deaths) was estimated to decrease to the fifth most common cause of cancer death. Conclusions and Relevance These findings suggest that there will be marked changes in the landscape of cancer incidence and deaths by 2040.

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Author and article information

Contributors

Ivana Novak: inovak@bio.ku.dk

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 25 April 2024

Publication date PMC-release: 25 April 2024

Publication date Collection: 2024

Volume: 24

Electronic Location Identifier: 148

Affiliations

[1 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Section for Cell Biology and Physiology, Department of Biology, , University of Copenhagen, ; Universitetsparken 13, 2100 Copenhagen Ø, Denmark

[2 ]Department of Drug Design and Pharmacology, University of Copenhagen, ( https://ror.org/035b05819) Copenhagen, Denmark

[3 ]Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte Hospital, ( https://ror.org/051dzw862) Herlev, Denmark

[4 ]Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, ( https://ror.org/05bpbnx46) Herlev, Denmark

[5 ]GRID grid.475435.4, Department of Clinical Biochemistry, , Copenhagen University Hospital Rigshospitalet, ; Copenhagen, Denmark

[6 ]Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, ( https://ror.org/035b05819) Copenhagen, Denmark

Article

Publisher ID: 3339

DOI: 10.1186/s12935-024-03339-9

PMC ID: 11044319

PubMed ID: 38664691

SO-VID: 31d7616d-7767-4b3a-a468-c948f6118f80

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 16 February 2024

Date accepted : 18 April 2024

Funding

Funded by: Marie Skłodowska-Curie COFUND Doctoral Programme TALENT

Award ID: grant number H2020-MSCA-COFUND-2017-801199

Award Recipient : Lara Magni Ivana Novak

Funded by: FundRef http://dx.doi.org/10.13039/100008392, Sundhed og Sygdom, Det Frie Forskningsråd;

Award ID: 8020-00254B

Award Recipient : Ivana Novak

Funded by: Copenhagen University

Open Access :

Open access funding provided by Copenhagen University

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: pancreatic ductal adenocarcinoma,snp,p2x7r,pancreatic stellate cells,pancreatic cancer cells,il-6

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: pancreatic ductal adenocarcinoma, snp, p2x7r, pancreatic stellate cells, pancreatic cancer cells, il-6

Human P2X7 receptor variants Gly150Arg and Arg276His polymorphisms have differential effects on risk association and cellular functions in pancreatic cancer

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Abstract

Background

Materials and methods

Results

Conclusion

Supplementary Information

Related collections

Karger: Oncology

Most cited references 50

Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods

Pancreatic cancer

Estimated Projection of US Cancer Incidence and Death to 2040

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