scholarly journals Glycoprotein 2 in health and disease: lifting the veil

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Yingsong Lin ◽  
Masahiro Nakatochi ◽  
Naoki Sasahira ◽  
Makoto Ueno ◽  
Naoto Egawa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Gastrointestinal Tract ◽  
Genome Wide Association Study ◽  
Cancer Susceptibility ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Intestinal Lumen ◽  
Zymogen Granules ◽  
A Genome ◽  
Health And Disease

AbstractIn 2020, we discovered glycoprotein 2 (GP2) variants associated with pancreatic cancer susceptibility in a genome-wide association study involving the Japanese population. Individuals carrying a missense coding variant (rs78193826) in the GP2 gene resulting in a p.V432M substitution had an approximately 1.5-fold higher risk of developing pancreatic cancer than those without this variant. GP2 is expressed on the inner surface of zymogen granules in pancreatic acinar cells, which are responsible for the sorting, storage and secretion of digestive enzymes. Upon neuronal, hormonal, or other stimulation, GP2 is cleaved from the membrane of zymogen granules and then secreted into the pancreatic duct and intestinal lumen. While the functions of GP2 remain poorly understood, emerging evidence suggests that it plays an antibacterial role in the gastrointestinal tract after being secreted from pancreatic acinar cells. Impaired GP2 functions may facilitate the adhesion of bacteria to the intestinal mucosa. In this review article, we summarize the role of GP2 in health and disease, emphasizing its functions in the gastrointestinal tract, as well as genetic variations in the GP2 gene and their associations with disease susceptibility. We hope that its robust genetic associations with pancreatic cancer, coupled with its emerging role in gastrointestinal mucosal immunity, will spur renewed research interest in GP2, which has been understudied over the past 30 years compared with its paralog uromodulin (UMOD).

scholarly journals Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer

2018 ◽  
Vol 115 (18) ◽  
pp. 4767-4772 ◽  
Author(s):  
Koji Tamura ◽  
Jun Yu ◽  
Tatsuo Hata ◽  
Masaya Suenaga ◽  
Koji Shindo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Er Stress ◽  
Odds Ratio ◽  
Cancer Susceptibility ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Familial Pancreatic Cancer ◽  
Coding Regions ◽  
Familial Cases ◽  
Genes Encoding

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15–76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.

scholarly journals A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33

2010 ◽  
Vol 42 (3) ◽  
pp. 224-228 ◽  
Author(s):  
Gloria M Petersen ◽  
Laufey Amundadottir ◽  
Charles S Fuchs ◽  
Peter Kraft ◽  
Rachael Z Stolzenberg-Solomon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Cancer Susceptibility ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome

scholarly journals A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Evangelina López de Maturana ◽  
◽  
Juan Antonio Rodríguez ◽  
Lola Alonso ◽  
Oscar Lao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Functional Analysis ◽  
Genetic Susceptibility ◽  
In Silico ◽  
Complex Disease ◽  
Meta Analysis ◽  
Low Frequency ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Phenotypic Variance

Abstract Background Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

scholarly journals SYNTHESIS AND MIGRATION OF PROTEINS IN THE CELLS OF THE EXOCRINE PANCREAS AS REVEALED BY SPECIFIC ACTIVITY DETERMINATION FROM RADIOAUTOGRAPHS

1963 ◽  
Vol 16 (1) ◽  
pp. 1-23 ◽  
Author(s):  
H. Warshawsky ◽  
C. P. Leblond ◽  
B. Droz
Keyword(s):  
Specific Activity ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Zymogen Granule ◽  
Zymogen Granules ◽  
The Mean ◽  
And Migration ◽  
Rats And Mice ◽  
Silver Grains ◽  
Golgi Zone

Radioautographs of pancreatic acinar cells were prepared in rats and mice sacrificed at various times after injection of leucine-, glycine-, or methionine-H3. Measurements of radioactivity concentration (number of silver grains per unit area) and relative protein concentration (by microspectrophotometry of Millon-treated sections) yielded the mean specific activity of proteins in various regions of the acinar cells. The 2 to 5 minute radioautographs as well as the specific activity time curves demonstrate protein synthesis in ergastoplasm. From there, most newly synthesized proteins migrate to and accumulate in the Golgi zone. Then they spread to the whole zymogen region and, finally, enter the excretory ducts. An attempt at estimating turnover times indicated that two classes of proteins are synthesized in the ergastoplasm: "sedentary" with a slow turnover (62.5 hours) and "exportable" with rapid turnover (4.7 minutes). It is estimated that the exportable proteins spend approximately 11.7 minutes in the Golgi zone where they are built up into zymogen granules, and thereafter 36.0 minutes as fully formed zymogen granules, before they are released outside the acinar cell as pancreatic secretion. The mean life span of a zymogen granule in the cell is estimated to be 47.7 minutes.

Abstract PO-056: Insulin receptor signaling in pancreatic acinar cells contributes to pancreatic cancer development

2021 ◽  
Author(s):  
Anni M. Y. Zhang ◽  
Jenny C. C. Yang ◽  
Twan J. J. de Winter ◽  
David F. Schaeffer ◽  
Janel L. Kopp ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Acinar Cells ◽  
Cancer Development ◽  
Pancreatic Acinar Cells ◽  
Receptor Signaling ◽  
Insulin Receptor Signaling

scholarly journals Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2606
Author(s):  
Carlotta Paoli ◽  
Alessandro Carrer
Keyword(s):  
Pancreatic Cancer ◽  
Ex Vivo ◽  
Acinar Cells ◽  
Lineage Tracing ◽  
Metabolic Reprogramming ◽  
Pancreatic Acinar Cells ◽  
Ductal Adenocarcinoma ◽  
Molecular Features ◽  
The Impact

The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.

scholarly journals Double immunocytochemical labeling applying the protein A-gold technique.

1982 ◽  
Vol 30 (1) ◽  
pp. 81-85 ◽  
Author(s):  
M Bendayan
Keyword(s):  
Tissue Section ◽  
Protein A ◽  
Antigenic Site ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Secretory Proteins ◽  
Zymogen Granules ◽  
Double Labeling ◽  
Gold Particles ◽  
Antigenic Sites

In the present study we report the modifications and the different steps of the protein A-gold (pAg) technique that allow the simultaneous demonstration of two antigenic sites on the same tissue section. The labeling is carried out in the following manner: face A of the tissue section is incubated with an antiserum followed by a pAg complex prepared with large gold particles; face B of the same tissue section is then incubated with a second antiserum followed by a pAg complex prepared with small gold particles. Each of the pAg complexes reveals a different antigenic site on opposite faces of the tissue section. The transparency of the section in the electron beam allows the visualization of the gold particles present on both faces. The double labeling pAg technique was applied for the simultaneous demonstration of two secretory proteins in the same Golgi, condensing vacuoles, and zymogen granules of the rat pancreatic acinar cells.

scholarly journals Macrophages in pancreatic cancer: Starting things off on the wrong track

2013 ◽  
Vol 202 (3) ◽  
pp. 403-405
Author(s):  
Xavier Deschênes-Simard ◽  
Yusuke Mizukami ◽  
Nabeel Bardeesy
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Inflammation ◽  
Acinar Cells ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Nuclear Factor ◽  
Oncogenic Transformation ◽  
Transcriptional Program ◽  
Cell Biol ◽  
Inflammatory Macrophages

Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor κB transcriptional program in normal pancreatic acinar cells, resulting in acinar–ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation.

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