PRSS1 mutations and the proteinase/antiproteinase imbalance in the pathogenesis of pancreatic cancer

Yi, Qiang; Dong, Feng; Lin, Lin; Liu, Qicai; Chen, Shu; Gao, Feng; He, Qingliang

doi:10.1007/s13277-015-3982-1

Cited by 13 publications

(13 citation statements)

References 19 publications

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“…The results revealed that multiple loci contained one of three genotypes: C/C, C/T or T/T (Fig. 1), which is similar to results that have been previously reported (18,19). Moreover, 58 patients with PDAC (43.75%) had the T/C genotype (Table I), which was regarded as a mutation.…”

Section: Resultssupporting

confidence: 90%

“…PRSS1 encodes trypsin-1, the main trypsinogen enzyme secreted by the pancreas. PRSS1 mutations have been associated with increased trypsin-1 serum levels as well as the trypsin and α1-antitrypsin imbalance observed in patients with pancreatic cancer, which may alter the pancreatic microenvironment and increase immunological escape and clonal proliferation of pancreatic cancer cells (19). However, the clinicopathological and prognostic significance of PRSS1 mutations in patients with PDAC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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PRSS1 genotype is associated with prognosis in patients with pancreatic ductal adenocarcinoma

Ding

Chen

et al. 2019

Oncol Lett

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The prognostic value of the genotype of the PRSS1 gene in patients with pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. The aim of the present study was to evaluate the association between the PRSS1 genotype and clinicopathological characteristics of patients with PDAC, as well as to explore the prognostic significance of the PRSS1 genotype in patients with PDAC. A total of 124 patients with PDAC patients were included in the current study and the PRSS1 genotype of the enrolled patients was determined by the polymerase chain reaction. Associations between the PRSS1 genotype and clinicopathological characteristics were subsequently analyzed using the Chi-square test. The impact of the PRSS1 genotype on patient prognosis was assessed using the Kaplan-Meier method, and predictive factors of overall survival (OS) time were analyzed by Cox regression. A total of 56 patients with PDAC (45.16%) had the T/C PRSS1 genotype, which was associated with large tumor sizes (P=0.027) and higher tumor node metastasis (TNM) stages (P=0.041). Following a median follow-up of 19 months, the T/C genotype of PRSS1 genotype was associated with a shorter OS time (P=0.037) compared with the C/C or T/T PRSS1 genotypes. Univariate and multivariate analyses revealed that PRSS1 genotype was identified to be an independent prognostic factor for the OS time of patients with PDAC. The results obtained in the current study suggested that the PRSS1 genotype, as well as factors such as the serum level of carbohydrate antigen 19-9 and the TNM stage, may act as independent prognostic factors for the OS time of patients with PDAC.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

PRSS1 genotype is associated with prognosis in patients with pancreatic ductal adenocarcinoma

Ding

Chen

et al. 2019

Oncol Lett

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“…The R117H mutation is a frequently observed germline mutation in PRSS1. N29I, A16V, D22G, K23R, A121T, and R122C mutations in the PRSS1 gene have also been reported to be rare mutations in cationic trypsinogen [39][40][41][42][43]. Among these mutations, we recurrently observed the A16V(C→T) mutation in 40% (8/20) of secretory carcinoma cases.…”

Section: Discussionmentioning

confidence: 69%

Characterization of novel genetic alterations in salivary gland secretory carcinoma

Hernández-Prera

Lim

et al. 2020

Modern Pathology

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Secretory carcinoma is a salivary gland tumor with a characteristic chromosomal translocation that results in an ETV6-NTRK3 fusion gene. Secretory carcinoma shows relatively frequent rates of lymph-node metastasis and tumor recurrence and has a characteristic histology. Except for the ETV6 translocation, genomic alterations in secretory carcinoma have not been reported. In the present study, we characterized the novel recurrent genetic mutations of secretory carcinoma. On the basis of histology, immunohistochemistry, and ETV6 gene break-apart fluorescence in situ hybridization assays, 22 tumors were classified as secretory carcinomas (19 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) and their clinicopathologic characteristics were reviewed. Targeted deep sequencing analyses were performed on 20 secretory carcinomas (17 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) to investigate their genetic alterations. The A16V (C→T) mutation in PRSS1, which encodes a cationic trypsinogen and has a mutation associated with hereditary pancreatitis and pancreatic adenocarcinoma, was observed in 40% (8/20) (7/17 of ETV6 translocation-positive and 1/3 of ETV6 translocation-negative secretory carcinomas). Pathogenic variants of MLH1, MUTYH, and STK11 were also identified. Variants of uncertain significance included mutations in KMT5A. These novel characteristic genetic alterations may advance current understandings of secretory carcinoma tumorigenesis and progression, leading to improved diagnoses and treatment strategies.

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“…31 Although the risk for pancreatic cancer may be lower than previously thought, 31 it may serve as a model for the role of pathological intracellular activation of trypsin that also play a role in pancreatic cancerogenesis. [32][33][34] However, direct mutation in the gene is unlikely to be the explanation in the vast majority of patients with PDAC, although being a likely key component in the risk of families with hereditary pancreatitis. 31,35 Trypsin in pancreatic precursor and other neoplastic lesions of the pancreas Trypsin has proliferative capacity, as demonstrated in several studies.…”

Section: An Enemy Within: a Trojan Horse To Cancer Invasiveness?mentioning

confidence: 99%

“…Further, gene expression may not reveal significant differences between normal and neoplastic tissue as trypsinogen is omnipresent in pancreatic tissue and ductal epithelial cells due to the physiological function of the exocrine role of the pancreas. In 1 study of 65 patients with pancreatic cancer, 8 (12.3%) patients had mutation in the serine protease 1 gene (PRSS1) coding for the cationic trypsinogen (trypsin 1), 33 with corresponding higher serum levels of trypsin compared to nonmutated cancers and controls. In another series of patients, mutation of PRSS1 did not seem to play a role in terms of pancreatic cancer development.…”

Section: Why Has Trypsin Yet To Be Investigated As a Major Player Befmentioning

confidence: 99%

Is There a Trojan Horse to Aggressive Pancreatic Cancer Biology? A Review of the Trypsin-PAR2 Axis to Proliferation, Early Invasion, and Metastasis

Søreide

Roalsø

Aunan

2020

Journal of Pancreatic Cancer

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Purpose: Pancreatic cancer is one of the most lethal of solid tumors and is associated with aggressive cancer biology. The purpose is to review the role of trypsin and effect on molecular and cellular processes potentially explaining the aggressive biology in pancreatic cancer. Methods: A narrative literature review of studies investigating trypsin and its effect on protease systems in cancer, with special reference to pancreatic cancer biology. Results: Proteases, such as trypsin, provides a significant advantage to developing tumors through the ability to remodel the extracellular matrix, promote cell invasion and migration, and facilitate angiogenesis. Trypsin is a digestive enzyme produced by the exocrine pancreas that is also related to mechanisms of proliferation, invasion and metastasis. Several of these mechanisms may be co-regulated or influenced by activation of proteinaseactivated receptor 2 (PAR-2). The current role in pancreatic cancer is not clear but emerging data suggest several potential mechanisms. Trypsin may act as a Trojan horse in the pancreatic gland, facilitating several molecular pathways from the onset, which leads to rapid progression of the disease. Pancreatic cancer cell lines containing PAR-2 proliferate upon exposure to trypsin, whereas cancer cell lines not containing PAR-2 fail to proliferate upon trypsin expression. Several mechanisms of action include a proinflammatory environment, signals inducing proliferation and migration, and direct and indirect evidence for mechanisms promoting invasion and metastasis. Novel techniques (such as organoid models) and increased understanding of mechanisms (such as the microbiome) may yield improved understanding into the role of trypsin in pancreatic carcinogenesis. Conclusion: Trypsin is naturally present in the pancreatic gland and may experience pathological activation intracellularly and in the neoplastic environment, which speeds up molecular mechanisms of proliferation, invasion, and metastasis. Further investigation of these processes will provide important insights into how pancreatic cancer evolves, and suggest new ways for treatment.

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PRSS1 mutations and the proteinase/antiproteinase imbalance in the pathogenesis of pancreatic cancer

Cited by 13 publications

References 19 publications

PRSS1 genotype is associated with prognosis in patients with pancreatic ductal adenocarcinoma

PRSS1 genotype is associated with prognosis in patients with pancreatic ductal adenocarcinoma

Characterization of novel genetic alterations in salivary gland secretory carcinoma

Is There a Trojan Horse to Aggressive Pancreatic Cancer Biology? A Review of the Trypsin-PAR2 Axis to Proliferation, Early Invasion, and Metastasis

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