Dataset Information

Increased expression of plakoglobin is associated with upregulated MAPK and PI3K/AKT signalling pathways in early resectable pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types, and it is associated with a 5-year survival rate of <10% due to limited early detection methods and ineffective therapeutic options. Thus, an improved understanding of the mechanisms involved in the early stages of PDAC tumorigenesis is crucial in order to identify potential novel diagnostic and therapeutic targets. The most common signalling aberrations in PDAC occur in the Wnt/Notch signalling pathway, as well as within the epidermal growth factor receptor (EGFR) pathway and its associated ligands, EGF and transforming growth factor-?. In addition, the RAS family of oncogenes, which act downstream of EGFR, are found mutated in most pancreatic cancer samples. Plakoglobin, a component of the EGFR signalling pathway, serves an important role in normal cell adhesion; however, its role in PDAC is largely unknown. The present study used transcriptome sequencing and focussed proteome microarrays to identify dysregulated genes and proteins in PDAC. The presence of upregulated plakoglobin expression levels was identified as a distinguishing feature between the PDAC microenvironment and normal pancreatic tissue. Furthermore, plakoglobin was demonstrated to be associated with the differential upregulation of the PI3K/AKT and MAPK signalling pathways in the tumour microenvironment, which suggested that it may serve an important role in PDAC tumourigenesis.

SUBMITTER: Nweke E

PROVIDER: S-EPMC7202312 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Increased expression of plakoglobin is associated with upregulated MAPK and PI3K/AKT signalling pathways in early resectable pancreatic ductal adenocarcinoma.

Nweke Ekene E Ntwasa Monde M Brand Martin M Devar John J Smith Martin M Candy Geoffrey G

Oncology letters 20200323 6

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types, and it is associated with a 5-year survival rate of <10% due to limited early detection methods and ineffective therapeutic options. Thus, an improved understanding of the mechanisms involved in the early stages of PDAC tumorigenesis is crucial in order to identify potential novel diagnostic and therapeutic targets. The most common signalling aberrations in PDAC occur in the Wnt/Notch signalling pathway, as well as w ...[more]

PMID: 32382352

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ?10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGF?-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.

Project description:Background Pancreatic ductal adenocarcinoma (PDAC) displays a typical mucin expression pattern which is characterized by MUC1 positive, MUC2 negative, and MUC5AC positive. More and more evidences show that mucins are involved in the development of pancreatic diseases. However, the relationship between mucin expression and prognosis of PDAC patients has been controversial in the past decades; therefore, we aim to figure out the association of mucin expression with survival in PDAC patients who underwent radical resection. Methods We performed immunohistochemistry (IHC) to detect the expression of MUC1, MUC2, and MUC5AC in resected PDAC specimens from Shanghai Cancer Center, Fudan University (FUSCC, n = 427) and obtained the corresponding clinical statistical data for retrospective study. Kaplan-Meier methods and Mantel-Cox tests were used to compare the survival curves, and the Cox regression model was employed for multivariate analyses to determine the independent risk factors. Survival analysis was also performed in the Queensland Centre for Medical Genomics (QCMG, n = 70) PDAC cohort to verify the conclusion. Results Both the FUSCC cohort and the QCMG cohort demonstrated that MUC1 absence was significantly correlated with worse overall survival (OS). The presence of MUC2 showed marginal significance in predicting shorter OS of PDAC patients, while MUC5AC had no prognostic value. In the FUSCC cohort, MUC1 absence was associated with increased proportion of stage III PDAC (p = 0.011), and MUC1 absence and MUC2 presence were associated with tumour perineural aggression (p = 0.011 and p = 0.030, respectively). Multivariable adjusted hazard ratios (HRs) for mortality of MUC1 and MUC2 were 0.492 (95% CI: 0.274-0.883, p = 0.017) and 1.596 (95% CI: 1.061-2.401, p = 0.025), respectively. Conclusions MUC1 absence or MUC2 presence is independently associated with poor OS among patients with resectable PDAC. MUC5AC absence tended to be associated with short-term death.

Dataset Information

Increased expression of plakoglobin is associated with upregulated MAPK and PI3K/AKT signalling pathways in early resectable pancreatic ductal adenocarcinoma.

Publications

Increased expression of plakoglobin is associated with upregulated MAPK and PI3K/AKT signalling pathways in early resectable pancreatic ductal adenocarcinoma.

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