scholarly journals Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Yuki Shibayama ◽  
Kazuo Takahashi ◽  
Hisateru Yamaguchi ◽  
Jun Yasuda ◽  
Daisuke Yamazaki ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Genomic Instability ◽  
Chromosomal Abnormalities ◽  
Point Mutations ◽  
Nuclear Bodies ◽  
Receptor Expression ◽  
Ductal Adenocarcinoma ◽  
Structural Variations ◽  
Aberrant Expression ◽  
Genome Level

Abstract(Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. Aberrant (P)RR expression is prevalent in pancreatic ductal adenocarcinoma (PDAC) which is the most common pancreatic cancer. Here we show whether aberrant expression of (P)RR directly leads to genomic instability in human pancreatic ductal epithelial (HPDE) cells. (P)RR-expressing HPDE cells show obvious cellular atypia. Whole genome sequencing reveals that aberrant (P)RR expression induces large numbers of point mutations and structural variations at the genome level. A (P)RR-expressing cell population exhibits tumour-forming ability, showing both atypical nuclei characterised by distinctive nuclear bodies and chromosomal abnormalities. (P)RR overexpression upregulates SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) through a direct molecular interaction, which results in the failure of several genomic stability pathways. These data reveal that aberrant (P)RR expression contributes to the early carcinogenesis of PDAC.

scholarly journals MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

Stresses ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 30-47
Author(s):  
Maria Mortoglou ◽  
David Wallace ◽  
Aleksandra Buha Buha Djordjevic ◽  
Vladimir Djordjevic ◽  
E. Damla Arisan ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Metabolic Stress ◽  
Resistance Mechanisms ◽  
Current Data ◽  
Cellular Damage ◽  
Ductal Adenocarcinoma ◽  
Aberrant Expression ◽  
Metabolic Alterations ◽  
Limited Effectiveness ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.

Differential alteration of TRAIL and its receptor expression profiles in patients with pancreatic ductal adenocarcinoma

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 15607-15607
Author(s):  
A. D. Sanlioglu ◽  
E. Dirice ◽  
O. Elpek ◽  
A. F. Korcum ◽  
M. K. Balci ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Expression Profiles ◽  
Receptor Expression ◽  
Ductal Adenocarcinoma

scholarly journals ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage

2017 ◽  
Vol 77 (20) ◽  
pp. 5576-5590 ◽  
Author(s):  
Lukas Perkhofer ◽  
Anna Schmitt ◽  
Maria Carolina Romero Carrasco ◽  
Michaela Ihle ◽  
Stephanie Hampp ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Genomic Instability ◽  
Ductal Adenocarcinoma ◽  
Adenocarcinoma Cells

Understanding the Genetics of Pancreatic Adenocarcinoma

2017 ◽  
Author(s):  
Apoorve Nayyar ◽  
Jen Jen Yeh
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
High Throughput Sequencing ◽  
Cellular Proliferation ◽  
Molecular Subtypes ◽  
Expression Patterns ◽  
Ductal Adenocarcinoma ◽  
Early Event ◽  
Familial Pancreatic Cancer ◽  
Structural Variations ◽  
Cancer Heterogeneity

The underlying molecular basis of pancreatic ductal adenocarcinoma (PDAC) is complex, with multiple genetic, epigenetic, and transcriptomic changes. Five to 10% of PDAC cases have a hereditary basis, with multiple risk-conferring genetic mutations running in the family. All PDAC tumors develop from noninvasive precursor lesions that reflect the temporal accumulation of mutations. Recent advances in high-throughput sequencing technologies have facilitated a better understanding of the diverse mutational landscape of PDAC, reaffirming the role of genes previously known to be mutated (K-ras, CDKN2A, TP53, SMAD4, SLIT/ROBO, SWI/SNF) and revealing novel insights into the differential gene expression patterns and structural variations involved. K-ras mutation, an early event in disease pathogenesis, plays a pivotal role in the initiation, progression, and maintenance of PDAC, with the mutation type impacting disease pathophysiology and prognosis. The subsequent loss of tumor suppressors (CDKN2A, TP53, SMAD4) promotes genetic instability and uncontrolled cellular proliferation. Molecular subtypes with potential prognostic and therapeutic relevance have been identified. The challenge now is to translate this wealth of knowledge to the clinic. This review contains 3 figures, 3 tables and 50 references Key words: familial pancreatic cancer, heterogeneity, molecular subtypes, pancreatic ductal adenocarcinoma, whole genome/exome sequencing

DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma

2002 ◽  
Vol 20 (23) ◽  
pp. 4531-4542 ◽  
Author(s):  
Andrew V. Biankin ◽  
Adrienne L. Morey ◽  
C.-Soon Lee ◽  
James G. Kench ◽  
Sandra A. Biankin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Prognostic Factors ◽  
Cell Signaling ◽  
Cyclin D1 ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Size ◽  
Perineural Invasion ◽  
Ductal Adenocarcinoma ◽  
Aberrant Expression ◽  
Smad4 Expression

PURPOSE: Prognostic indicators in pancreatic cancer (PC) are poorly defined and difficult to quantify preoperatively, hence they may lead to inappropriate patient selection for treatment. We examined the protein expression of key cell-cycle regulatory and cell-signaling molecules that occur at high frequency in PC and assessed their relationship to clinicopathologic parameters, response to operative resection, and outcome.PATIENTS AND METHODS: We identified 348 patients with pancreatic ductal adenocarcinoma and assessed the influence of reported clinicopathologic prognostic factors and the expression of the cell-cycle regulatory genes p21WAF1/CIP1(CDKN1A), cyclin D1 (CCND1), p53, and p16INK4A(CDKN2) and the cell-signaling molecule DPC4/Smad4 (MADH4) using immunohistochemistry in a subgroup of 129 patients.RESULTS: Independent prognostic factors in resected patients were tumor size greater than 45 mm (P = .0015), involvement of surgical margins (P < .0001), and perineural invasion (P = .014). Loss of DPC4/Smad4 expression cosegregated with resectability (P < .0001) and was associated with improved survival after resection (P < .0001), whereas resection did not improve survival in patients whose tumor expressed DPC4/Smad4 (P = .5). Aberrant expression of p21WAF1/CIP1, cyclin D1, p53, or p16INK4Awas not associated with a difference in survival.CONCLUSION: Tumor size (> 45 mm), resection margin involvement, and perineural invasion were independent prognostic factors. Preoperative assessment of DPC4/Smad4 expression has potential as a prognostic indicator in patients with PC since resection did not benefit those patients whose cancers expressed DPC4/Smad4 and accurate assessment of DPC4/Smad4 expression, unlike tumor size, margin status, and perineural invasion, does not require resection.

scholarly journals Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4993
Author(s):  
Danilo Ranieri ◽  
Luisa Guttieri ◽  
Salvatore Raffa ◽  
Maria Rosaria Torrisi ◽  
Francesca Belleudi
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Intracellular Signaling ◽  
Specific Protein ◽  
Ductal Adenocarcinoma ◽  
Aberrant Expression ◽  
Downstream Signaling ◽  
Adenocarcinoma Cells ◽  
Autophagic Process ◽  
Signaling Activation

Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant malignancy characterized by a high malignant phenotype including acquired EMT signature and deregulated autophagy. Since we have previously described that the aberrant expression of the mesenchymal FGFR2c and the triggering of the downstream PKCε signaling are involved in epidermal carcinogenesis, the aim of this work has been to assess the contribution of these oncogenic events also in the pancreatic context. Biochemical, molecular and immunofluorescence approaches showed that FGFR2c expression impacts on PDAC cell responsiveness to FGF2 in terms of intracellular signaling activation, upregulation of EMT-related transcription factors and modulation of epithelial and mesenchymal markers compatible with the pathological EMT. Moreover, shut-off via specific protein depletion of PKCε signaling, activated by high expression of FGFR2c resulted in a reversion of EMT profile, as well as in a recovery of the autophagic process. The detailed biochemical analysis of the intracellular signaling indicated that PKCε, bypassing AKT and directly converging on ERK1/2, could be a signaling molecule downstream FGFR2c whose inhibition could be considered as possible effective therapeutic approach in counteracting aggressive phenotype in cancer.

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