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Immunity, Inflammation and Disease Jul 2023The expression of cytoplasmic poly (A) binding protein-1 (PABPC1) has been reported in multiple cancer types. This protein is known to modulate cancer progression....
BACKGROUND
The expression of cytoplasmic poly (A) binding protein-1 (PABPC1) has been reported in multiple cancer types. This protein is known to modulate cancer progression. However, the effects of PABPC1 expression in pancreatic adenocarcinoma (PAAD) have not been investigated. Here, we investigate the regulatory targets and molecular mechanisms of PABPC1 in PAAD.
METHODS
PABPC1 and collagen type XII α1 chain (COL12A1) expression in PAAD and their role in tumor prognosis and tumor stage were investigated using The Cancer Genome Atlas database analysis. After silencing PABPC1, messenger RNA sequencing and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. The expression of differentially expressed genes (DEGs), cell viability, apoptosis, and cell migration and invasion were explored using reverse transcription-quantitative polymerase chain reaction, Cell Counting Kit-8 assay, flow cytometry assay, and transwell assay, respectively. The relationship between PABPC1 and COL12A1 expression was assessed by Pearson's correlation analysis. The regulatory function of COL12A1 in PABPC1-affected BXPC3 cell behavior was studied after COL12A1 was overexpressed.
RESULTS
PABPC1 and COL12A1 expression was upregulated in patients with PAAD and was linked to poor prognosis. Four hundred and seventy-four DEGs were observed in BXPC3 cells after PABPC1 silencing. GO and KEGG analyses revealed that the top 10 DEGs were enriched in cell adhesion pathways. Additionally, PABPC1 silencing inhibited cell viability, migration, and invasion and accelerated apoptosis in BXPC3 cells. PABPC1 silencing increased AZGP1 and ARHGAP30 expression and decreased CAV1 and COL12A1 expression in BXPC3 cells. PABPC1 positively mediated COL12A1 expression, whereas PABPC1 knockdown induced the inhibition of BXPC3 cell proliferation, migration, and invasion.
CONCLUSION
The results of this study indicate that PABPC1 may function as a tumor promoter in PAAD, accelerating BXPC3 cell proliferation and metastasis by regulating COL12A1 expression.
Topics: Humans; Adenocarcinoma; Cell Proliferation; Collagen Type XII; GTPase-Activating Proteins; Pancreatic Neoplasms; Prognosis; Poly(A)-Binding Protein I
PubMed: 37506150
DOI: 10.1002/iid3.919 -
Gut Mar 2024Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.
DESIGN
To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.
RESULTS
Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92).
CONCLUSION
A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.
Topics: Humans; CA-19-9 Antigen; Biomarkers, Tumor; Cell-Free Nucleic Acids; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Pancreas; Adenocarcinoma; DNA Methylation
PubMed: 38123998
DOI: 10.1136/gutjnl-2023-331074 -
Frontiers in Endocrinology 2023The excess deposition of intra-pancreatic fat deposition (IPFD) has been reported to be associated with type 2 diabetes, chronic pancreatitis, and pancreatic ductal...
AIMS
The excess deposition of intra-pancreatic fat deposition (IPFD) has been reported to be associated with type 2 diabetes, chronic pancreatitis, and pancreatic ductal adenocarcinoma. In the current study, we aimed to identify a relationship between lifestyle factors and IPFD.
MATERIALS AND METHODS
99 patients admitted to the Osaka University Hospital who had undergone abdominal computed tomography were selected. We evaluated the mean computed tomography values of the pancreas and spleen and then calculated IPFD score. Multiple regression analyses were used to assess the associations between IPFD score and lifestyle factors.
RESULTS
Fast eating speed, late-night eating, and early morning awakening were significantly associated with a high IPFD score after adjusting for age, sex, diabetes status and Body Mass Index (p=0.04, 0.01, 0.01, respectively).
CONCLUSION
The current study has elucidated the significant associations of fast eating speed, late-night eating, and early morning awakening with IPFD.
Topics: Humans; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Pancreas; Pancreatic Neoplasms; Life Style
PubMed: 37576958
DOI: 10.3389/fendo.2023.1219579 -
Redox Biology Dec 2023Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant...
Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability. Here we demonstrate that PDA cells are sensitive to the inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protect from ferroptosis. We attacked the susceptibility of PDA cells to ferroptotic death with selenorganic compounds, including dibenzyl diselenide (DBDS) that exhibits potent pro-oxidant properties and inhibits tumor growth in vitro and in vivo. DBDS treatment induces the mobilization of iron from mitochondria enabling uncontrolled lipid peroxidation. Finally, we showed that DBDS and statins act synergistically to promote ferroptosis and provide evidence that combined treatment is a viable strategy to combat PDA.
Topics: Humans; Ferroptosis; Selenium; Pancreas; Pancreatic Neoplasms; Lipid Peroxidation
PubMed: 38029455
DOI: 10.1016/j.redox.2023.102962 -
Animal Models and Experimental Medicine Oct 2023Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and receive effective chemotherapy have the best chance for long-term survival....
BACKGROUND
Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and receive effective chemotherapy have the best chance for long-term survival. Unfortunately, because of the heterogeneity of pancreatic cancer, it is difficult to find a personalized treatment strategy for patients. Organoids are ideal preclinical models for personalized medicine. Therefore, we explore the cultivation conditions and construction methods of PDAC organoid models to screen the individualized therapy strategy.
METHODS
Fresh PDAC tissues from surgical resection were collected and digested with digestive enzymes; then the tumor cells were embedded in Matrigel with a suitable medium to establish the PDAC organoid models. The genetic stability of the organoids was analyzed using whole exon sequencing; hematoxylin and eosin staining and immunohistochemistry of organoids were performed to analyze their consistency with the pathological morphology of the patient's tumor tissue; After 2 days of organoid culture, we selected four commonly used clinical chemotherapy drugs for single or combined treatment to analyze drug sensitivity.
RESULTS
Two cases of PDAC organoid models were successfully established, and the results of their pathological characteristics and exome sequencing were consistent with those of the patient's tumor tissue. Both PDAC organoids showed more sensitivity to gemcitabine and cisplatin, and the combined treatment was more effective than monotherapy.
CONCLUSION
Both organoids better retained the pathological characteristics, genomic stability, and heterogeneity with the original tumor. Individual PDAC organoids exhibited different sensitivities to the same drugs. Thus, this study provided ideal experimental models for screening individualized therapy strategy for patients with PDAC.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Precision Medicine; Organoids
PubMed: 37890865
DOI: 10.1002/ame2.12352 -
Pancreatology : Official Journal of the... Dec 2023Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based...
BACKGROUND
Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based prognostic model for PDAC by using relevant proteomic biomarkers data from The Cancer Genome Atlas (TCGA).
METHODS
We obtained PDAC's proteomic and clinical data from TCGA and used various analytical tools to identify differentially expressed proteins between normal and cancer tissues. We constructed our protein-based prognostic model and confirmed its accuracy using receiver operating characteristic curve and Kaplan-Meier survival analyses. We elucidated clinical factor-signature protein correlations by clinical correlation assessments and protein coexpression networks. We also used immunohistochemistry (protein expression assessment), Gene Set Enrichment Analysis (protein role identification) and CIBERSORT (infiltrating immune cell distribution assessment).
RESULTS
CIITA, BRAF_pS445, AR, YTHDF2, IGFBP2 and CDK1_pT14 were identified as PDAC-associated prognostic proteins. All risk scores calculated using our model provided 1-, 3-, 5-year survival probability at 70 % accuracy. The reliability of our model was validated by the GEO as well. In high- and low-risk groups, age, sex, T- and N- stage disparities were significant, and prognostic and coexpressed proteins correlated. PDAC tissues demonstrated significant CDK1_pT14 overexpression but significant BRAF_pS445, YTHDF2, and IGFBP2 underexpression. Downstream proteins of BRAF were validated by IHC. Low-risk tissues demonstrated more naïve B cells, eosinophils, activated NK cells and regulatory T cells, whereas high-risk tissues demonstrated more activated memory T cells, monocytes, neutrophils, dendritic cells and resting NK cells.
CONCLUSIONS
Our protein-based prognostic model for PDAC, along with six signature proteins, might aid in predicting PDAC prognosis and therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Prognosis; Adenocarcinoma; Proteomics; Proto-Oncogene Proteins B-raf; Reproducibility of Results; Carcinoma, Pancreatic Ductal; Biomarkers; Biomarkers, Tumor
PubMed: 37923686
DOI: 10.1016/j.pan.2023.10.021 -
World Journal of Gastroenterology Sep 2023Pancreatic ductal adenocarcinoma (PDAC) remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed countries. Despite advances in cancer treatment, the 5-year survival rate for patients with PDAC remains less than 5%. In recent years, neoadjuvant therapy (NAT) has emerged as a promising treatment option for many cancer types, including locally advanced PDAC, with the potential to improve patient outcomes. To analyze the role of NAT in the setting of locally advanced PDAC over the past decade, a systematic literature search was conducted using PubMed and Web of Science. The results suggest that NAT may reduce the local mass size, promote tumor downstaging, and increase the likelihood of resection. These findings are supported by the latest evidence-based medical literature and the clinical experience of our center. Despite the potential benefits of NAT, there are still challenges that need to be addressed. One such challenge is the lack of consensus on the optimal timing and duration of NAT. Improved criteria for patient selection are needed to further identify PDAC patients likely to respond to NAT. In conclusion, NAT has emerged as a promising treatment option for locally advanced PDAC. However, further research is needed to optimize its use and to better understand the role of NAT in the management of this challenging disease. With continued advances in cancer treatment, there is hope of improving the outcomes of patients with PDAC in the future.
Topics: Humans; Neoadjuvant Therapy; Pancreas; Pancreatic Neoplasms; Neoplasms, Second Primary; Carcinoma, Pancreatic Ductal
PubMed: 37744290
DOI: 10.3748/wjg.v29.i35.5094 -
Deutsches Arzteblatt International Oct 2023Ampullary or papillary carcinoma is a malignant tumor arising from the mucosa in the region of the major duodenal papilla, also known as the ampulla of Vater. Uniform... (Review)
Review
BACKGROUND
Ampullary or papillary carcinoma is a malignant tumor arising from the mucosa in the region of the major duodenal papilla, also known as the ampulla of Vater. Uniform treatment recommendations are lacking both for the adjuvant situation and for palliative care.
METHODS
A selective literature search was carried out in PubMed in order to identify the most informative publications concerning the epidemiology, clinico-pathological background, and surgical and medical treatment of this condition.
RESULTS
Ampullary carcinoma has an incidence of 0.5 to 0.9 per 100 000 persons and a poor prognosis, with a 5-year survival rate of 41% to 45% for locally confined and 4% to 7% for metastatic disease. Most such tumors are of an intestinal or a pan - creaticobiliary immunohistochemical subtype; the latter has a worse prognosis (median survival, 72-80 vs. 33-41 months). Targeted treatment is not yet available for either subtype, nor is there enough scientific evidence available for the formulation of specific therapeutic recommendations in either the adjuvant or the palliative situation. The treatment of choice for ampullary carcinoma is radical oncological resection of the head of the pancreas with systematic lymphadenectomy. Five-year overall survival is between 10% and 75% depending on the stage. No definitive recommendation for adjuvant therapy can be given. Palliative therapy can be oriented to the published treatment strategies for cancer of the colon, pancreas, and bile duct.
CONCLUSION
The current state of the evidence on the treatment of ampullary carcinoma is poor. Therapeutic decisions should be discussed in an interdisciplinary tumor board and should, in our opinion, take the histological subtype into account.
Topics: Humans; Ampulla of Vater; Adenocarcinoma; Prognosis; Pancreatic Neoplasms; Combined Modality Therapy
PubMed: 37656482
DOI: 10.3238/arztebl.m2023.0195 -
Journal of Experimental & Clinical... Oct 2023Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes...
BACKGROUND
Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes PDAC are still not fully understood. Regnase-1, an endoribonuclease, regulates immune responses by degrading mRNAs of inflammation-related genes. Herein, we investigated the role of Regnase-1 in PDAC.
METHODS
Clinical significance of intratumor Regnase-1 expression was evaluated by immunohistochemistry in 39 surgically-resected PDAC patients. The functional role of Regnase-1 was investigated by pancreas-specific Regnase-1 knockout mice and Kras-mutant Regnase-1 knockout mice. The mechanistic studies with gene silencing, RNA immunoprecipitation sequencing (RIP-seq) and immune cell reconstitution were performed in human/mouse PDAC cell lines and a syngeneic orthotopic tumor transplantation model of KrasG12D-mutant and Trp53-deficient PDAC cells.
RESULTS
Regnase-1 expression was negatively correlated with the clinical outcomes and an independent predictor of poor relapse-free and overall survival in PDAC patients. Pancreas-specific Regnase-1 deletion in mice promoteed pancreatic cancer with PMN-MDSC infiltration and shortened their survival. A syngeneic orthotopic PDAC model exhibited that Regnase-1 downregulation accelerated tumor progression via recruitment of intratumor CD11b MDSCs. Mechanistically, Regnase-1 directly negatively regulated a variety of chemokines/cytokines important for MDSC recruitment and activation, including CXCL1, CXCL2, CSF2, and TGFβ, in pancreatic cancer cells. We subsequently showed that IL-1β-mediated Regnase-1 downregulation recruited MDSCs to tumor sites and promoted pancreatic cancer progression via mitigation of cytotoxic T lympohocytes-mediated antitumor immunity.
CONCLUSIONS
IL-1b-mediated Regnase-1 downregulation induces MDSCs and promotes pancreatic cancer through the evasion of anticancer immunity.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Down-Regulation; Inflammation; Mice, Knockout; Myeloid-Derived Suppressor Cells; Pancreatic Neoplasms; Ribonucleases
PubMed: 37814340
DOI: 10.1186/s13046-023-02831-w -
Cancer Letters Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a solid organ malignancy with a high mortality rate. Statistics indicate that its incidence has been increasing as well as the... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a solid organ malignancy with a high mortality rate. Statistics indicate that its incidence has been increasing as well as the associated deaths. Most patients with PDAC show poor response to therapies making the clinical management of this cancer difficult. Stromal cells in the tumor microenvironment (TME) contribute to the development of resistance to therapy in PDAC cancer cells. Cancer-associated fibroblasts (CAFs), the most prevalent stromal cells in the TME, promote a desmoplastic response, produce extracellular matrix proteins and cytokines, and directly influence the biological behavior of cancer cells. These multifaceted effects make it difficult to eradicate tumor cells from the body. As a result, CAF-targeting synergistic therapeutic strategies have gained increasing attention in recent years. However, due to the substantial heterogeneity in CAF origin, definition, and function, as well as high plasticity, majority of the available CAF-targeting therapeutic approaches are not effective, and in some cases, they exacerbate disease progression. This review primarily elucidates on the effect of CAFs on therapeutic efficiency of various treatment modalities, including chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Strategies for CAF targeting therapies are also discussed.
Topics: Humans; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Tumor Microenvironment; Immunotherapy; Animals; Molecular Targeted Therapy
PubMed: 38615928
DOI: 10.1016/j.canlet.2024.216859