Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets

AbstractPancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer with an abysmal prognosis rate over the last few decades. Early diagnosis and prevention could effectively combat this malignancy. Therefore, it is crucial to discover potential biomarkers to identify asymptomatic premalignant or early malignant tumors of PDAC. Gene expression analysis is a powerful technique to identify candidate biomarkers involved in disease progression. In the present study, five independent gene expression datasets, including 321 PDAC tissues and 208 adjacent non-cancerous tissue samples, were subjected to statistical and bioinformatics analysis. A total of 20 differentially expressed genes (DEGs) were identified in PDAC tissues compared to non-cancerous tissue samples. Gene ontology and pathway enrichment analysis showed that DEGs were mainly enriched in extracellular matrix (ECM), cell adhesion, ECM–receptor interaction, and focal adhesion signaling. The protein–protein interaction network was constructed, and the hub genes were evaluated. Collagen type XII alpha 1 chain (COL12A1), fibronectin 1 (FN1), integrin subunit alpha 2 (ITGA2), laminin subunit beta 3 (LAMB3), laminin subunit gamma 2 (LAMC2), thrombospondin 2 (THBS2), and versican (VCAN) were identified as hub genes. The correlation analysis revealed that identified hub genes were significantly interconnected. Wherein COL12A1, FN1, ITGA2, LAMB3, LAMC2, and THBS2 were significantly associated with PDAC pathological stages. The Kaplan–Meier survival plots revealed that ITGA2, LAMB3, and LAMC2 expression were inversely correlated with a prolonged patient survival period. Furthermore, the Human Protein Atlas database was used to validate the expression and cellular origins of hub genes encoded proteins. The protein expression of hub genes was higher in pancreatic cancer tissue than in normal pancreatic tissue samples, wherein ITGA2, LAMB3, and LAMC2 were exclusively expressed in pancreatic cancer cells. Pancreatic cancer cell-specific expression of these three proteins may play pleiotropic roles in cancer progression. Our results collectively suggest that ITGA2, LAMB3, and LAMC2 could provide deep insights into pancreatic carcinogenesis molecular mechanisms and provide attractive therapeutic targets.

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Network Pharmacology-based Elucidation of Molecular Biological Mechanisms of Kanglaite Injection for Treatment of Pancreatic Ductal Adenocarcinoma

10.21203/rs.3.rs-19866/v1 ◽

2020 ◽

Author(s):

Bowen Xu ◽

Wenchao Dan ◽

Jie Lj ◽

Xiaoxiao Zhang ◽

Luchang Cao ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Candidate Genes ◽

Differentially Expressed Genes ◽

Drug Targets ◽

Differentially Expressed ◽

Ductal Adenocarcinoma ◽

Network Pharmacology ◽

Biological Mechanisms ◽

Pathway Network ◽

Gene Pathway

Abstract Background: Kanglaite injection (KLTi) has shown good clinical efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). However, its molecular biological mechanisms are still unclear. This study used network pharmacology approach to investigate the molecular biological mechanisms of KLTi.Methods: Compounds in KLTi were screened using TCMSP and drug targets were obtained from the DRUGBANK. Next, the GEO database was searched for differentially expressed genes in cancerous tissues and healthy tissues of PDAC patients to identify targets. Subsequently, the protein-protein interaction data of KLTi and PDAC targets were constructed by BisoGenet. A visual analysis was done to extract KLTi candidate genes for PDAC. The candidate genes were enriched using GO and KEGG by Metascape, and the gene-pathway network was constructed to further screen the key genes.Results: A total of 10 active compounds and 36 drug targets were screened for KLTi, 919 differentially expressed genes associated with PDAC were identified from GEO, and 139 KLTi candidate genes against PDAC were excavated by BisoGenet. The gene-pathway network showed RELA, NFKB1, IKBKG, JUN, MAPK1, TP53, and AKT1 as the core genes, predicting that KLTi intervenes in PDAC by acting on these genes.Conclusions: Our study suggested that KLTi plays an anti-PDAC role by intervening in the cell cycle, inducing apoptosis, regulating protein binding, inhibiting nerve invasion, and down-regulating the NF-κB, MAPK, and PI3K-Akt signaling pathways. In addition, it might also directly participate in the pancreatic cancer pathway. These results provide new evidence and therapeutic direction for subsequent clinical applications and basic research on KLTi in PDAC.

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Targets (Metabolic Mediators) of Therapeutic Importance in Pancreatic Ductal Adenocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21228502 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8502

Author(s):

Vikrant Rai ◽

Swati Agrawal

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Tumor Cells ◽

Therapeutic Potential ◽

Therapeutic Targets ◽

The United States ◽

Metabolic Reprogramming ◽

Ductal Adenocarcinoma ◽

Advanced Stages ◽

Novel Therapeutic

Pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive invasive cancer, is the fourth most common cause of cancer-related death in the United States. The higher mortality in PDAC is often attributed to the inability to detect it until it has reached advanced stages. The major challenge in tackling PDAC is due to its elusive pathology, minimal effectiveness, and resistance to existing therapeutics. The aggressiveness of PDAC is due to the capacity of tumor cells to alter their metabolism, utilize the diverse available fuel sources to adapt and grow in a hypoxic and harsh environment. Therapeutic resistance is due to the presence of thick stroma with poor angiogenesis, thus making drug delivery to tumor cells difficult. Investigating the metabolic mediators and enzymes involved in metabolic reprogramming may lead to the identification of novel therapeutic targets. The metabolic mediators of glucose, glutamine, lipids, nucleotides, amino acids and mitochondrial metabolism have emerged as novel therapeutic targets. Additionally, the role of autophagy, macropinocytosis, lysosomal transport, recycling, amino acid transport, lipid transport, and the role of reactive oxygen species has also been discussed. The role of various pro-inflammatory cytokines and immune cells in the pathogenesis of PDAC and the metabolites involved in the signaling pathways as therapeutic targets have been previously discussed. This review focuses on the therapeutic potential of metabolic mediators in PDAC along with stemness due to metabolic alterations and their therapeutic importance.

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ITGA2, LAMB3, and LAMC2 May Be the Potential Therapeutic Targets in Pancreatic Ductal Adenocarcinoma: an Integrated Bioinformatics Analysis

10.21203/rs.3.rs-379158/v1 ◽

2021 ◽

Author(s):

Shajedul Islam ◽

Takao Kitagawa ◽

Byron Baron ◽

Yoshihiro Abiko ◽

Itsuo Chiba ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Bioinformatics Analysis ◽

Therapeutic Targets ◽

Ductal Adenocarcinoma ◽

Integrin Subunit ◽

Hub Genes ◽

Cancerous Tissue ◽

Tissue Samples

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer with an abysmal prognosis rate over the last few decades. Early diagnosis and prevention could effectively combat this malignancy. Therefore, it is crucial to discover potential biomarkers to identify asymptomatic premalignant or early malignant tumors of PDAC. Gene expression analysis is a powerful technique to identify candidate biomarkers involved in disease progression. In the present study, five independent gene expression datasets, including 321 PDAC tissues and 208 adjacent non-cancerous tissue samples, were subjected to statistical and bioinformatics analysis. A total of 20 differentially expressed genes (DEGs) were identified in PDAC tissues compared to non-cancerous tissue samples. Gene ontology and pathway enrichment analysis showed that DEGs were mainly enriched in extracellular matrix (ECM), cell adhesion, ECM-receptor interaction, and focal adhesion signaling. The protein protein interaction network was constructed, and the hub genes were evaluated. Collagen type XII alpha 1 chain (COL12A1), fibronectin 1 (FN1), integrin subunit alpha 2 (ITGA2), laminin subunit beta 3 (LAMB3), laminin subunit gamma 2 (LAMC2), thrombospondin 2 (THBS2), and versican (VCAN) were identified as hub genes. The correlation analysis revealed that identified hub genes were significantly interconnected. Wherein COL12A1, FN1, ITGA2, LAMB3, LAMC2, and THBS2 were significantly associated with PDAC pathological stages. The Kaplan-Meier survival plots revealed that ITGA2, LAMB3, and LAMC2 expression were inversely correlated with a prolonged patient survival period. Furthermore, the Human Protein Atlas database was used to validate the expression and cellular origins of hub genes encoded proteins. The protein expression of hub genes was higher in pancreatic cancer tissue than in normal pancreatic tissue samples, wherein ITGA2, LAMB3, and LAMC2 were exclusively expressed in pancreatic cancer cells. Pancreatic cancer cell-specific expression of these three proteins may play pleiotropic roles in cancer progression. Our results collectively suggest that ITGA2, LAMB3, and LAMC2 could provide deep insights into pancreatic carcinogenesis molecular mechanisms and provide attractive therapeutic targets.

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