• Micro RNA (miR) sponging
• replacement therapy
• review
• short-hairpin RNA (shRNA)
• small-interfering RNA (siRNA)
• target validation
• xenograft models

• Humans
• RNA, Circular/genetics
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/therapy
• Pancreatic Neoplasms/metabolism
• Animals
• Molecular Targeted Therapy/methods

• Diabetes mellitus
• Diabetic nephropathy
• Microencapsulated islet transplantation
• Notch pathway
• Podocytes

• Complementary medicine
• Gemcitabine
• Orthosiphon stamineus
• Pancreatic cancer

• Apoptosis
• Cell Line, Tumor
• Cinnamates
• Deoxycytidine/analogs & derivatives
• Depsides
• Humans
• Orthosiphon/chemistry
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use
• Gemcitabine
• Rosmarinic Acid

• immunotherapy
• pancreatic cancer
• targeted therapy

• Humans
• Immunotherapy
• Pancreatic Neoplasms/therapy
• Survival Rate

• pancreatic cancer
• pancreatic cancer stem cells
• pancreatic ductal adenocarcinoma
• stem cells

Background and Objectives: The Notch signaling pathway plays an important role both in the development of the ductal systems of the pancreas and the bile ducts as well as in cancer development and progression. The aim of this study was to examine the expression of central proteins of the Notch signaling pathway in pancreatobiliary tumors and its influence on patient survival. Materials and Methods: We compared the receptors (Notch1, Notch4), activating splicing factors (ADAM17), and target genes (HES1) of the Notch pathway and progenitor cell markers with relevance for the Notch signaling pathway (CD44, MSI1) between pancreatic adenocarcinomas (PDAC, n = 14), intrahepatic cholangiocarcinoma (iCC, n = 24), and extrahepatic cholangiocarcinoma (eCC, n = 22) cholangiocarcinomas via immunohistochemistry and ImageJ software-assisted analysis. An Immunohistochemistry (IHC)-score was determined by the percentage and intensity of stained (positive) cells (scale 0–7) and normal and malignant tissue was compared. In the IHC results, patients’ (gender, age) and tumor (TNM Classification of Malignant Tumors, Union Internationale contre le Cancer (UICC) stages, grading, and lymphangitic carcinomatosa) characteristics were correlated to patient survival. Results: For eCC, the expression of CD44 (p = 0.043, IHC-score 3.94 vs. 3.54) and for iCC, the expression of CD44 (p = 0.026, IHC-score 4.04 vs. 3.48) and Notch1 (p < 0.001, IHC-score 2.87 vs. 1.78) was significantly higher in the tumor compared to non-malignant tissue. For PDAC, the expression of ADAM17 (p = 0.008, IHC-score 3.43 vs. 1.73), CD44 (p = 0.012, IHC-score 3.64 vs. 2.27), Notch1 (p = 0.012, IHC-score 2.21 vs. 0.64), and Notch4 (p = 0.008, IHC-score 2.86 vs. 0.91) was significantly higher in the tumor tissue. However, none of the analyzed Notch-signaling related components showed an association to patient survival. Conclusion: A significant overexpression of almost all studied components of the Notch signaling pathway can be found in the tumor tissue, however, without a significant influence on patient survival. Therefore, further studies are warranted to draw conclusions on Notch pathway’s relevance for patient survival.

• cancer stem cells
• cholangiocarcinoma
• notch pathway
• pancreatic cancer

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms/genetics
• Bile Ducts, Intrahepatic
• Cholangiocarcinoma/genetics
• Female
• Humans
• Male
• Middle Aged
• Nerve Tissue Proteins
• RNA-Binding Proteins
• Receptor, Notch1
• Receptors, Notch
• Signal Transduction

• Biomarker
• Ductal adenocarcinoma
• Liver cancer
• Network analysis
• Pancreas

• taurine
• taurine haloamines
• taurine upregulated gene 1 ncRNA
• inflammation
• cancer

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• Disease Models, Animal
• Disease Progression
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/immunology
• Humans
• Inflammation/drug therapy
• Inflammation/genetics
• Inflammation/immunology
• Inflammation/metabolism
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/metabolism
• Prognosis
• RNA, Long Noncoding/metabolism
• Taurine/analogs & derivatives
• Taurine/metabolism
• Taurine/pharmacology
• Taurine/therapeutic use

• EMT
• Notch1 pathway
• Pancreatic cancer
• TUG1
• miR-299-3p

• HES1
• Notch
• gastrointestinal
• lung
• neuroendocrine neoplasm
• pancreas

BMSCs are important in replacement therapy of diabetic nephropathy (DN). MiR‐124a exerts effect on the differentiation capability of pancreatic progenitor cells. The objective of this study was to explore the molecular mechanisms, the functions of miR‐124a and bone marrow mesenchymal stem cells (BMSCs) in the treatment of DN. Characterizations of BMSCs were identified using the inverted microscope and flow cytometer. The differentiations of BMSCs were analysed by immunofluorescence assay and DTZ staining. The expression levels of islet cell‐specific transcription factors, apoptosis‐related genes, podocytes‐related genes and Notch signalling components were detected using quantitative real‐time reverse transcription PCR (qRT‐PCR) and Western blot assays. The production of insulin secretion was detected by adopting radioimmunoassay. Cell proliferation and apoptosis abilities were detected by CCK‐8, flow cytometry and TUNEL assays. We found that BMSCs was induced into islet‐like cells and that miR‐124a could promote the BMSCs to differentiate into islet‐like cells. BMSCs in combination with miR‐124a regulated islet cell‐specific transcription factors, apoptosis‐related genes, podocytes‐related genes as well as the activity of Notch signalling pathway. However, BMSCs in combination with miR‐124a relieved renal lesion caused by DN and decreased podocyte apoptosis caused by HG. The protective effect of BMSCs in combination with miR‐124a was closely related to the inactivation of Notch signalling pathway. MSCs in combination with miR‐124a protected kidney tissue from impairment and inhibited nephrocyte apoptosis in DN.

• Notch
• apoptosis
• diabetic nephropathy
• kidney injury
• miR-124a
• podocyte

• Pancreatic cancer
• cellular signaling
• notch
• target
• therapy

• greedy searching
• lung squamous carcinoma
• multi-stage carcinogenesis
• network-based
• prognostic module

• Adult
• Aged
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Female
• Gene Expression Profiling
• Gene Regulatory Networks
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Male
• Middle Aged
• Prognosis

• Algorithms
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• DNA Copy Number Variations/genetics
• DNA Methylation/genetics
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Genes, Developmental
• Genes, Neoplasm
• Genomics
• Humans
• Kaplan-Meier Estimate
• Meta-Analysis as Topic
• Multivariate Analysis
• Mutation/genetics
• Neoplasm Staging
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic
• Proportional Hazards Models
• Reproducibility of Results
• Transcriptome/genetics

• U24 AA020801 NIAAA NIH HHS

During normal development, heterogeneous expression of Notch ligands can result in pathway suppression in the signal-sending cell, a process known as lateral inhibition. It is unclear if an analogous phenomenon occurs in malignant cells. We observed significant induction of Notch ligands in glioblastoma neurospheres and pancreatic carcinoma cells cultured in low oxygen, suggesting that this phenomenon could occur around hypoxic regions. To model lateral inhibition in these tumors, the ligand Jagged1 was overexpressed in glioblastoma and pancreatic carcinoma cells, resulting in overall induction of pathway targets. However, when ligand high and ligand low cells from a single line were co-cultured and then separated, we noted suppression of Notch pathway targets in the former and induction in the latter, suggesting that neoplastic lateral inhibition can occur. We also found that repression of Notch pathway targets in signal-sending cells may occur through the activity of a Notch ligand intracellular domain, which translocates into the nucleus. Understanding how this neoplastic lateral inhibition process functions in cancer cells may be important in targeting ligand driven Notch signaling in solid tumors.

Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.

• Pancreatic cancer
• Genomic alterations
• Signaling pathways
• Therapeutic targets
• Personalized medicine

Immune response-related genes play a major role in colorectal carcinogenesis by mediating inflammation or immune-surveillance evasion. Although remarkable progress has been made to investigate the underlying mechanism, the understanding of the complicated carcinogenesis process was enormously hindered by large-scale tumor heterogeneity. Development and carcinogenesis share striking similarities in their cellular behavior and underlying molecular mechanisms. The association between embryonic development and carcinogenesis makes embryonic development a viable reference model for studying cancer thereby circumventing the potentially misleading complexity of tumor heterogeneity. Here we proposed that the immune genes, responsible for intra-immune cooperativity disorientation (defined in this study as disruption of developmental expression correlation patterns during carcinogenesis), probably contain untapped prognostic resource of colorectal cancer. In this study, we determined the mRNA expression profile of 137 human biopsy samples, including samples from different stages of human colonic development, colorectal precancerous progression and colorectal cancer samples, among which 60 were also used to generate miRNA expression profile. We originally established Spearman correlation transition model to quantify the cooperativity disorientation associated with the transition from normal to precancerous to cancer tissue, in conjunction with miRNA-mRNA regulatory network and machine learning algorithm to identify genes with prognostic value. Finally, a 12-gene signature was extracted, whose prognostic value was evaluated using Kaplan–Meier survival analysis in five independent datasets. Using the log-rank test, the 12-gene signature was closely related to overall survival in four datasets (GSE17536, n = 177, p = 0.0054; GSE17537, n = 55, p = 0.0039; GSE39582, n = 562, p = 0.13; GSE39084, n = 70, p = 0.11), and significantly associated with disease-free survival in four datasets (GSE17536, n = 177, p = 0.0018; GSE17537, n = 55, p = 0.016; GSE39582, n = 557, p = 4.4e-05; GSE14333, n = 226, p = 0.032). Cox regression analysis confirmed that the 12-gene signature was an independent factor in predicting colorectal cancer patient’s overall survival (hazard ratio: 1.759; 95% confidence interval: 1.126–2.746; p = 0.013], as well as disease-free survival (hazard ratio: 2.116; 95% confidence interval: 1.324–3.380; p = 0.002).

• Aged
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Female
• Gene Expression Profiling
• Gene Regulatory Networks
• Humans
• Male
• MicroRNAs/genetics
• Middle Aged
• Prognosis
• RNA, Messenger/genetics
• Survival Analysis

• U24 AA020801 NIAAA NIH HHS

• AKT inhibitors
• KRas
• MAPK kinase inhibitors
• MRK-003
• MS-275
• PEGylated hyaluronidase
• PF-03084014
• Ras
• Sonic hedgehog
• apricoxib
• c-Met
• cabozantinib
• celecoxib
• crizotinib
• cyclooxygenase-2
• cytidine deaminase
• delta-like ligand 4
• demcizumab
• desmoplasia
• gemcitabine
• histone deacetylases
• hyaluronan
• local drug eluter
• notch signaling
• pancreatic adenocarcinoma
• urokinase
• urokinase plasminogen activator receptor
• vorinostat
• γ-secretase inhibitors

• Adenocarcinoma/drug therapy
• Adenocarcinoma/genetics
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/genetics
• Clinical Trials as Topic
• Drug Evaluation, Preclinical
• Humans
• Hyaluronoglucosaminidase/genetics
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• RNA, Small Interfering/genetics
• Signal Transduction/drug effects
• Signal Transduction/genetics
• ras Proteins/genetics
• Pancreatic Neoplasms

Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRAS^G12D during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRAS^G12D expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing the inducible oncogenic KRAS^G12D line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRAS^G12D showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch pathways. Increase in TGFβ, following KRAS^G12D activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.

• KRAS
• Medulloblastoma
• Notch
• Pancreatic adenocarcinoma
• Reporters
• Shh
• TGFβ
• Zebrafish

Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer.