• Oral squamous cell carcinoma (OSCC)
• epithelial-to-mesenchymal transition (EMT)
• exosome

• Humans
• Exosomes/pathology
• Exosomes/metabolism
• Epithelial-Mesenchymal Transition/physiology
• Mouth Neoplasms/pathology
• Mouth Neoplasms/metabolism
• Tumor Microenvironment
• Squamous Cell Carcinoma of Head and Neck/pathology
• Signal Transduction
• Carcinoma, Squamous Cell/pathology
• Animals

• Cancer signaling pathway
• Cancer stem-like cells
• GLI1
• H&N Cancer
• Hedgehog signaling
• Non-canonical activation

• Humans
• Zinc Finger Protein GLI1/metabolism
• Zinc Finger Protein GLI1/genetics
• Hedgehog Proteins/metabolism
• Hedgehog Proteins/genetics
• Signal Transduction/genetics
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/pathology
• Head and Neck Neoplasms/metabolism
• Male
• Computational Biology/methods
• Female
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Middle Aged
• India
• Gene Expression Regulation, Neoplastic
• Prognosis

• Hedgehog signaling pathway
• PRKCI
• Pancreatic cancer
• Self-renewal ability
• Stem cell characteristics
• microRNA-630

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Neoplastic Stem Cells/metabolism
• Humans
• Hedgehog Proteins/metabolism
• Hedgehog Proteins/genetics
• Signal Transduction
• Animals
• Mice
• Cell Line, Tumor
• Protein Kinase C/metabolism
• Protein Kinase C/genetics
• Gene Expression Regulation, Neoplastic
• Isoenzymes

• Cytotoxicity
• Docking studies
• NanoBRET
• Pancreatic cancer
• Purine derivatives
• SMO ligands

• Humans
• Smoothened Receptor/antagonists & inhibitors
• Smoothened Receptor/metabolism
• Purines/chemistry
• Purines/pharmacology
• Purines/chemical synthesis
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/metabolism
• Ligands
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/chemical synthesis
• Animals
• Mice
• Structure-Activity Relationship
• Drug Screening Assays, Antitumor
• Molecular Structure
• Cell Proliferation/drug effects
• Dose-Response Relationship, Drug
• HEK293 Cells
• Cell Line, Tumor
• NIH 3T3 Cells
• Molecular Docking Simulation
• Hedgehog Proteins/metabolism
• Hedgehog Proteins/antagonists & inhibitors

• CBC
• Colorectal cancer
• Derivatives
• GLI inhibitors
• Hedgehog signalling pathway

• Humans
• Zinc Finger Protein GLI1/metabolism
• Zinc Finger Protein GLI1/antagonists & inhibitors
• Zinc Finger Protein GLI1/genetics
• Cell Proliferation/drug effects
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/metabolism
• Hedgehog Proteins/metabolism
• Hedgehog Proteins/antagonists & inhibitors
• Animals
• Apoptosis/drug effects
• Signal Transduction/drug effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/chemical synthesis
• Mice
• Cell Line, Tumor
• Mice, Nude
• Structure-Activity Relationship
• Drug Screening Assays, Antitumor
• Mice, Inbred BALB C

• Humans
• Cilia/metabolism
• TOR Serine-Threonine Kinases/metabolism
• Signal Transduction/physiology
• Autophagy/physiology
• Homeostasis

• P30 EY026877 NEI NIH HHS
• R01 EY026885 NEI NIH HHS
• R01 EY032159 NEI NIH HHS
• R01 EY033600 NEI NIH HHS
• R01 EY025295 NEI NIH HHS
• I01 CX001481 CSRD VA

• Caralluma europaea (Guss.)
• acute toxicity
• chemoresistance
• gemcitabine
• pancreatic cancer
• subacute toxicity

• RNA-Seq
• chemosensitivity
• chemotherapy
• patient-tailored therapy
• regression analysis
• statistical comparison of populations

• Humans
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreas
• Cell Line
• Phenotype
• Tumor Microenvironment/genetics

• CD133
• cancer stem cells
• gene therapy
• immunotherapy
• nanotechnology
• prominin-1

• UMO-2021/43/B/NZ7/02476 National Science Center

• KRAS
• MYC
• Oncogenic signaling
• PDAC
• PanIN
• Single-cell transcriptomics

Pancreatic cancer remains a significant public health problem with an ever-rising incidence of disease. Cancers of the pancreas are characterised by various molecular aberrations, including changes in the proteomics and genomics landscape of the tumour cells. Therefore, there is a need to identify the proteomic landscape of pancreatic cancer and the specific genomic and molecular alterations associated with disease subtypes. Here, we carry out an integrative bioinformatics analysis of The Cancer Genome Atlas dataset, including proteomics and whole-exome sequencing data collected from pancreatic cancer patients. We apply unsupervised clustering on the proteomics dataset to reveal the two distinct subtypes of pancreatic cancer. Using functional and pathway analysis based on the proteomics data, we demonstrate the different molecular processes and signalling aberrations of the pancreatic cancer subtypes. In addition, we explore the clinical characteristics of these subtypes to show differences in disease outcome. Using datasets of mutations and copy number alterations, we show that various signalling pathways previously associated with pancreatic cancer are altered among both subtypes of pancreatic tumours, including the Wnt pathway, Notch pathway and PI3K-mTOR pathways. Altogether, we reveal the proteogenomic landscape of pancreatic cancer subtypes and the altered molecular processes that can be leveraged to devise more effective treatments.

• Cluster Analysis
• Gene Ontology
• Humans
• Mutation/genetics
• Neoplasm Grading
• Pancreatic Neoplasms/classification
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Proteogenomics
• Proteomics
• Signal Transduction/genetics

• Circadian rhythm
• circadian clock genes
• pancreatic adenocarcinoma
• prognosis’

• Gli2
• Primary leukemia cells
• TGF-β1
• TNF-α

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

• FOXS1
• epithelial–mesenchymal transition
• hedgehog pathway
• hepatocellular carcinoma

• 4E-BP1
• GLI1
• GLI2
• GLI3
• Mammalian target of rapamycin
• S6K
• TSC
• autophagy
• eIF4E
• primary cilia

• Animals
• Autophagy
• Cilia/metabolism
• Hedgehog Proteins/metabolism
• Homeobox Protein Nkx-2.2
• Homeodomain Proteins
• Humans
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Models, Biological
• Nuclear Proteins
• Signal Transduction
• Transcription Factors

• CML
• Cancer detection
• Leukaemia detection
• Sonic Hedgehog gene

• ATAD2
• Hedgehog signaling pathway
• cancer stem cells
• esophageal squamous cell carcinoma
• proliferation

Pancreatic cancer is a highly malignant cancer associated with high expression levels of sonic hedgehog signaling molecule (Shh), patched 1 (Ptch1), smoothened frizzled class receptor (Smo) and glioma-associated oncogene family zinc finger 1 (Gli1) in the hedgehog (Hh) signaling pathway. Inhibition of the Hh signaling pathway is a potential therapeutic target for pancreatic cancer. The aim of the present study was to investigate the effects of dauricine in a pancreatic cancer BxPC-3 ×enograft animal model and examine the underlying molecular mechanisms through Hh signaling pathway. High-and low-dose dauricine treatment significantly suppressed tumor growth with no concomitant effect on the spleen index. In addition, dauricine induced apoptosis and cell cycle arrest in pancreatic cancer BxPC-3 cells. The inhibitory effects of dauricine on pancreatic cancer may be mediated by the suppression of the Hh signaling pathway, as indicated by the decreases in the gene and protein expression levels of Shh, Ptch1, Smo and Gli1. The effects of dauricine were similar to those of 5-fluorouracil. Dauricine, a naturally occurring alkaloid, may be a potential anticancer agent for the treatment of pancreatic cancer.

• dauricine
• hedgehog signaling pathway
• pancreatic cancer

• Akt
• Glioblastoma
• Glioblastoma-initiating cells
• NVP-BEZ-235
• NVP-LDE-225
• PI3K
• Sonic hedgehog
• mTOR

• Colorectal cancer
• GLI1
• Hedgehog
• Prognosis
• mTOR
• p-S6K

The present study focused on the roles of members of the Hedgehog (Hh) signaling pathway in the maintenance of malignant biological characteristics, such as tumorigenesis, similar to that of pancreatic tumor cells. Cluster of differentiation (CD)44⁺CD24⁺/CD44⁻CD24⁻ cells were isolated from three different pancreatic cancer cell lines by flow cytometry. Among the three pancreatic cancer cell lines, the SW1990 cell line exhibited the highest percentage of CD44⁺CD24⁺ cells, which accounted for 39.9% of the total. The expression of members of the Hh signaling pathway in CD44⁺CD24⁺/CD44⁻CD24⁻ cells was detected using reverse transcription-polymerase chain reaction and western blot analysis. The results demonstrated that members of the Hh signaling pathway were differentially expressed in CD44⁺CD24⁺ cells compared with CD44⁻CD24⁻, normal pancreatic duct cells and unsorted SW1990 cells. In addition, lentiviral expression vectors expressing Smoothened (Smo) small interfering RNA (siRNA) were constructed. Following transfection with the lentiviral expression vectors, Smo expression was markedly reduced in CD44⁺CD24⁺ cells. The present study represents a preliminary investigation into the biological characteristics of CD44⁺CD24⁺ pancreatic cancer cells.

• Hh signaling
• lentivirus
• pancreatic cancer

The Hedgehog (Hh) signalling pathway is involved in cell differentiation, growth and tissue polarity. This pathway is also involved in the progression and invasion of various human cancers. Osteosarcoma, a subtype of bone cancer, is commonly seen in children and adolescents. Typically, pulmonary osteosarcoma metastases are especially difficult to control. In the present paper, we summarise recent studies on the regulation of osteosarcoma progression and metastasis by downregulating Hh signalling. We also summarise the crosstalk between the Hh pathway and other cancer-related pathways in the tumourigenesis of various cancers. We further summarise and highlight the therapeutic value of potential inhibitors of Hh signalling in the clinical therapy of human cancers.

Alterations in Wiskott-Aldrich syndrome protein family verprolinhomologous protein 3 (WAVE3) expression play various roles in certain types of cancer. However, the roles of WAVE3 expression in pancreatic cancer remain unknown. The present retrospective study demonstrated that WAVE3 expression was higher in cancerous pancreatic tissues than in non-neoplastic tissues. Moreover, WAVE3 overexpression was related to lymphatic metastasis, a poor differentiation and high pre-operative CA19-9 levels and was an adverse prognostic factor for patients with pancreatic cancer. In vitro, the knockdown of WAVE3 inhibited the proliferative, migratory and invasive potential of pancreatic cancer cells and promoted cell apoptosis. Western blot analysis demonstrated that WAVE3 influenced the protein kinase B (PBK/AKT) pathway by suppressing the expression of pyruvate dehydrogenase kinase isoform 2 (PDK2) and then negatively inhibiting the phosphorylation of Ser473 on AKT. Furthermore, the expression of AKT pathway downstream proteins [certain epithelial-mesenchymal transition (EMT)-related proteins, p53, Bcl-2 and cyclin D1] was accordingly altered. Taken together, our findings suggest that WAVE3 influences cell proliferation, migration and invasion via the AKT pathway, and targeting WAVE3 and/or the AKT pathway may potentially serve as a treatment strategy for pancreatic cancer.

The lack of efficient treatment options for pancreatic cancer highlights the critical need for the development of novel and effective chemotherapeutic agents. The medicinal properties found in plants have been used to treat many different illnesses including cancers. This study focuses on the anticancer effects of gedunin, a natural compound isolated from Azadirachta indica.

Anti–proliferative effect of gedunin on pancreatic cancer cells was assessed using MTS assay. We used matrigel invasion assay, scratch assay, and soft agar colony formation assay to measure the anti–metastatic potential of gedunin. Immunoblotting was performed to analyze the effect of gedunin on the expression of key proteins involved in pancreatic cancer growth and metastasis. Gedunin induced apoptosis was measured using flow cytometric analysis. To further validate, xenograft studies with HPAC cells were performed.

Gedunin treatment is highly effective in inducing death of pancreatic cancer cells via intrinsic and extrinsic mediated apoptosis. Our data further indicates that gedunin inhibited metastasis of pancreatic cancer cells by decreasing their EMT, invasive, migratory and colony formation capabilities. Gedunin treatment also inhibited sonic hedgehog signaling pathways. Further, experiments with recombinant sonic hedgehog protein and Gli inhibitor (Gant-61) demonstrated that gedunin induces its anti–metastatic effect through inhibition of sonic hedgehog signaling. The anti–cancer effect of gedunin was further validated using xenograft mouse model.

Overall, our data suggests that gedunin could serve as a potent anticancer agent against pancreatic cancers.

• apoptosis
• gedunin
• hedgehog/gli signaling
• metastasis
• pancreatic cancer

Hedgehog (Hh) pathway is involved in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) maintenance resulting in tumor progression. GDC-0449, an inhibitor of Hh pathway component smoothened (Smo) has shown promise in the treatment of various cancers including pancreatic cancer. However, the emergence of resistance during GDC-0449 treatment with numerous side effects limits its use. Therefore, here we report the design, synthesis and evaluation of novel GDC-0449 analogs using N-[3-(2-pyridinyl) phenyl] benzamide scaffold. Cell-based screening followed by molecular simulation revealed 2-chloro-N¹-[4-chloro-3-(2-pyridinyl)phenyl]-N⁴,N⁴-bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) as most potent analog, binding with an extra interactions in seven-transmembrane (7-TM) domain of Smo due to an additional 2-pyridylmethyl group than GDC-0449. Moreover, MDB5 was more efficient in inhibiting Hh pathway components as measured by Gli-1 and Shh at transcriptional and translational levels. Additionally, a significant reduction of ALDH1, CD44 and Oct-3/4, key markers of pancreatic CSC was observed when MIA PaCa-2 cells were treated with MDB5 compared to GDC-0449. In a pancreatic tumor mouse model, MDB5 containing nanoparticles treated group showed significant inhibition of tumor growth without loss in body weight. These evidence highlight the enhanced Hh pathway inhibition and anticancer properties of MDB5 leaving a platform for mono and/or combination therapy.

Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.

• microRNA
• molecular pathogenesis
• mutations
• non-coding RNAs
• pancreatic ductal adenocarcinoma
• tumor microenvironment

• Biomarkers, Tumor/genetics
• Disease Progression
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Humans
• Molecular Targeted Therapy
• Mutation
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Tumor Microenvironment

• R01 CA175772 NCI NIH HHS

• Gli
• Hedgehog pathway
• Siegesbeckia glabrescens
• compositae
• pancreatic cancer
• sesquiterpene lactone

AIM: To construct a recombinant lentiviral vector carrying siRNA targeting the SMO gene, and to confirm its inhibitory effect on SMO gene expression in pancreatic cancer cells.

METHODS: Three SMO gene-targeted siRNA fragments were designed and synthesized, and recombinant DNA technology was used to introduce these three fragments into a lentiviral expression vector. After determination of the virus titer, the constructed lentiviral vector was tranfected into human pancreatic cancer cell line SW1990. RT-PCR was used to detect the expression of SMO gene and identify the best interference expression vector. SMO protein expression was detected by Western blot.

RESULTS: Gene sequencing and restriction endonuclease digestion results suggested successful synthesis of SMO-targeted siRNA fragments and correct insertion into the lentiviral vector. The virus titers were 5.31 × 10⁸ TU/mL, 1.49 × 10⁹ TU/mL and 8.50 × 10⁸ TU/mL, respectively. After transfecting SW1990 cells, the SMO gene expression inhibition rates were 86.00%, 74.85% and 19.22%, respectively. The best interference expression vector can achieve an SMO protein inhibition rate > 80% in SW1990 cells.

CONCLUSION: We have successfully constructed an SMO gene-targeted siRNA lentiviral vector, and the vector can effectively inhibit the expression of SMO gene in pancreatic cancer cells, thus providing a good experimental tool for further research.

• Pancreatic cancer
• SMO gene
• siRNA
• Lentiviral vector

Cancer poses a serious health problem in society and is increasingly surpassing cardiovascular disease as the leading cause of mortality in the United States. Current therapeutic strategies for cancer are extreme and harsh to patients and often have limited success; the danger of cancer is intensified as it metastasizes to secondary locations such as lung, bone, and liver, posing a dire threat to patient treatment and survival. Hedgehog signaling is an important pathway for normal development. Initially identified in Drosophila, the vertebrate and mammalian equivalent of the pathway has been studied extensively for its role in cancer development and progression. As this pathway regulates key target genes involved in development, its action also allows for the modulation of the microenvironment to prepare a tumor-suitable niche by manipulating tumor cell growth, differentiation, and immune regulation, thus creating an enabling environment for progression and metastasis. In this review, we will summarize recent scientific discoveries reporting the impact of the Hedgehog signaling pathway on the tumor initiation process and metastatic cascade, shedding light on the ability of the tumor to take over a mechanism crucially intended for development and normal function.

• Angiogenesis
• Cancer
• Cancer stem cells
• Drug resistance
• Epithelial-mesenchymal transition
• Hedgehog signaling
• Metastasis
• Microenvironment

Hedgehog (Hh) signaling is crucially involved in tumorigenesis. This study aimed to assess the role of Hh signaling in the regulation of epithelial-mesenchymal transition (EMT), stemness properties and chemoresistance of human pancreatic Panc-1 cancer stem cells (CSCs). Panc-1 cells were transfected with recombinant lentiviral vectors to silence SMO and serum-free floating-culture system was used to isolate Panc-1 tumorspheres. The expression of CSC and EMT markers was detected by flow cytometry, real-time RT-PCR and Western blot analysis. Malignant behaviors of Panc-1 CSC were evaluated by tumorigenicity assays and nude mouse lung metastasis model. We found that tumorspheres derived from pancreatic cancer cell line Panc-1 possessed self-renewal, differentiation and stemness properties. Hh pathway and EMT were active in Panc-1 tumorspheres. Inhibition of Hh signaling by SMO knockdown inhibited self-renewal, EMT, invasion, chemoresistance, pulmonary metastasis, tumorigenesis of pancreatic CSCs. In conclusion, Hh signaling contributes to the maintenance of stem-like properties and chemoresistance of pancreatic CSC and promotes the tumorigenesis and metastasis of pancreatic cancer. Hh pathway is a potential molecular target for the development of therapeutic strategies for pancreatic CSCs.

• Hedgehog
• cancer stem cell
• epithelial-mesenchymal transition
• pancreatic cancer

Hedgehog (Hh) signaling pathway consists of ligands such as Hh, receptor (patched), transmembrane protein Smo, nuclear transcription factor Gli, and downstream target genes. This pathway plays an important role in cell differentiation, tissue development and organ formation in the embryonic stage. In recent years, the Hh signaling pathway has been reported to play an important role in the development of pancreatic cancer. It can induce differentiation, proliferation and invasion of pancreatic cancer cells. Blocking the Hh signaling pathway in pancreatic cancer cells will provide a new and effective method for the treatment of pancreatic cancer. In this review, we will summarize the composition of the Hh signaling pathway and its relationship with the development of pancreatic cancer.

• Hedgehog
• Signaling pathway
• Pancreatic cancer

• Acquired resistance
• Advanced hepatocellular carcinoma (HCC)
• Cancer stem cells (CSCs)
• Epithelial–mesenchymal transitions (EMT) and mesenchymal–epithelial transitions (MET)
• Microenvironment

• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/enzymology
• Carcinoma, Hepatocellular/pathology
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition/drug effects
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/enzymology
• Liver Neoplasms/pathology
• Molecular Targeted Therapy
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/enzymology
• Neoplastic Stem Cells/pathology
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/therapeutic use
• Protein Kinase Inhibitors/therapeutic use
• Signal Transduction/drug effects
• Sorafenib
• Tumor Microenvironment/drug effects

Aberrant hedgehog signaling contributes to the development of various malignancies, including glioblastoma (GBM). However, the potential mechanism of hedgehog signaling in GBM migration and invasion has remained to be elucidated. The present study showed that enhanced hedgehog signaling by recombinant human sonic hedgehog N-terminal peptide (rhSHH) promoted the adhesion, invasion and migration of GBM cells, accompanied by increases in mRNA and protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9. However, inhibition of hedgehog signaling with cyclopamine suppressed the adhesion, invasion and migration of GBM cells, accompanied by decreases in mRNA and protein levels of MMP-2 and -9. Furthermore, it was found that MMP-2- and MMP-9-neutralizing antibodies or GAM6001 reversed the inductive effects of rhSHH on cell migration and invasion. In addition, enhanced hedgehog signaling by rhSHH increased AKT phosphorylation, whereas blockade of hedgehog signaling decreased AKT phosphorylations. Further experiments showed that LY294002, an inhibitor of phosphoinositide-3 kinase (PI3K), decreased rhSHH-induced upregulation of MMP-2 and -9. Finally, the protein expression of glioblastoma-associated oncogene 1 was positively correlated with levels of phosphorylated AKT as well as protein expressions of MMP-2 and -9 in GBM tissue samples. In conclusion, the present study indicated that the hedgehog pathway regulates GBM-cell migration and invasion by increasing MMP-2 and MMP-9 production via the PI3K/AKT pathway.

• Animals
• Arsenicals/pharmacology
• Cell Cycle Checkpoints/drug effects
• Cell Cycle Checkpoints/genetics
• Cell Line
• Fibrosis
• Glutathione/analogs & derivatives
• Glutathione/pharmacology
• Humans
• Kidney/metabolism
• Kidney/pathology
• Kidney Diseases/drug therapy
• Kidney Diseases/genetics
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Kruppel-Like Transcription Factors/antagonists & inhibitors
• Kruppel-Like Transcription Factors/genetics
• Kruppel-Like Transcription Factors/metabolism
• Mice
• Mice, Knockout
• Myofibroblasts/metabolism
• Myofibroblasts/pathology
• Pyridines/pharmacology
• Pyrimidines/pharmacology
• Zinc Finger Protein GLI1
• Zinc Finger Protein Gli2

• R01 DK088923 NIDDK NIH HHS
• R01 DK093574 NIDDK NIH HHS
• U01 DK104308 NIDDK NIH HHS
• P30 DK079337 NIDDK NIH HHS
• DK104308 NIDDK NIH HHS
• T32 DK007527 NIDDK NIH HHS
• DK088923 NIDDK NIH HHS
• P30-DK079337 NIDDK NIH HHS

AIM: To detect the expression of Hedgehog pathway components Sonic Hedgehog (Shh), Patched1 (Ptch1), Smoothened (Smo) and glioma-associated oncogene homolog 1 (Gli1) genes in pancreatic cancer, and to discuss their biological significance.

METHODS: Expression of Shh, Ptch1, Smo and Gli1 mRNAs was evaluated by RT-PCR in 48 cases of pancreatic cancer and matched tumor adjacent tissue.

RESULTS: The relative expression levels of Shh, Ptch1, Smo and Gli1 mRNAs in pancreatic cancer were 0.652 ± 0.036, 0.604 ± 0.063, 0.493 ± 0.011 and 0.512 ± 0.052, respectively, significantly higher than those in tumor adjacent tissue (0.312 ± 0.013, 0.319 ± 0.053, 0.214 ± 0.046 and 0.247 ± 0.059) (P < 0.05). Overexpression of these genes was associated with tumor differentiation (P < 0.05), but not with age, gender, tumorous size, TNM stage, lymph node metastasis, or CA19-9 (P > 0.05).

CONCLUSION: The expression of Shh, Ptch1, Smo and Gli1 is increased in human pancreatic cancer. The genesis and development of pancreatic cancer may be associated with the abnormal activation of Hedgehog signaling pathway.

• Pancreatic cancer
• Shh
• Ptch1
• Smo
• Gli1

Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16^INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.

• Pancreatic cancer
• CTHRC1
• RAC1
• RalGEF-RAl
• Notch Signaling
• Nodal/Activin Signaling
• NDRG1
• Hypoxic condition
• DR5
• PAR2
• HER3
• IAP
• Non-coding RNA
• HDAC
• BMI1
• EZH2
• Pancreatic cancer stem cell
• Tumour microenvironment

• Animals
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Drug Design
• Epigenesis, Genetic/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Molecular Targeted Therapy
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• RNA, Untranslated/metabolism
• Signal Transduction/drug effects
• Tumor Microenvironment

• Cancer stem cells
• Cancer stem cells signaling pathways
• Pancreatic cancer
• Targeted therapy
• miRNA

• Animals
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Drug Resistance, Neoplasm
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Signal Transduction

• Akt
• Cancer prevention
• Notch
• Pancreatic cancer
• Rottlerin
• Sonic Hedgehog

• Acetophenones/pharmacology
• Angiogenesis Inhibitors/pharmacology
• Angiogenic Proteins/metabolism
• Animals
• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/metabolism
• Benzopyrans/pharmacology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Epithelial-Mesenchymal Transition/drug effects
• Genes, ras
• Hedgehog Proteins/antagonists & inhibitors
• Hedgehog Proteins/metabolism
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mice, Transgenic
• Neovascularization, Pathologic
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Protein Kinase Inhibitors/pharmacology
• Proto-Oncogene Proteins c-akt/antagonists & inhibitors
• Proto-Oncogene Proteins c-akt/metabolism
• Receptors, Notch/antagonists & inhibitors
• Receptors, Notch/metabolism
• Signal Transduction/drug effects
• Time Factors
• Tumor Burden/drug effects
• Tumor Microenvironment
• Xenograft Model Antitumor Assays

The Hedgehog (Hh) signaling pathway regulates a variety of tumor-related diseases, including leukemia. The present study aimed to determine whether there was an interaction between the Hh signaling pathway and transforming growth factor (TGF)-β in the KG-1 cell line. KG-1 cells were treated with TGF-β, tumor necrosis factor (TNF)-α and specific inhibitor of smad3 (SIS3). The expression level of Gli family zinc finger 2 (Gli2) was detected by quantitative polymerase chain reaction (qPCR) and western blot analyses. The results revealed that TGF-β significantly decreased the expression level of Gli2 in KG-1 cells, and that TNF-α and TGF-β together further reduced Gli2 expression in KG-1 cells. SIS3 inhibited the effect of TGF-β. These results suggest that Gli2 expression in KG-1 cells is suppressed by TGF-β in a Smad3-dependent manner, TNF-α can enhance the effect of TGF-β on Gli2 expression and that this occurs independently of Hh receptor signaling.

• Gli family zinc finger 2
• specific inhibitor of smad3
• transforming growth factor-β
• tumor necrosis factor α

Pancreatic cancer is a deadly disease, and therefore effective treatment and/or prevention strategies are urgently needed. The objectives of this study were to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer cell growth in vitro, and xenografts in Balb C nude mice, and pancreatic cancer cell growth isolated from Kras^G12D transgenic mice. XTT assays were performed to measure cell viability. AsPC-1 cells were injected subcutaneously into Balb c nude mice and treated with embelin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of Akt, and Sonic Hedgehog (Shh) and their target gene products were measured by the immunohistochemistry, and Western blot analysis. The effects of embelin on pancreatic cancer cells isolated from 10-months old Kras^G12D mice were also examined. Embelin inhibited cell viability in pancreatic cancer AsPC-1, PANC-1, MIA PaCa-2 and Hs 766T cell lines, and these inhibitory effects were blocked either by constitutively active Akt or Shh protein. Embelin-treated mice showed significant inhibition in tumor growth which was associated with reduced expression of markers of cell proliferation (Ki67, PCNA and Bcl-2) and cell cycle (cyclin D1, CDK2, and CDK6), and induction of apoptosis (activation of caspase-3 and cleavage of PARP, and increased expression of Bax). In addition, embelin inhibited the expression of markers of angiogenesis (COX-2, VEGF, VEGFR, and IL-8), and metastasis (MMP-2 and MMP-9) in tumor tissues. Antitumor activity of embelin was associated with inhibition of Akt and Shh pathways in xenografts, and pancreatic cancer cells isolated from Kras^G12D mice. Furthermore, embelin also inhibited epithelial-to-mesenchymal transition (EMT) by up-regulating E-cadherin and inhibiting the expression of Snail, Slug, and ZEB1. These data suggest that embelin can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt and Shh pathways, and can be developed for the treatment and/or prevention of pancreatic cancer.

• Animals
• Benzoquinones/pharmacology
• Cell Line, Tumor
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Heterografts
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Mutant Strains
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Xenograft Model Antitumor Assays
• ras Proteins/genetics
• ras Proteins/metabolism

• R01 CA114469 NCI NIH HHS

• Cell signaling
• Combination chemotherapy
• Hedgehog
• Novel antitumor agents
• Smoothened
• Targeted therapy

Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses among all cancers. Over the past several decades, investigators have made great advances in the research of PDAC pathogenesis. Importantly, identification of pancreatic cancer stem cells (PCSCs) in pancreatic cancer cases has increased our understanding of PDAC biology and therapy. PCSCs are responsible for pancreatic tumorigenesis and tumor progression via a number of mechanisms, including extensive proliferation, self-renewal, high tumorigenic ability, high propensity for invasiveness and metastasis, and resistance to conventional treatment. Furthermore, emerging evidence suggests that PCSCs are involved in the malignant transformation of pancreatic intraepithelial neoplasia. The molecular mechanisms that control PCSCs are related to alterations of various signaling pathways, for instance, Hedgehog, Notch, Wnt, B-cell-specific Moloney murine leukemia virus insertion site 1, phosphoinositide 3-kinase/AKT, and Nodal/Activin. Also, authors have reported that the proliferation-specific transcriptional factor Forkhead box protein M1 is involved in PCSC self-renewal and proliferation. In this review, we describe the current knowledge about the signaling pathways related to PCSCs and the early stages of PDAC development, highlighting the pivotal roles of Forkhead box protein M1 in PCSCs and their impacts on the development and progression of pancreatic intraepithelial neoplasia.