• Nrf2
• Ulcerative colitis
• cannabidiol
• intestinal fibrosis
• oxidative stress

• Colorectal cancer
• Metabolic reprogramming
• Metastasis
• Mitogen-activated protein kinase signaling
• Nicotinamide adenine dinucleotide phosphate oxidase 4

• Mechanism
• Nicotinamide adenine dinucleotide phosphate hydrogen oxides
• Pancreatic cancer
• Pancreatitis
• Reactive oxygen species

• Humans
• Reactive Oxygen Species
• NADP
• Epithelial-Mesenchymal Transition
• NADPH Oxidases/metabolism
• Oxidative Stress
• Pancreatitis

TGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the activation of SMAD pathways, predominantly SMAD2/3/4. Though SMAD2 and 3 are rarely mutated in cancers, SMAD4 is lost in about 50% of PDAC, and the role of SMAD2/3 in a SMAD4-null context remains understudied. We herein provide evidence of a SMAD2/3 oncogenic effect in response to TGF-β1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2/3 in the absence of SMAD4. Using a PDAC patient cohort, we reveal that SMAD4-negative tumors with high levels of phospho-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC leads to an oncogenic gain-of-function of SMAD2/3, and to the onset of associated deleterious effects.

In pancreatic ductal adenocarcinoma cells and patient tissue, SMAD2/3 is shown to mediate oncogenic effects of TGF-β in the absence of SMAD4.

• NADPH Oxidase 4
• Pancreatic cancer
• Reactive oxygen species

• Animals
• Hydrogen Peroxide
• Mice
• NADPH Oxidase 4
• NADPH Oxidases
• Pancreatic Neoplasms
• Reactive Oxygen Species

• Gene expression
• NOX4
• Non-small-cell lung cancer
• Nrf2

• Cancer stem cells (CSCs)
• Epithelial‐to‐mesenchymal transition
• Metastasis
• Pancreatic cancer
• Reactive Oxygen Species (ROS)
• TGFβ signalling pathway

• Humans
• Neoplasm Metastasis
• Pancreatic Neoplasms/genetics
• Reactive Oxygen Species/metabolism
• Signal Transduction
• Transforming Growth Factor beta/metabolism

• 25064 Cancer Research UK
• 349/106 The Kennedy Trust for Rheumatology Research
• 349/106 Daphne Jackson Trust
• C59392/A25064 Cancer Research UK

This study investigated the effects of transforming growth factor-β1 (TGF-β1) and cyclooxygenase-2 (COX-2) on bone morphogenetic protein 9 (BMP9) in mesenchymal stem cells (MSCs). We found that BMP9 increased mRNA levels of TGF-β1 and COX-2 in C3H10T1/2 cells. BMP9-induced osteogenic markers were enhanced by TGF-β1 and reduced by TGF-βRI-specific inhibitor LY364947. BMP9 increased level of p-Smad2/3, which were either enhanced or reduced by COX-2 and its inhibitor NS398. BMP9-induced osteogenic markers were decreased by NS398 and it was partially reversed by TGF-β1. COX-2 increased BMP9-induced osteogenic marker levels, which almost abolished by LY364947. BMP9-induced bone formation was enhanced by TGF-β1 but reduced by silencing TGF-β1 or COX-2. BMP9’s osteogenic ability was inhibited by silencing COX-2 but partially reversed by TGF-β1. TGF-β1 and COX-2 enhanced activation of p38 signaling, which was induced by BMP9 and reduced by LY364947. The ability of TGF-β1 to increase the BMP9-induced osteogenic markers was reduced by p38-specific inhibitor, while BMP9-induced TGF-β1 expression was reduced by NS398, but enhanced by COX-2. Furthermore, CREB interacted with Smad1/5/8 to regulate TGF-β1 expression in MSCs. These findings suggest that COX-2 overexpression leads to increase BMP9’s osteogenic ability, resulting from TGF-β1 upregulation which then activates p38 signaling in MSCs.

• BMP9
• COX-2
• TGF-β1
• osteogenic differentiation
• p38 MAPK

• A549 cells
• Cell migration
• Epithelial-mesenchymal transition
• NF-κB
• NOX4

Inside the adult CNS, oligodendrocyte progenitor cells (OPC_S) are able to proliferate, migrate and differentiate into mature oligodendrocytes (OLs) which are responsible for the production of myelin sheet and energy supply for neurons. Moreover, in demyelinating diseases, OPCs are recruited to the lesion areas where they undergo differentiation and myelin synthesis. Serotonin (5-hydroxytryptamine, 5-HT) is involved in OLs’ development and myelination, but so far the molecular mechanisms involved or the effects of 5-HT on mitochondria function have not yet been well documented. Our data show that 5-HT inhibits migration and proliferation committing cells toward differentiation in an immortalized human oligodendrocyte precursor cell line, M03-13. Migration blockage is mediated by reactive oxygen species (ROS) generation since antioxidants, such as Vit C and Cu-Zn superoxide dismutase, prevent the inhibitory effects of 5-HT on cell migration. 5-HT inhibits OPC migration and proliferation and increases OL phenotypic markers myelin basic protein (MBP) and Olig-2 via protein kinase C (PKC) activation since the inhibitor of PKC, bis-indolyl-maleimide (BIM), counteracts 5-HT effects. NOX inhibitors as well, reverse the effects of 5-HT, indicating that 5-HT influences the maturation process of OPCs by NOX-dependent ROS production. Finally, 5-HT increases mitochondria function and antioxidant activity. The identification of the molecular mechanisms underlying the effects of 5-HT on maturation and energy metabolism of OPCs could pave the way for the development of new treatments for autoimmune demyelinating diseases such as Multiple Sclerosis where oligodendrocytes are the primary target of immune attack.

• 5-hydroxytryptamine
• NOX
• differentiation
• migration
• mitochondria
• oligodendrocyte precursor cells
• proliferation
• reactive oxygen species

• RAC1
• RAC1B
• Smad
• cancer
• pancreatic ductal adenocarcinoma
• signaling
• transforming growth factor β, cell migration

• epithelial mesenchymal plasticity
• pancreatic cancer
• review
• target discovery

• Amyloid precursor-like protein 2
• HLA class I molecule
• beta 2-microglobulin
• migration
• pancreatic cancer

• Bioinformatics
• Cancer risk
• Connectivity
• Diabetic treatment
• Drug safety
• Functional network study
• Pancreatic cancer
• Pioglitazone
• Prostate cancer
• Side effect

• National Natural Science Foundation of China
• Natural Science Foundation of Guangdong Province
• National Undergraduate Training Programs for Innovation and Entrepreneurship

Vascular endothelial growth factors (VEGFs) include five molecules (VEGF-A, -B, -C, -D, and placental growth factor), and have various roles that crucially regulate cellular functions in many kinds of cells and tissues. Intracellular signal transduction induced by VEGFs has been extensively studied and is usually initiated by their binding to two classes of transmembrane receptors: receptor tyrosine kinase VEGF receptors (VEGF receptor-1, -2 and -3) and neuropilins (NRP1 and NRP2). In addition to many established results reported by other research groups, we have previously identified small G proteins, especially Ras homologue gene (Rho) and Ras-related protein (Rap), as important mediators of VEGF-A-stimulated signaling in cancer cells as well as endothelial cells. This review article describes the VEGF-A-induced signaling pathways underlying diverse cellular functions, including cell proliferation, migration, and angiogenesis, and the involvement of Rho, Rap, and their related molecules in these pathways.

• angiogenesis
• cell adhesion
• cell migration
• cell proliferation
• growth factor
• small G protein
• tumor progression

• Animals
• Humans
• Models, Biological
• Neovascularization, Physiologic
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor Receptor-2/metabolism
• rap GTP-Binding Proteins/metabolism
• rho GTP-Binding Proteins/metabolism