ArticleMolecular endocrinology (Baltimore, Md.)2015
Insights Into SMAD4 Loss in Pancreatic Cancer From Inducible Restoration of TGF-β Signaling.
Article in Molecular endocrinology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Review
- Ectopic Pancreatic Adenocarcinoma Arising in the Mesentery of the Jejunum: A Case Report.Surgical case reports · 2026Article
- Article
- In Vitro Organoid-Based Assays Reveal SMAD4 Tumor-Suppressive Mechanisms for Serrated Colorectal Cancer Invasion.Cancers · 2023Article
- Article
- Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids.Materials (Basel, Switzerland) · 2023Article
- TGFβ Signaling in the Pancreatic Tumor Microenvironment.Cancers · 2021Review
- SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy.Oncogene · 2021Article
- A pan-cancer analysis reveals nonstop extension mutations causing SMAD4 tumour suppressor degradation.Nature cell biology · 2020Article
- Novel Non-integrating DNA Nano-S/MAR Vectors Restore Gene Function in Isogenic Patient-Derived Pancreatic Tumor Models.Molecular therapy. Methods & clinical development · 2020Article
- Article
- Article
- Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Identification of key microRNAs and their targets in exosomes of pancreatic cancer using bioinformatics analysis.Medicine · 2018Article
- Microglial SMAD4 regulated by microRNA-146a promotes migration of microglia which support tumor progression in a glioma environment.Oncotarget · 2018Article
- Identification of Epithelial-Mesenchymal Transition-related Target Genes Induced by the Mutation of Smad3 Linker Phosphorylation.Journal of cancer prevention · 2018Article
- SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line.Oncotarget · 2018Article
- Neutralizing TGF-β promotes anti-tumor immunity of dendritic cells against pancreatic cancer by regulating T lymphocytes.Central-European journal of immunology · 2018Article
- PDAC-derived exosomes enrich the microenvironment in MDSCs in aOncotarget · 2017Article
- Targeting reactive oxygen species in development and progression of pancreatic cancer.Expert review of anticancer therapy · 2017Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer death in the United States. The TGF-β signaling protein SMAD family member 4 is lost in 60% of PDAC, and this has been associated with poorer prognosis. However, the mechanisms by which SMAD4 loss promotes PDAC development are not fully understood. We expressed SMAD4 in human PDAC cell lines BxPC3 and CFPAC1 by selection of stable clones containing an inducible SMAD4 tetracycline inducible expression system construct. After 24 hours of SMAD4 expression, TGF-β signaling-dependent G1 arrest was observed in BxPC3 cells with an increase in the G1 phase fraction from 48.9% to 71.5%. Inhibition of cyclin-dependent kinase inhibitor 1A by small interfering RNA eliminated the antiproliferative effect, indicating that up-regulation of cyclin-dependent kinase inhibitor 1A/p21 by TGF-β signaling is necessary for the phenotype. SMAD4 expression had no impact on invasion in BxPC3 cells, but reduced migration. Microarray analysis of gene expression at 8, 24, and 48 hours after SMAD4 expression characterized the regulatory impact of SMAD4 expression in a SMAD4-null PDAC cell line and identified novel targets of TGF-β signaling. Among the novel TGF-β targets identified are anthrax toxin receptor 2 (3.58× at 8 h), tubulin, β-3 class III (7.35× at 8 h), cell migration inducing protein, hyaluronan binding (8.07× at 8 h), IL-1 receptor-like 1 (0.403× at 8 h), regulator of G protein signaling 4 (0.293× at 8 h), and THAP domain containing 11 (0.262× at 8 h). The gene expression changes we observed upon restoration of TGF-β signaling provide numerous new targets for future investigations into PDAC biology and progression.
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