TGFβ promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1

P. H. Huang, P. J. Lu, L. Y. Ding, P. C. Chu, W. Y. Hsu, C. S. Chen, C. C. Tsao, B. H. Chen, C. T. Lee, Y. S. Shan, C. S. Chen

研究成果: Article

4 引文 (Scopus)

摘要

The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-To-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor β treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant Kras G12D. Pharmacological inhibition of TGFβ-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KP fl/fl C mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFβ-VAV1 axis represents a therapeutic target.

原文English
頁(從 - 到)2202-2214
頁數13
期刊Oncogene
36
發行號16
DOIs
出版狀態Published - 2017 四月 20

指紋

Pancreatic Neoplasms
Epigenomics
Phenotype
Epithelial-Mesenchymal Transition
gemcitabine
Neoplasms
Adenocarcinoma
DNA Fingerprinting
Transforming Growth Factors
DNA Methylation
Individuality
Genes
Homeostasis
Radiotherapy
Therapeutics
Biomarkers
Pharmacology
Neoplasm Metastasis
Liver

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

引用此文

Huang, P. H. ; Lu, P. J. ; Ding, L. Y. ; Chu, P. C. ; Hsu, W. Y. ; Chen, C. S. ; Tsao, C. C. ; Chen, B. H. ; Lee, C. T. ; Shan, Y. S. ; Chen, C. S. / TGFβ promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1. 於: Oncogene. 2017 ; 卷 36, 編號 16. 頁 2202-2214.
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abstract = "The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-To-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor β treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant Kras G12D. Pharmacological inhibition of TGFβ-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KP fl/fl C mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFβ-VAV1 axis represents a therapeutic target.",
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TGFβ promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1. / Huang, P. H.; Lu, P. J.; Ding, L. Y.; Chu, P. C.; Hsu, W. Y.; Chen, C. S.; Tsao, C. C.; Chen, B. H.; Lee, C. T.; Shan, Y. S.; Chen, C. S.

於: Oncogene, 卷 36, 編號 16, 20.04.2017, p. 2202-2214.

研究成果: Article

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T1 - TGFβ promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1

AU - Huang, P. H.

AU - Lu, P. J.

AU - Ding, L. Y.

AU - Chu, P. C.

AU - Hsu, W. Y.

AU - Chen, C. S.

AU - Tsao, C. C.

AU - Chen, B. H.

AU - Lee, C. T.

AU - Shan, Y. S.

AU - Chen, C. S.

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AB - The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-To-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor β treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant Kras G12D. Pharmacological inhibition of TGFβ-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KP fl/fl C mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFβ-VAV1 axis represents a therapeutic target.

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