MiR-143 Targeting TAK1 Attenuates Pancreatic Ductal Adenocarcinoma Progression via MAPK and NF-κB Pathway In Vitro
- 13 February 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Digestive Diseases and Sciences
- Vol. 62 (4), 944-957
- https://doi.org/10.1007/s10620-017-4472-7
Abstract
Background Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is one of the major regulators of inflammation-induced cancer cell growth and progression. MiR-143 dysregulation is a common event in a variety of human diseases including pancreatic ductal adenocarcinoma (PDA). Aims To identify the interaction between TAK1 and miR-143 in PDA. Methods Data mining of TAK1 expression in PDA patient gene profiling was conducted. QRT-PCR and western blot were performed to detect the expression of TAK1 in PDA tissues and cell lines. Ectopic miR-143 and TAK1 were introduced to PDA cells. Cell growth, apoptosis and migration were examined. Xenograft models were used to examine the function of TAK1 in vivo. Western blot and luciferase assay were carried out to investigate the direct target of miR-143. Results PDA patient gene profiling data (GSE15471 and GSE16515) showed that TAK1 mRNA was aberrantly up-regulated in PDA tissues. TAK1 protein levels were overexpressed in PDA tissues and cell lines. Overexpression of TAK1 was strongly associated with positive lymph node metastasis. Inhibition of TAK1 suppressed cell growth, migration, and induced cell apoptosis in vitro and in vivo. Further studies demonstrated that TAK1 was a direct target gene of miR-143. MiR-143 also inhibited PDA cells proliferation and migration, induced apoptosis and G1/S arrest. Moreover, TAK1 depletion inactivated MAPK and NF-κB pathway, mimicking the function of miR-143. Conclusions The study highlights that miR-143 acts as a tumor suppressor in PDA through directly targeting TAK1, and their functional regulation may provide potential therapeutic strategies in clinics.Keywords
Funding Information
- National Natural Science Foundation of China (81572348, 81602123)
- the Science and Technology Foundation of the Guangdong Province (2013B021800099, 2014A020212386, 2016A020215060)
- the Natural Science Foundation of Guangdong Province (2016A030313363, 2015A030313115)
- Funding from Guangzhou Science and Technology Bureau (201510010206)
This publication has 53 references indexed in Scilit:
- TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon CancersCell, 2012
- Modulation of Pancreatic Cancer Chemoresistance by Inhibition of TAK1JNCI Journal of the National Cancer Institute, 2011
- Transforming Growth Factor-β (TGF-β1) Activates TAK1 via TAB1-mediated Autophosphorylation, Independent of TGF-β Receptor Kinase Activity in Mesangial CellsPublished by Elsevier BV ,2009
- miR-145 and miR-143 regulate smooth muscle cell fate and plasticityNature, 2009
- Profound Asymmetry in the Structure of the cAMP-free cAMP Receptor Protein (CRP) from Mycobacterium tuberculosisJournal of Biological Chemistry, 2009
- TAK1 is required for the survival of hematopoietic cells and hepatocytes in miceThe Journal of Experimental Medicine, 2008
- Nuclear factor-κB in cancer development and progressionNature, 2006
- Combinatorial microRNA target predictionsNature Genetics, 2005
- Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA TargetsCell, 2005
- Prediction of Mammalian MicroRNA TargetsCell, 2003