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Human alveolar epithelial cells type II are capable of TGF?-dependent epithelial-mesenchymal-transition and collagen-synthesis.

ABSTRACT: BACKGROUND:The origin of collagen-producing cells in lung fibrosis is unclear. The involvement of embryonic signaling pathways has been acknowledged and trans-differentiation of epithelial cells is discussed critically. The work presented here investigates the role of TGFB in cytoskeleton remodeling and the expression of Epithelial-Mesenchymal-Transition markers by Alveolar Epithelial Cells Type II and tests the hypothesis if human alveolar epithelial cells are capable of trans-differentiation and production of pro-fibrotic collagen. METHODS:Primary human alveolar epithelial cells type II were extracted from donor tissues and stimulated with TGF? and a TGF?-inhibitor. Transcriptome and pathway analyses as well as validation of results on protein level were conducted. RESULTS:A TGF?-responsive fingerprint was found and investigated for mutual interactions. Interaction modules exhibited enrichment of genes that favor actin cytoskeleton remodeling, differentiation processes and collagen metabolism. Cross-validation of the TGF?-responsive fingerprint in an independent IPF dataset revealed overlap of genes and supported the direction of regulated genes and TGF?-specificity. CONCLUSIONS:Primary human alveolar epithelial cells type II seem undergo a TGF?-dependent phenotypic change, exhibit differential expression of EMT markers in vitro and acquire the potential to produce collagen.

SUBMITTER: Goldmann T

PROVIDER: S-EPMC6056940 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Human alveolar epithelial cells type II are capable of TGFβ-dependent epithelial-mesenchymal-transition and collagen-synthesis.

Goldmann Torsten T Zissel Gernot G Watz Henrik H Drömann Daniel D Reck Martin M Kugler Christian C Rabe Klaus F KF Marwitz Sebastian S

Respiratory research 20180724 1

<h4>Background</h4>The origin of collagen-producing cells in lung fibrosis is unclear. The involvement of embryonic signaling pathways has been acknowledged and trans-differentiation of epithelial cells is discussed critically. The work presented here investigates the role of TGFB in cytoskeleton remodeling and the expression of Epithelial-Mesenchymal-Transition markers by Alveolar Epithelial Cells Type II and tests the hypothesis if human alveolar epithelial cells are capable of trans-different ...[more]

PMID: 30041633

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Project description:Aberrant T-cell factor (TCF) transcription is implicated in the majority of colorectal cancers (CRCs). TCF transcription induces epithelial-mesenchymal transition (EMT), promoting a tumor-initiating cell (TIC) phenotype characterized by increased proliferation, multidrug resistance (MDR), invasion and metastasis. The data presented herein characterize topoisomerase II? (TopoII?) as a required component of TCF transcription promoting EMT. Using chromatin immunoprecipitation (ChIP) and protein co-immunoprecipitation (co-IP) studies, we show that TopoII? forms protein-protein interactions with ?-catentin and TCF4 and interacts with Wnt response elements (WREs) and promoters of direct target genes of TCF transcription, including: MYC, vimentin, AXIN2 and LEF1. Moreover, both TopoII? and TCF4 ChIP with the N-cadherin promoter, which is a new discovery indicating that TCF transcription may directly regulate N-cadherin expression. TopoII? N-terminal ATP-competitive inhibitors, exemplified by the marine alkaloid neoamphimedine (neo), block TCF activity in vitro and in vivo. Neo effectively inhibits TopoII? and TCF4 from binding WREs/promoter sites, whereas protein-protein interactions remain intact. Neo inhibition of TopoII?-dependent TCF transcription also correlates with significant antitumor effects in vitro and in vivo, including the reversion of EMT, the loss of TIC-mediated clonogenic colony formation, and the loss of cell motility and invasion. Interestingly, non-ATP-competitive inhibitors of TopoII?, etoposide and merbarone, were ineffective at preventing TopoII?-dependent TCF transcription. Thus, we propose that TopoII? participation in TCF transcription may convey a mechanism of MDR to conventional TopoII? inhibitors. However, our results indicate that TopoII? N-terminal ATP-binding sites remain conserved and available for drug targeting. This article defines a new strategy for targeted inhibition of TCF transcription that may lead to effective therapies for the treatment of CRC and potentially other Wnt-dependent cancers.

Dataset Information

Human alveolar epithelial cells type II are capable of TGF?-dependent epithelial-mesenchymal-transition and collagen-synthesis.

Publications

Human alveolar epithelial cells type II are capable of TGFβ-dependent epithelial-mesenchymal-transition and collagen-synthesis.

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