Dataset Information

Kruppel-like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF-?1/Smad/snail pathway.

ABSTRACT: Krüppel-like factor 4 (KLF4) was closely associated with epithelial-mesenchymal transition and stemness in colorectal cancer stem cells (CSCs)-enriched spheroid cells. Nonetheless, the underlying molecular mechanism is unclear. This study showed that KLF4 overexpression was accompanied with stemness and mesenchymal features in Lgr5⁺ CD44⁺ EpCAM⁺ colorectal CSCs. KLF4 knockdown suppressed stemness, mesenchymal features and activation of the TGF-?1 pathway, whereas enforced KLF4 overexpression activated TGF-?1, phosphorylation of Smad 2/3 and Snail expression, and restored stemness and mesenchymal phenotypes. Furthermore, TGF-?1 pathway inhibition invalidated KLF4-facilitated stemness and mesenchymal features without affecting KLF4 expression. The data from the current study are the first to demonstrate that KLF4 maintains stemness and mesenchymal properties through the TGF-?1/Smad/Snail pathway in Lgr5⁺ CD44⁺ EpCAM⁺ colorectal CSCs.

SUBMITTER: Leng Z

PROVIDER: S-EPMC6991673 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Krüppel-like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF-β1/Smad/snail pathway.

Leng Zhengwei Z Li Yong Y Zhou Guojun G Lv Xiaojiang X Ai Walden W Li Jianshui J Hou Lingmi L

Journal of cellular and molecular medicine 20191212 2

Krüppel-like factor 4 (KLF4) was closely associated with epithelial-mesenchymal transition and stemness in colorectal cancer stem cells (CSCs)-enriched spheroid cells. Nonetheless, the underlying molecular mechanism is unclear. This study showed that KLF4 overexpression was accompanied with stemness and mesenchymal features in Lgr5+ CD44+ EpCAM+ colorectal CSCs. KLF4 knockdown suppressed stemness, mesenchymal features and activation of the TGF-β1 pathway, whereas ...[more]

PMID: 31830379

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Project description:An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for HCC. The aim of this work was to validate a new in vitro model based on engineering three-dimensional (3D) healthy and cirrhotic human liver scaffolds with HCC cells recreating the micro-environmental features favoring HCC. Healthy and cirrhotic human livers ECM scaffolds were developed using a high shear stress oscillation-decellularization procedure. The scaffolds bio-physical/bio-chemical properties were analyzed by qualitative and quantitative approaches. Cirrhotic 3D scaffolds were characterized by biomechanical properties and microarchitecture typical of the native cirrhotic tissue. Proteomic analysis was employed on decellularized 3D scaffolds and showed specific enriched proteins in cirrhotic ECM in comparison to healthy ECM proteins. Cell repopulation of cirrhotic scaffolds highlighted a unique up-regulation in genes related to epithelial to mesenchymal transition (EMT) and TGFβ signaling. This was also supported by the presence and release of higher concentration of endogenous TGFβ1 in cirrhotic scaffolds in comparison to healthy scaffolds. Fibronectin secretion was significantly upregulated in cells grown in cirrhotic scaffolds in comparison to cells engrafted in healthy scaffolds. TGFβ1 induced the phosphorylation of canonical proteins Smad2/3, which was ECM scaffold-dependent. Important, TGFβ1-induced phosphorylation of Smad2/3 was significantly reduced and ECM scaffold-independent when pre/simultaneously treated with the TGFβ-R1 kinase inhibitor Galunisertib. In conclusion, the inherent features of cirrhotic human liver ECM micro-environment were dissected and characterized for the first time as key pro-carcinogenic components in HCC development.

Dataset Information

Kruppel-like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF-?1/Smad/snail pathway.

Publications

Krüppel-like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF-β1/Smad/snail pathway.

Similar Datasets

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