Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer

Background: Extracellular matrix (ECM)-derived mechanical stimuli regulate many cellular processes and phenotypes through mechanotransduction signaling pathways. Substrate stiffness changes cell phenotypes and promotes angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in tumor...

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Autores principales:	Xichao Xu, Yi Zhang, Xing Wang, Shun Li, Liling Tang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	substrate stiffness lncRNA <i>NEAT1</i> WNT/β-catenin EMT Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/aa4dd06363614ca083a98a0eddc12809
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spelling	oai:doaj.org-article:aa4dd06363614ca083a98a0eddc128092021-11-11T17:27:43ZSubstrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer10.3390/ijms2221120661422-00671661-6596https://doaj.org/article/aa4dd06363614ca083a98a0eddc128092021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12066https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Background: Extracellular matrix (ECM)-derived mechanical stimuli regulate many cellular processes and phenotypes through mechanotransduction signaling pathways. Substrate stiffness changes cell phenotypes and promotes angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in tumors. Enhanced liver tissue matrix stiffness plays a crucial role in the tumorigenesis and malignant development of liver cancer and is associated with unfavorable survival outcomes. However, how liver cancer cells sense changes in ECM stiffness and the underlying molecular mechanisms are largely unknown. Methods: Seeding HepG2 cells on the micropillar gels, HepG2 cells were assessed for responsiveness to mechanotransduction using Western blot and immunofluorescence. Conclusions: We found that higher substrate stiffness dramatically enhanced malignant cell phenotypes and promoted G1/S transition in HepG2 cells. Furthermore, nuclear paraspeckle assembly transcript 1 (<i>NEAT1</i>) was identified as a matrix stiffness-responsive long non-coding RNA (lncRNA) regulating proliferation and EMT in response to increasing matrix stiffness during the progression of HepG2 cells towards liver cancer phenotypes. Higher matrix stiffness contributed to enhancing <i>NEAT1</i> expression, which activated the WNT/β-catenin pathway. β-catenin translocates and enters the nucleus and the EMT transcription factor zinc finger E-box binding homeobox 1 (ZEB1) was upregulated to trigger EMT. Additionally, the proteins required for matrix stiffness-induced proliferation and resistance were strikingly upregulated in HepG2 cells. Therefore, our findings provide evidence that ECM-derived mechanical signals regulate cell proliferation and drive EMT through a <i>NEAT1</i>/WNT/β-catenin mechanotransduction pathway in the tumor microenvironment of liver cancer.Xichao XuYi ZhangXing WangShun LiLiling TangMDPI AGarticlesubstrate stiffnesslncRNA <i>NEAT1</i>WNT/β-cateninEMTBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12066, p 12066 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	substrate stiffness lncRNA <i>NEAT1</i> WNT/β-catenin EMT Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	substrate stiffness lncRNA <i>NEAT1</i> WNT/β-catenin EMT Biology (General) QH301-705.5 Chemistry QD1-999 Xichao Xu Yi Zhang Xing Wang Shun Li Liling Tang Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer
description	Background: Extracellular matrix (ECM)-derived mechanical stimuli regulate many cellular processes and phenotypes through mechanotransduction signaling pathways. Substrate stiffness changes cell phenotypes and promotes angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in tumors. Enhanced liver tissue matrix stiffness plays a crucial role in the tumorigenesis and malignant development of liver cancer and is associated with unfavorable survival outcomes. However, how liver cancer cells sense changes in ECM stiffness and the underlying molecular mechanisms are largely unknown. Methods: Seeding HepG2 cells on the micropillar gels, HepG2 cells were assessed for responsiveness to mechanotransduction using Western blot and immunofluorescence. Conclusions: We found that higher substrate stiffness dramatically enhanced malignant cell phenotypes and promoted G1/S transition in HepG2 cells. Furthermore, nuclear paraspeckle assembly transcript 1 (<i>NEAT1</i>) was identified as a matrix stiffness-responsive long non-coding RNA (lncRNA) regulating proliferation and EMT in response to increasing matrix stiffness during the progression of HepG2 cells towards liver cancer phenotypes. Higher matrix stiffness contributed to enhancing <i>NEAT1</i> expression, which activated the WNT/β-catenin pathway. β-catenin translocates and enters the nucleus and the EMT transcription factor zinc finger E-box binding homeobox 1 (ZEB1) was upregulated to trigger EMT. Additionally, the proteins required for matrix stiffness-induced proliferation and resistance were strikingly upregulated in HepG2 cells. Therefore, our findings provide evidence that ECM-derived mechanical signals regulate cell proliferation and drive EMT through a <i>NEAT1</i>/WNT/β-catenin mechanotransduction pathway in the tumor microenvironment of liver cancer.
format	article
author	Xichao Xu Yi Zhang Xing Wang Shun Li Liling Tang
author_facet	Xichao Xu Yi Zhang Xing Wang Shun Li Liling Tang
author_sort	Xichao Xu
title	Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer
title_short	Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer
title_full	Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer
title_fullStr	Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer
title_full_unstemmed	Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer
title_sort	substrate stiffness drives epithelial to mesenchymal transition and proliferation through the <i>neat1</i>-wnt/β-catenin pathway in liver cancer
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/aa4dd06363614ca083a98a0eddc12809
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_version_	1718432083497451520

Substrate Stiffness Drives Epithelial to Mesenchymal Transition and Proliferation through the <i>NEAT1</i>-Wnt/β-Catenin Pathway in Liver Cancer

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