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Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade

As one of the most malignant cancer types, hepatocellular carcinoma (HCC) is highly invasive and capable of metastasizing to distant organs. Intermedin (IMD), an endogenous peptide belonging to the calcitonin family, has been suggested playing important roles in cancer cell survival and invasion, in...

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Autores principales: Xiao, Fei, Li, Hongyu, Feng, Zhongxue, Huang, Luping, Kong, Lingmiao, Li, Min, Wang, Denian, Liu, Fei, Zhu, Zhijun, Wei, Yong’gang, Zhang, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803743/
https://www.ncbi.nlm.nih.gov/pubmed/33436794
http://dx.doi.org/10.1038/s41598-020-80066-x
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author Xiao, Fei
Li, Hongyu
Feng, Zhongxue
Huang, Luping
Kong, Lingmiao
Li, Min
Wang, Denian
Liu, Fei
Zhu, Zhijun
Wei, Yong’gang
Zhang, Wei
author_facet Xiao, Fei
Li, Hongyu
Feng, Zhongxue
Huang, Luping
Kong, Lingmiao
Li, Min
Wang, Denian
Liu, Fei
Zhu, Zhijun
Wei, Yong’gang
Zhang, Wei
author_sort Xiao, Fei
collection PubMed
description As one of the most malignant cancer types, hepatocellular carcinoma (HCC) is highly invasive and capable of metastasizing to distant organs. Intermedin (IMD), an endogenous peptide belonging to the calcitonin family, has been suggested playing important roles in cancer cell survival and invasion, including in HCC. However, how IMD affects the behavior of HCC cells and the underlying mechanisms have not been fully elucidated. Here, we show that IMD maintains an important homeostatic state by activating the ERK1/2-EGR1 (early growth response 1) signaling cascade, through which HCC cells acquire a highly invasive ability via significantly enhanced filopodia formation. The inhibition of IMD blocks the phosphorylation of ERK1/2, resulting in EGR1 downregulation and endoplasmic reticulum stress (ER) stress, which is evidenced by the upregulation of ER stress marker DDIT3 (DNA damage-inducible transcript 3). The high level of DDIT3 induces HCC cells into an ER-stress related apoptotic pathway. Along with our previous finding that IMD plays critical roles in the vascular remodeling process that improves tumor blood perfusion, IMD may facilitate the acquisition of increased invasive abilities and a survival benefit by HCC cells, and it is easier for HCC cells to obtain blood supply via the vascular remodeling activities of IMD. According to these results, blockade of IMD activity may have therapeutic potential in the treatment of HCC.
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spelling pubmed-78037432021-01-13 Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade Xiao, Fei Li, Hongyu Feng, Zhongxue Huang, Luping Kong, Lingmiao Li, Min Wang, Denian Liu, Fei Zhu, Zhijun Wei, Yong’gang Zhang, Wei Sci Rep Article As one of the most malignant cancer types, hepatocellular carcinoma (HCC) is highly invasive and capable of metastasizing to distant organs. Intermedin (IMD), an endogenous peptide belonging to the calcitonin family, has been suggested playing important roles in cancer cell survival and invasion, including in HCC. However, how IMD affects the behavior of HCC cells and the underlying mechanisms have not been fully elucidated. Here, we show that IMD maintains an important homeostatic state by activating the ERK1/2-EGR1 (early growth response 1) signaling cascade, through which HCC cells acquire a highly invasive ability via significantly enhanced filopodia formation. The inhibition of IMD blocks the phosphorylation of ERK1/2, resulting in EGR1 downregulation and endoplasmic reticulum stress (ER) stress, which is evidenced by the upregulation of ER stress marker DDIT3 (DNA damage-inducible transcript 3). The high level of DDIT3 induces HCC cells into an ER-stress related apoptotic pathway. Along with our previous finding that IMD plays critical roles in the vascular remodeling process that improves tumor blood perfusion, IMD may facilitate the acquisition of increased invasive abilities and a survival benefit by HCC cells, and it is easier for HCC cells to obtain blood supply via the vascular remodeling activities of IMD. According to these results, blockade of IMD activity may have therapeutic potential in the treatment of HCC. Nature Publishing Group UK 2021-01-12 /pmc/articles/PMC7803743/ /pubmed/33436794 http://dx.doi.org/10.1038/s41598-020-80066-x Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xiao, Fei
Li, Hongyu
Feng, Zhongxue
Huang, Luping
Kong, Lingmiao
Li, Min
Wang, Denian
Liu, Fei
Zhu, Zhijun
Wei, Yong’gang
Zhang, Wei
Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade
title Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade
title_full Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade
title_fullStr Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade
title_full_unstemmed Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade
title_short Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade
title_sort intermedin facilitates hepatocellular carcinoma cell survival and invasion via erk1/2-egr1/ddit3 signaling cascade
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803743/
https://www.ncbi.nlm.nih.gov/pubmed/33436794
http://dx.doi.org/10.1038/s41598-020-80066-x
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