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Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma

Little is known about how chronic inflammation contributes to the progression of hepatocellular carcinoma (HCC), especially the initiation of cancer. To uncover the critical transition from chronic inflammation to HCC and the molecular mechanisms at a network level, we analyzed the time-series prote...

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Autores principales: Li, Meiyi, Li, Chen, Liu, Wei-Xin, Liu, Conghui, Cui, Jingru, Li, Qingrun, Ni, Hong, Yang, Yingcheng, Wu, Chaochao, Chen, Chunlei, Zhen, Xing, Zeng, Tao, Zhao, Mujun, Chen, Lei, Wu, Jiarui, Zeng, Rong, Chen, Luonan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907842/
https://www.ncbi.nlm.nih.gov/pubmed/28655161
http://dx.doi.org/10.1093/jmcb/mjx021
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author Li, Meiyi
Li, Chen
Liu, Wei-Xin
Liu, Conghui
Cui, Jingru
Li, Qingrun
Ni, Hong
Yang, Yingcheng
Wu, Chaochao
Chen, Chunlei
Zhen, Xing
Zeng, Tao
Zhao, Mujun
Chen, Lei
Wu, Jiarui
Zeng, Rong
Chen, Luonan
author_facet Li, Meiyi
Li, Chen
Liu, Wei-Xin
Liu, Conghui
Cui, Jingru
Li, Qingrun
Ni, Hong
Yang, Yingcheng
Wu, Chaochao
Chen, Chunlei
Zhen, Xing
Zeng, Tao
Zhao, Mujun
Chen, Lei
Wu, Jiarui
Zeng, Rong
Chen, Luonan
author_sort Li, Meiyi
collection PubMed
description Little is known about how chronic inflammation contributes to the progression of hepatocellular carcinoma (HCC), especially the initiation of cancer. To uncover the critical transition from chronic inflammation to HCC and the molecular mechanisms at a network level, we analyzed the time-series proteomic data of woodchuck hepatitis virus/c-myc mice and age-matched wt-C57BL/6 mice using our dynamical network biomarker (DNB) model. DNB analysis indicated that the 5th month after birth of transgenic mice was the critical period of cancer initiation, just before the critical transition, which is consistent with clinical symptoms. Meanwhile, the DNB-associated network showed a drastic inversion of protein expression and coexpression levels before and after the critical transition. Two members of DNB, PLA2G6 and CYP2C44, along with their associated differentially expressed proteins, were found to induce dysfunction of arachidonic acid metabolism, further activate inflammatory responses through inflammatory mediator regulation of transient receptor potential channels, and finally lead to impairments of liver detoxification and malignant transition to cancer. As a c-Myc target, PLA2G6 positively correlated with c-Myc in expression, showing a trend from decreasing to increasing during carcinogenesis, with the minimal point at the critical transition or tipping point. Such trend of homologous PLA2G6 and c-Myc was also observed during human hepatocarcinogenesis, with the minimal point at high-grade dysplastic nodules (a stage just before the carcinogenesis). Our study implies that PLA2G6 might function as an oncogene like famous c-Myc during hepatocarcinogenesis, while downregulation of PLA2G6 and c-Myc could be a warning signal indicating imminent carcinogenesis.
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spelling pubmed-59078422018-04-24 Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma Li, Meiyi Li, Chen Liu, Wei-Xin Liu, Conghui Cui, Jingru Li, Qingrun Ni, Hong Yang, Yingcheng Wu, Chaochao Chen, Chunlei Zhen, Xing Zeng, Tao Zhao, Mujun Chen, Lei Wu, Jiarui Zeng, Rong Chen, Luonan J Mol Cell Biol Original Article Little is known about how chronic inflammation contributes to the progression of hepatocellular carcinoma (HCC), especially the initiation of cancer. To uncover the critical transition from chronic inflammation to HCC and the molecular mechanisms at a network level, we analyzed the time-series proteomic data of woodchuck hepatitis virus/c-myc mice and age-matched wt-C57BL/6 mice using our dynamical network biomarker (DNB) model. DNB analysis indicated that the 5th month after birth of transgenic mice was the critical period of cancer initiation, just before the critical transition, which is consistent with clinical symptoms. Meanwhile, the DNB-associated network showed a drastic inversion of protein expression and coexpression levels before and after the critical transition. Two members of DNB, PLA2G6 and CYP2C44, along with their associated differentially expressed proteins, were found to induce dysfunction of arachidonic acid metabolism, further activate inflammatory responses through inflammatory mediator regulation of transient receptor potential channels, and finally lead to impairments of liver detoxification and malignant transition to cancer. As a c-Myc target, PLA2G6 positively correlated with c-Myc in expression, showing a trend from decreasing to increasing during carcinogenesis, with the minimal point at the critical transition or tipping point. Such trend of homologous PLA2G6 and c-Myc was also observed during human hepatocarcinogenesis, with the minimal point at high-grade dysplastic nodules (a stage just before the carcinogenesis). Our study implies that PLA2G6 might function as an oncogene like famous c-Myc during hepatocarcinogenesis, while downregulation of PLA2G6 and c-Myc could be a warning signal indicating imminent carcinogenesis. Oxford University Press 2017-12 2017-07-14 /pmc/articles/PMC5907842/ /pubmed/28655161 http://dx.doi.org/10.1093/jmcb/mjx021 Text en © The Author (2017). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Li, Meiyi
Li, Chen
Liu, Wei-Xin
Liu, Conghui
Cui, Jingru
Li, Qingrun
Ni, Hong
Yang, Yingcheng
Wu, Chaochao
Chen, Chunlei
Zhen, Xing
Zeng, Tao
Zhao, Mujun
Chen, Lei
Wu, Jiarui
Zeng, Rong
Chen, Luonan
Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
title Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
title_full Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
title_fullStr Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
title_full_unstemmed Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
title_short Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
title_sort dysfunction of pla2g6 and cyp2c44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907842/
https://www.ncbi.nlm.nih.gov/pubmed/28655161
http://dx.doi.org/10.1093/jmcb/mjx021
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