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Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice

Activation of the Ras/MAPK pathway is prevalently involved in the occurrence and development of hepatocellular carcinoma (HCC). However, its effects on the deregulated cellular metabolic processes involved in HCC in vivo remain unknown. In this study, a mouse model of HCC induced by hepatocyte‐speci...

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Autores principales: Fan, Tingting, Rong, Zhuona, Dong, Jianyi, Li, Juan, Wang, Kangwei, Wang, Xinxin, Li, Huiling, Chen, Jun, Wang, Fujin, Wang, Jingyu, Wang, Aiguo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633588/
https://www.ncbi.nlm.nih.gov/pubmed/28941178
http://dx.doi.org/10.1002/cam4.1177
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author Fan, Tingting
Rong, Zhuona
Dong, Jianyi
Li, Juan
Wang, Kangwei
Wang, Xinxin
Li, Huiling
Chen, Jun
Wang, Fujin
Wang, Jingyu
Wang, Aiguo
author_facet Fan, Tingting
Rong, Zhuona
Dong, Jianyi
Li, Juan
Wang, Kangwei
Wang, Xinxin
Li, Huiling
Chen, Jun
Wang, Fujin
Wang, Jingyu
Wang, Aiguo
author_sort Fan, Tingting
collection PubMed
description Activation of the Ras/MAPK pathway is prevalently involved in the occurrence and development of hepatocellular carcinoma (HCC). However, its effects on the deregulated cellular metabolic processes involved in HCC in vivo remain unknown. In this study, a mouse model of HCC induced by hepatocyte‐specific expression of the Hras12V oncogene was investigated using an integrative analysis of metabolomics and transcriptomics data. Consistent with the phenotype of abundant lipid droplets in HCC, the lipid biosynthesis in HCC was significantly enhanced by (1) a sufficient supply of acetyl‐CoA from enhanced glycolysis and citrate shuttle activity; (2) a sufficient supply of NADPH from enhanced pentose phosphate pathway (PPP) activity; (3) upregulation of key enzymes associated with lipid biosynthesis; and (4) downregulation of key enzymes associated with bile acid biosynthesis. In addition, glutathione (GSH) was significantly elevated, which may result from a sufficient supply of 5‐oxoproline and L‐glutamate as well as an enhanced reduction in the process of GSSG being turned into GSH by NADPH. The high level of GSH along with elevated Bcl2 and Ucp2 expression may contribute to a normal level of reactive oxygen species (ROS) in HCC. In conclusion, our results suggest that the lipid metabolism, glycolysis, PPP, tricarboxylic acid (TCA) cycle, citrate shuttle activity, bile acid synthesis, and redox homeostasis in the HCC induced by ras oncogene are significantly perturbed, and these altered metabolic processes may play crucial roles in the carcinogenesis, development, and pathological characteristics of HCC.
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spelling pubmed-56335882017-10-17 Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice Fan, Tingting Rong, Zhuona Dong, Jianyi Li, Juan Wang, Kangwei Wang, Xinxin Li, Huiling Chen, Jun Wang, Fujin Wang, Jingyu Wang, Aiguo Cancer Med Cancer Biology Activation of the Ras/MAPK pathway is prevalently involved in the occurrence and development of hepatocellular carcinoma (HCC). However, its effects on the deregulated cellular metabolic processes involved in HCC in vivo remain unknown. In this study, a mouse model of HCC induced by hepatocyte‐specific expression of the Hras12V oncogene was investigated using an integrative analysis of metabolomics and transcriptomics data. Consistent with the phenotype of abundant lipid droplets in HCC, the lipid biosynthesis in HCC was significantly enhanced by (1) a sufficient supply of acetyl‐CoA from enhanced glycolysis and citrate shuttle activity; (2) a sufficient supply of NADPH from enhanced pentose phosphate pathway (PPP) activity; (3) upregulation of key enzymes associated with lipid biosynthesis; and (4) downregulation of key enzymes associated with bile acid biosynthesis. In addition, glutathione (GSH) was significantly elevated, which may result from a sufficient supply of 5‐oxoproline and L‐glutamate as well as an enhanced reduction in the process of GSSG being turned into GSH by NADPH. The high level of GSH along with elevated Bcl2 and Ucp2 expression may contribute to a normal level of reactive oxygen species (ROS) in HCC. In conclusion, our results suggest that the lipid metabolism, glycolysis, PPP, tricarboxylic acid (TCA) cycle, citrate shuttle activity, bile acid synthesis, and redox homeostasis in the HCC induced by ras oncogene are significantly perturbed, and these altered metabolic processes may play crucial roles in the carcinogenesis, development, and pathological characteristics of HCC. John Wiley and Sons Inc. 2017-09-21 /pmc/articles/PMC5633588/ /pubmed/28941178 http://dx.doi.org/10.1002/cam4.1177 Text en © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cancer Biology
Fan, Tingting
Rong, Zhuona
Dong, Jianyi
Li, Juan
Wang, Kangwei
Wang, Xinxin
Li, Huiling
Chen, Jun
Wang, Fujin
Wang, Jingyu
Wang, Aiguo
Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice
title Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice
title_full Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice
title_fullStr Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice
title_full_unstemmed Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice
title_short Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice
title_sort metabolomic and transcriptomic profiling of hepatocellular carcinomas in hras12v transgenic mice
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633588/
https://www.ncbi.nlm.nih.gov/pubmed/28941178
http://dx.doi.org/10.1002/cam4.1177
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