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利用基因组规模代谢模型阐明结直肠癌代谢重编程

Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling.

作者信息

Zhang Cheng, Aldrees Mohammed, Arif Muhammad, Li Xiangyu, Mardinoglu Adil, Aziz Mohammad Azhar

机构信息

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.

Department of Medical Genomics, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.

出版信息

Front Oncol. 2019 Jul 30;9:681. doi: 10.3389/fonc.2019.00681. eCollection 2019.

DOI:10.3389/fonc.2019.00681
PMID:31417867
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6682621/
Abstract

Colorectal cancer is the third most incidental cancer worldwide, and the response rate of current treatment for colorectal cancer is very low. Genome-scale metabolic models (GEMs) are systems biology platforms, and they had been used to assist researchers in understanding the metabolic alterations in different types of cancer. Here, we reconstructed a generic colorectal cancer GEM by merging 374 personalized GEMs from the Human Pathology Atlas and used it as a platform for systematic investigation of the difference between tumor and normal samples. The reconstructed model revealed the metabolic reprogramming in glutathione as well as the arginine and proline metabolism in response to tumor occurrence. In addition, six genes including ODC1, SMS, SRM, RRM2, SMOX, and SAT1 associated with arginine and proline metabolism were found to be key players in this metabolic alteration. We also investigated these genes in independent colorectal cancer patients and cell lines and found that many of these genes showed elevated level in colorectal cancer and exhibited adverse effect in patients. Therefore, these genes could be promising therapeutic targets for treatment of a specific colon cancer patient group.

摘要

结直肠癌是全球第三大偶发性癌症，目前结直肠癌治疗的有效率很低。基因组规模代谢模型（GEMs）是系统生物学平台，已被用于帮助研究人员了解不同类型癌症中的代谢改变。在此，我们通过合并来自人类病理图谱的374个个性化GEMs重建了一个通用的结直肠癌GEM，并将其作为系统研究肿瘤样本与正常样本差异的平台。重建模型揭示了谷胱甘肽代谢重编程以及精氨酸和脯氨酸代谢对肿瘤发生的响应。此外，发现包括ODC1、SMS、SRM、RRM2、SMOX和SAT1在内的六个与精氨酸和脯氨酸代谢相关的基因是这种代谢改变的关键因素。我们还在独立的结直肠癌患者和细胞系中研究了这些基因，发现其中许多基因在结直肠癌中表达水平升高，并在患者中表现出不良影响。因此，这些基因可能是治疗特定结肠癌患者群体的有前景的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/2d56e761af1d/fonc-09-00681-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/ad3b068e930b/fonc-09-00681-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/0d64571c4d00/fonc-09-00681-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/232f80d4d095/fonc-09-00681-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/a8da63e71286/fonc-09-00681-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/2d56e761af1d/fonc-09-00681-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/ad3b068e930b/fonc-09-00681-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/0d64571c4d00/fonc-09-00681-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/232f80d4d095/fonc-09-00681-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/a8da63e71286/fonc-09-00681-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d745/6682621/2d56e761af1d/fonc-09-00681-g0005.jpg

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