Identification and Characterization of Robust Hepatocellular Carcinoma Prognostic Subtypes Based on an Integrative Metabolite-Protein Interaction Network,Advanced Science

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Identification and Characterization of Robust Hepatocellular Carcinoma Prognostic Subtypes Based on an Integrative Metabolite-Protein Interaction Network
Advanced Science ( IF 14.3 ) Pub Date : 2021-07-11 , DOI: 10.1002/advs.202100311
Di Chen ₁ , Yiran Zhang _{1,

2} , Wen Wang _{1,

2} , Huan Chen _{1,

2} , Ting Ling _{1,

2} , Renyu Yang _{1,

2} , Yawei Wang _{1,

3} , Chao Duan _{1,

3} , Yu Liu _{1,

3} , Xin Guo ₁ , Lei Fang ₁ , Wuguang Liu ₁ , Xiumei Liu ₁ , Jing Liu ₁ , Wuxiyar Otkur ₁ , Huan Qi ₁ , Xiaolong Liu ₁ , Tian Xia ₁ , Hong-Xu Liu ₃ , Hai-Long Piao _{1,

2}

Affiliation

Metabolite-protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis-distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up-regulation, and exhausted T-cell infiltration. Notably, the immune pathway up-regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub-populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early-stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity.

中文翻译：

基于综合代谢物-蛋白质相互作用网络的稳健肝细胞癌预后亚型的识别和表征

代谢物-蛋白质相互作用（MPIs）在癌症代谢中发挥着关键作用。然而，由于癌细胞的复杂性，我们目前对癌症中 MPI 的了解仍然有限。在此，作者构建了一个综合的 MPI 网络，并提出了一个基于 MPI 网络的肝细胞癌 (HCC) 亚型分型和机制探索工作流程。根据 MPI 网络上枢纽蛋白的表达，鉴定出两种预后独特的 HCC 亚型。同时，观察到不良预后亚型的多个相互依赖的特征，包括缺氧、代谢途径的DNA高甲基化、脂肪酸积累、免疫途径上调和疲惫的T细胞浸润。值得注意的是，免疫通路上调可能是由积累的不饱和脂肪酸诱导的，预计这些脂肪酸会与 SRC 和 TGFB1 等多种免疫调节因子相互作用。此外，根据肿瘤微环境组成，预后不良的亚型进一步分为两个代谢差异显着的亚群。亚型分型在包括早期 HCC 在内的多个 HCC 队列中显示出很强的一致性。总体而言，作者重新定义了稳健的 HCC 预后亚型，并确定了将代谢与免疫调节联系起来的潜在 MPI，从而促进了对 HCC 代谢异质性的理解和临床应用。

更新日期：2021-09-09

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