Low-Grade Dysplastic Nodules Revealed as the Tipping Point during Multistep Hepatocarcinogenesis by Dynamic Network Biomarkers

doi:10.3390/genes8100268

	Low-Grade Dysplastic Nodules Revealed as the Tipping Point during Multistep Hepatocarcinogenesis by Dynamic Network Biomarkers
	Lu, Lina 1; Jiang, Zhonglin 1; Dai, Yulin 2; Chen, Luonan1,3
	2017-10
发表期刊	GENES (IF:2.8[JCR-2023],3.3[5-Year])
ISSN	2073-4425
卷号	8 期号:10
发表状态	已发表
DOI	10.3390/genes8100268
摘要	Hepatocellular carcinoma (HCC) is a complex disease with a multi-step carcinogenic process from preneoplastic lesions, including cirrhosis, low-grade dysplastic nodules (LGDNs), and high-grade dysplastic nodules (HGDNs) to HCC. There is only an elemental understanding of its molecular pathogenesis, for which a key problem is to identify when and how the critical transition happens during the HCC initiation period at a molecular level. In this work, for the first time, we revealed that LGDNs is the tipping point (i.e., pre-HCC state rather than HCC state) of hepatocarcinogenesis based on a series of gene expression profiles by a new mathematical model termed dynamic network biomarkers (DNB)-a group of dominant genes or molecules for the transition. Different from the conventional biomarkers based on the differential expressions of the observed genes (or molecules) for diagnosing a disease state, the DNB model exploits collective fluctuations and correlations of the observed genes, thereby predicting the imminent disease state or diagnosing the critical state. Our results show that DNB composed of 59 genes signals the tipping point of HCC (i.e., LGDNs). On the other hand, there are a large number of differentially expressed genes between cirrhosis and HGDNs, which highlighted the stark differences or drastic changes before and after the tipping point or LGDNs, implying the 59 DNB members serving as the early-warning signals of the upcoming drastic deterioration for HCC. We further identified the biological pathways responsible for this transition, such as the type I interferon signaling pathway, Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, transforming growth factor (TGF)-beta signaling pathway, retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway, cell adhesion molecules, and cell cycle. In particular, pathways related to immune system reactions and cell adhesion were downregulated, and pathways related to cell growth and death were upregulated. Furthermore, DNB was validated as an effective predictor of prognosis for HCV-induced HCC patients by survival analysis on independent data, suggesting a potential clinical application of DNB. This work provides biological insights into the dynamic regulations of the critical transitions during multistep hepatocarcinogenesis.
关键词	dynamic network biomarkers hepatocellular carcinoma low-grade dysplastic nodules tipping point
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China (NSFC)[91439103] ; National Natural Science Foundation of China (NSFC)[91529303] ; National Natural Science Foundation of China (NSFC)[31771476] ; National Natural Science Foundation of China (NSFC)[81471047]
WOS研究方向	Genetics & Heredity
WOS类目	Genetics & Heredity
WOS记录号	WOS:000414862300033
出版者	MDPI
WOS关键词	ALPHA THERAPEUTIC RESPONSE ; HEPATOCELLULAR-CARCINOMA ; CANCER ; GENE ; DIAGNOSIS ; PATHWAY ; PROTEIN ; LESIONS ; IMPACT ; ISG15
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/10059
专题	生命科学与技术学院_特聘教授组_陈洛南组
通讯作者	Chen, Luonan
作者单位	1.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol,CAS Ctr Excellence Mol C, Innovat Ctr Cell Signaling Network,Key Lab Syst B, Shanghai 200031, Peoples R China 2.Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Ctr Precis Hlth, 7000 Fannin St,Suite 820, Houston, TX 77030 USA 3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Lu, Lina,Jiang, Zhonglin,Dai, Yulin,et al. Low-Grade Dysplastic Nodules Revealed as the Tipping Point during Multistep Hepatocarcinogenesis by Dynamic Network Biomarkers[J]. GENES,2017,8(10).
APA	Lu, Lina,Jiang, Zhonglin,Dai, Yulin,&Chen, Luonan.(2017).Low-Grade Dysplastic Nodules Revealed as the Tipping Point during Multistep Hepatocarcinogenesis by Dynamic Network Biomarkers.GENES,8(10).
MLA	Lu, Lina,et al."Low-Grade Dysplastic Nodules Revealed as the Tipping Point during Multistep Hepatocarcinogenesis by Dynamic Network Biomarkers".GENES 8.10(2017).