Ge Jiayun, Bai Yannan, Tang Bo, Wei Dong, Yan Maolin
Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Wuhua District, Kunming, Yunnan (650101), China.
Department of Hepatobiliary Surgery, Fujian Provincial Hospital, The Shengli Clinical Medical College of Fujian Medical University, Fuzhou (350001), Fujian, China.
J Oncol. 2021 Apr 2;2021:6630535. doi: 10.1155/2021/6630535. eCollection 2021.
Nonalcoholic fatty liver disease (NAFLD) is becoming a critical risk of hepatocellular carcinoma (HCC). As both NAFLD and HCC are heterogeneous diseases, this study aims to identify the similarity between the subtypes of NAFLD and HCC based on gene modules.
Coexpressed gene modules were extracted for both NAFLD and HCC. The association between the coexpressed gene modules of NAFLD and HCC was evaluated by Fisher's exact test. The overlapping coexpressed gene module was validated in three independent human NAFLD datasets. Furthermore, the preserved gene module was assessed in four independent NAFLD mouse datasets. The significantly enriched motifs within the gene module were inferred from upstream sequences.
Four coexpressed gene modules were extracted from NAFLD. Of the four coexpressed gene modules, one was significantly overlapping with a module of HCC. This overlapping gene module was regarded as the HCC-associated NAFLD gene module (HANM). Enrichment analysis of biological processes revealed inflammatory response in HANM. Specifically, within the inflammatory response biological process, IL-17, TNF-, and NF-B signaling pathways were enriched. HANM was found to be strongly or moderately conserved across four mouse NAFLD datasets. Motif analysis of the upstream genomic sequences of HANM revealed nine transcription factors (FLI1, NRF1, ZBTB33, ELK1, YY1, ZNF143, TAF1, SF1, and E2F1), of which three transcription factors (YY1, E2F1, and ZNF143) were significantly highly expressed in the NAFLD patients and exhibited survival significance in HCC.
This study demonstrated a robust way to identify the sharing gene signature between subtypes of NAFLD and HCC, which contributed to a comprehensive understanding of pathogenesis from NAFLD to HCC.
非酒精性脂肪性肝病（NAFLD）正成为肝细胞癌（HCC）的一项关键风险因素。由于NAFLD和HCC均为异质性疾病，本研究旨在基于基因模块确定NAFLD和HCC亚型之间的相似性。
提取NAFLD和HCC的共表达基因模块。通过Fisher精确检验评估NAFLD和HCC共表达基因模块之间的关联。在三个独立的人类NAFLD数据集中验证重叠的共表达基因模块。此外，在四个独立的NAFLD小鼠数据集中评估保留的基因模块。从上游序列推断基因模块内显著富集的基序。
从NAFLD中提取了四个共表达基因模块。在这四个共表达基因模块中，有一个与HCC的一个模块显著重叠。这个重叠的基因模块被视为与HCC相关的NAFLD基因模块（HANM）。生物学过程的富集分析揭示了HANM中的炎症反应。具体而言，在炎症反应生物学过程中，IL-17、TNF-和NF-κB信号通路得到富集。发现HANM在四个小鼠NAFLD数据集中具有强或中度保守性。对HANM上游基因组序列的基序分析揭示了九个转录因子（FLI1、NRF1、ZBTB33、ELK1、YY1、ZNF143、TAF1、SF1和E2F1），其中三个转录因子（YY1、E2F1和ZNF143）在NAFLD患者中显著高表达，并在HCC中具有生存意义。
本研究展示了一种可靠的方法来确定NAFLD和HCC亚型之间共享的基因特征，这有助于全面理解从NAFLD到HCC的发病机制。
