Key Laboratory of Systems Biology, CAS center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, Shanghai, China.
J Mol Cell Biol. 2017 Dec 1;9(6):489-503. doi: 10.1093/jmcb/mjx021.
Little is known about how chronic inflammation contributes to the progression of hepatocellular carcinoma (HCC), especially the initiation of cancer. To uncover the critical transition from chronic inflammation to HCC and the molecular mechanisms at a network level, we analyzed the time-series proteomic data of woodchuck hepatitis virus/c-myc mice and age-matched wt-C57BL/6 mice using our dynamical network biomarker (DNB) model. DNB analysis indicated that the 5th month after birth of transgenic mice was the critical period of cancer initiation, just before the critical transition, which is consistent with clinical symptoms. Meanwhile, the DNB-associated network showed a drastic inversion of protein expression and coexpression levels before and after the critical transition. Two members of DNB, PLA2G6 and CYP2C44, along with their associated differentially expressed proteins, were found to induce dysfunction of arachidonic acid metabolism, further activate inflammatory responses through inflammatory mediator regulation of transient receptor potential channels, and finally lead to impairments of liver detoxification and malignant transition to cancer. As a c-Myc target, PLA2G6 positively correlated with c-Myc in expression, showing a trend from decreasing to increasing during carcinogenesis, with the minimal point at the critical transition or tipping point. Such trend of homologous PLA2G6 and c-Myc was also observed during human hepatocarcinogenesis, with the minimal point at high-grade dysplastic nodules (a stage just before the carcinogenesis). Our study implies that PLA2G6 might function as an oncogene like famous c-Myc during hepatocarcinogenesis, while downregulation of PLA2G6 and c-Myc could be a warning signal indicating imminent carcinogenesis.
目前对于慢性炎症如何促进肝细胞癌（HCC）的进展，特别是癌症的发生，知之甚少。为了揭示从慢性炎症到 HCC 的关键转变以及在网络水平上的分子机制，我们使用我们的动态网络生物标志物（DNB）模型分析了土拨鼠肝炎病毒/c-myc 小鼠和年龄匹配的 wt-C57BL/6 小鼠的时间序列蛋白质组学数据。DNB 分析表明，转基因小鼠出生后第 5 个月是癌症发生的关键时期，就在关键转变之前，这与临床症状一致。同时，DNB 相关网络显示在关键转变前后蛋白质表达和共表达水平发生了急剧反转。DNB 的两个成员 PLA2G6 和 CYP2C44 及其相关差异表达蛋白被发现诱导花生四烯酸代谢功能障碍，通过炎症介质调节瞬时受体电位通道进一步激活炎症反应，最终导致肝脏解毒功能受损和恶性转化为癌症。作为 c-Myc 的靶标，PLA2G6 在表达上与 c-Myc 呈正相关，在致癌过程中呈下降-上升趋势，关键转变或临界点时达到最低点。在人类肝癌发生过程中也观察到了 PLA2G6 和 c-Myc 的这种同源趋势，在高级别异型增生结节（癌变前的一个阶段）时达到最低点。我们的研究表明，PLA2G6 在肝癌发生过程中可能像著名的 c-Myc 一样发挥癌基因的作用，而 PLA2G6 和 c-Myc 的下调可能是预示即将发生癌变的警告信号。
