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Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma
Meiyi Li 1,2,3†, Chen Li 1,2,†, Wei-Xin Liu 1,4,5 ,Conghui Liu 1,2,5, Jingru Cui 1,2, Qingrun Li 1,2, Hong Ni 1,2, Yingcheng Yang 6, Chaochao Wu 1,2, Chunlei Chen 1,2, Xing Zhen 2, Tao Zeng 1,2, Mujun Zhao 2, Lei Chen 6,7, Jiarui Wu 1,2,4,8,*, Rong Zeng 1,2,4,*, Luonan Chen 1,2,3,4,*
1 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

2 Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, Shanghai, China

3 Minhang Hospital, Fudan University, Shanghai, China

4 School of Life Science and Technology, ShanghaiTech University, Shanghai, China

5 University of Chinese Academy of sciences, Beijing, China

6 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China

7 National Center for Liver Cancer, Shanghai, China

8 Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China

†These authors contributed equally to this work. *Correspondence to:Luonan Chen, E-mail:; Rong Zeng, E-mail:; Jiarui Wu, E-mail:
J Mol Cell Biol, Volume 9, Issue 6, December 2017, Pages 489-503
Keyword: dynamical network biomarker, inflammation-induced HCC, critical transition, early diagnosis, high-grade dysplastic nodules, tipping point
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.