Time serial transcriptome reveals Cyp2c29 as a key gene in hepatocellular carcinoma development
(
), Anyuan Guo1 (), Abstract
Hepatocellular carcinoma (HCC) is a severely lethal cancer that usually originates from chronic liver injury and inflammation. Although progress on diagnosis and treatment is obvious, the cause of HCC remains unclear. In this study, we sought to determine key genes in HCC development.
To identify key regulators during HCC progression, we performed transcriptome sequencing to obtain time series gene expression data from a mouse model with diethylnitrosamine-induced liver tumors and further verified gene expression and function in vitro and in vivo.
Among the differentially expressed genes, Cyp2c29 was continuously downregulated during HCC progression. Overexpression of Cyp2c29 suppressed NF-κB activation and proinflammatory cytokine production by increasing the production of 14,15-epoxyeicosatrienoic acid in vitro. Furthermore, overexpression of Cyp2c29 in vivo protected against liver inflammation in mouse models of liver injury induced by both acetaminophen and CCl4. Two human homologs of mouse Cyp2c29, CYP2C8 and CYP2C9, were found to be downregulated in human HCC progression, and their expression was positively correlated with overall survival in patients with HCC (significance: P = 0.046 and 0.0097, respectively).
Collectively, through systematic analysis and verification, we determined that Cyp2c29 is a novel gene involved in liver injury and inflammation, which may be a potential biomarker for HCC prevention and prognosis determination.
Electronic Supplementary Material
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN2012. Int J Cancer. 2015; 136: E359-86.
Colombo M, Maisonneuve P. Controlling liver cancer mortality on a global scale: still a long way to go. J Hepatol. 2017; 67: 216-7.
He G, Karin M. NF-kappa B and STAT3 – key players in liver inflammation and cancer. Cell Res. 2011; 21: 159-68.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2013; 357: 539-45.
Ray K. A complex interplay between inflammation and immunity in liver cancer. Nat Rev Gastro Hepat. 2018; 15: 3.
Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014; 60: 1090-6.
Li H, Clarke JD, Dzierlenga AL, Bear J, Goedken MJ, Cherrington NJ. In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice. J Biochem Mol Toxicol. 2017; 32: 10.1002/jbt.21840.
Yu D, Green B, Marrone A, Guo Y, Kadlubar S, Lin D, et al. Suppression of CYP2C9 by microRNA hsa-miR-128-3p in human liver cells and association with hepatocellular carcinoma. Sci Rep. 2015; 5: 8534.
Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 2006; 6: 947-60.
Schuck RN, Zha W, Edin ML, Gruzdev A, Vendrov KC, Miller TM, et al. The Cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease. PLoS One. 2014; 9: e110162.
Tsunedomi R, Iizuka N, Hamamoto Y, Uchimura S, Miyamoto T, Tamesa T, et al. Patterns of expression of cytochrome P450 genes in progression of hepatitis C virus-associated hepatocellular carcinoma. Int J Oncol. 2005; 27: 661-7.
Xu XR, Huang J, Xu ZG, Qian BZ, Zhu ZD, Yan Q, et al. Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. Proc Natl Acad Sci USA. 2001; 98: 15089-94.
Wang X, Yu T, Liao X, Yang C, Han C, Zhu G, et al. The prognostic value of CYP2C subfamily genes in hepatocellular carcinoma. Cancer Med. 2018; 7: 966-80.
Zhou L, Du Y, Kong L, Zhang X, Chen Q. Identification of molecular target genes and key pathways in hepatocellular carcinoma by bioinformatics analysis. Oncotargets Ther. 2018; 11: 1861-9.
Lin Y, Sibanda VL, Zhang HM, Hu H, Liu H, Guo AY. MiRNA and TF co-regulatory network analysis for the pathology and recurrence of myocardial infarction. Sci Rep. 2015; 5: 9653.
Lin Y, Zhang Q, Zhang HM, Liu W, Liu CJ, Li Q, et al. Transcription factor and miRNA co-regulatory network reveals shared and specific regulators in the development of B cell and T cell. Sci Rep. 2015; 5: 15215.
Ye H, Liu X, Lv M, Wu Y, Kuang S, Gong J, et al. MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia. Nucleic Acids Res. 2012; 40: 5201-14.
Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010; 140: 197-208.
Bakiri L, Wagner EF. Mouse models for liver cancer. Mol Oncol. 2013; 7: 206-23.
Hoque R, Sohail MA, Salhanick S, Malik AF, Ghani A, Robson SC, et al. P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am J Physiol Gastrointest Liver Physiol. 2012; 302: G1171-9.
Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc. 2016; 11: 1650-67.
Xia J, Sinelnikov IV, Han B, Wishart DS. MetaboAnalyst 3.0 – making metabolomics more meaningful. Nucleic Acids Res. 2015; 43: w251-7.
Liu F, Song Y, Liu D. Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther. 1999; 6: 1258-66.
Shen GF, Jiang JG, Fu XN, Wang DW. Promotive effects of epoxyeicosatrienoic acids (EETs) on proliferation of tumor cells. Ai Zheng. 2008; 27: 1130-6 [article in Chinese].
Amaral SS, Oliveira AG, Marques PE, Quintão JL, Pires DA, Resende RR, et al. Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity. Cell Commun Signal. 2013; 11: 10.
Aparicio-Vergara M, Tencerova M, Morgantini C, Barreby E, Aouadi M. Isolation of Kupffer cells and hepatocytes from a single mouse liver. Methods Mol Biol. 2017; 1639: 161-71.
Aparicio-Vergara M, Tencerova M, Morgantini C, Barreby E, Aouadi M. Isolation of non-parenchymal cells from the mouse liver. Methods Mol Biol. 2015; 1325: 3-17.
Zhang HM, Kuang S, Xiong X, Gao T, Liu C, Guo AY. Transcription factor and microRNA co-regulatory loops: important regulatory motifs in biological processes and diseases. Brief Bioinform. 2015; 16: 45-58.
Kockmann T, Trachsel C, Panse C, Wahlander A, Selevsek N, Grossmann J, et al. Targeted proteomics coming of age – SRM, PRM and DIA performance evaluated from a core facility perspective. Proteomics. 2016; 16: 2183-92.
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015; 347: 1260419.
Liu CJ, Hu FF, Xia MX, Han L, Zhang Q, Guo AY. GSCALite: a web server for gene set cancer analysis. Bioinformatics. 2018; 34: 3771-2.
Polonikov A, Bykanova M, Ponomarenko I, Sirotina S, Bocharova A, Vagaytseva K, et al. The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population. Clin Exp Hypertens. 2017; 39: 306-11.
Ross AC, Zolfaghari R. Cytochrome P450s in the regulation of cellular retinoic acid metabolism. Annu Rev Nutr. 2011; 31: 65-87.
Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab. 2002; 3: 561-97.
Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006; 43: S54-62.
Sun D, Yang YM, Jiang H, Wu H, Ojaimi C, Kaley G, et al. Roles of CYP2C29 and RXR gamma in vascular EET synthesis of female mice. Am J Physiol Regu Integr Comp Physiol. 2010; 298: R862-9.
Tacconelli S, Patrignani P. Inside epoxyeicosatrienoic acids and cardiovascular disease. Front Pharmacol. 2014; 5: 239.
Boron WF, Boulpaep EL. Medical physiology: a cellular and molecular approach. Philadelphia, PA: Elsevier. 2002.
Luedde T, Schwabe RF. NF-κB in the liver-linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastro Hepat. 2011; 8: 108-18.
Tan H, He Q, Li R, Lei F, Lei X. Trillin reduces liver chronic inflammation and fibrosis in carbon tetrachloride (CCl4) induced liver injury in mice. Immunol Invest. 2016; 45: 371-82.
Jiang L, Yue S, Li C, Ke M, Busuttil RW, Kupiec-Weglinski JW, et al. TAK1 signaling is essential for NLRP3 activation in mouse drug-induced damage-associated hepatitis. J Hepatol. 2017; 66: S396.
McGuinness PH, Painter D, Davies S, McCaughan GW. Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C infection. Gut. 2000; 46: 260-9.
Taniguchi K, Karin M. NF-kappa B, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018; 18: 309-24.
Bishop-Bailey D, Thomson S, Askari A, Faulkner A, Wheeler-Jones C. Lipid-metabolizing CYPs in the regulation and dysregulation of metabolism. Annu Rev Nutr. 2014; 34: 261-79.
Bishayee A. The role of inflammation and liver cancer. Adv Experimental Med Biol (Inflamm Cancer). 2014; 816: 401-35.
Theken KN, Deng Y, Kannon MA, Miller TM, Poloyac SM, Lee CR. Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism. Drug Metab Dispos. 2011; 39: 22-9.
Schmelzer KR, Kubala L, Newman JW, Kim IH, Eiserich JP, Hammock BD. Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc Natl Acad Sci USA. 2005; 102: 9772-7.
Oni-Orisan A, Deng Y, Schuck RN, Theken KN, Edin ML, Lih FB, et al. Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice. Prostaglandins Other Lipid Mediat. 2013; 104: 67-73.
Davis BB, Thompson DA, Howard LL, Morisseau C, Hammock BD, Weiss RH. Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. Proc Natl Acad Sci USA. 2002; 99: 2222-7.
Karin M, Lin A. NF-kappa B at the crossroads of life and death. Nat Immunol. 2002; 3: 221-7.
Iimuro Y, Nishiura T, Hellerbrand C, Behrns KE, Schoonhoven R, Grisham JW, et al. NF kappa B prevents apoptosis and liver dysfunction during liver regeneration. J Clin Invest. 1998; 101: 802-11.
Ruepp SU, Tonge RP, Shaw J, Wallis N, Pognan F. Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. Toxicol Sci. 2002; 65: 135-50.
Son G, Iimuro Y, Seki E, Hirano T, Kaneda Y, Fujimoto J. Selective inactivation of NF-kappa B in the liver using NF-kappa B decoy suppresses CCl4-induced liver injury and fibrosis. Am J Physiol Gastrointest Liver Physiol. 2007; 293: G631-9.
Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009; 9: 537-49.
Grivennikov SI, Karin M. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis. 2011; 70: i104-8.
Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 2001; 107: 7-11.
Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, et al. Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res. 2005; 65: 4707-15.
Panigrahy D, Kaipainen A, Greene ER, Huang S. Cytochrome P450-derived eicosanoids: the neglected pathway in cancer. Cancer Metastasis Rev. 2010; 29: 723-35.
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