title: Genetic deletion of AEG-1 prevents hepatocarcinogenesis.
abstract: Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-κB in liver macrophages. Because AEG-1 is an essential component of NF-κB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1-deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of AKT, ERK, and β-catenin, compared with wild-type control animals. However, AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL6 production and STAT3 activation, two key mediators of HCC development, were also deficient along with other biologic and epigenetics findings in the tumor microenvironment, confirming that AEG-1 supports an NF-κB-mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-κB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Chadia L
authors.initials: CL
authors.lastname: Robertson
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Srivastava
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Devaraja
authors.initials: D
authors.lastname: Rajasekaran
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Maaged
authors.initials: M
authors.lastname: Akiel
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pathology, New York Hospital Medical Center, Flushing, New York, New York.
authors.forename: Shah
authors.initials: S
authors.lastname: Giashuddin
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia. dsarkar@vcu.edu.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000556:secondary; D008565:Membrane Proteins; D051379:Mice; D016328:NF-kappa B; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D016601:RNA-Binding Proteins