title: Interleukin 6-dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis.
abstract: Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For patients with liver cancer, surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long-term survival of these patients. We have shown that partial hepatectomy in multidrug resistance 2 knockout (Mdr2-/-) mice, a model of chronic inflammation-associated liver cancer, significantly accelerates hepatocarcinogenesis. Here, we explore the postsurgical mechanisms that drive accelerated hepatocarcinogenesis in Mdr2-/-mice by perioperative pharmacological inhibition of interleukin-6 (IL6), which is a crucial liver regeneration priming cytokine. We demonstrate that inhibition of IL6 signaling dramatically impedes tumorigenesis following partial hepatectomy without compromising survival or liver mass recovery. IL6 blockade significantly inhibited hepatocyte cell cycle progression while promoting a hypertrophic regenerative response, without increasing apoptosis. Mdr2-/-mice contain hepatocytes with a notable persistent DNA damage response (γH2AX, 53BP1) due to chronic inflammation. We show that liver regeneration in this microenvironment leads to a striking increase in hepatocytes bearing micronuclei, a marker of genomic instability, which is suppressed by IL6 blockade.
  
  
  
  Our findings indicate that genomic instability derived during the IL6-mediated liver regenerative response within a milieu of chronic inflammation links partial hepatectomy to accelerated hepatocarcinogenesis; this suggests a new therapeutic approach through the usage of an anti-IL6 treatment to extend the tumor-free survival of patients undergoing surgical resection. (Hepatology 2017;65:1600-1611).
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Tali
authors.initials: T
authors.lastname: Lanton
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Anat
authors.initials: A
authors.lastname: Shriki
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Yael
authors.initials: Y
authors.lastname: Nechemia-Arbely
authors.affiliation: Goldyne Savad Institute of Gene Therapy.|Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy Laboratory, Human Biology Research Center.
authors.forename: Rinat
authors.initials: R
authors.lastname: Abramovitch
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Orr
authors.initials: O
authors.lastname: Levkovitch
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Revital
authors.initials: R
authors.lastname: Adar
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Nofar
authors.initials: N
authors.lastname: Rosenberg
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Mor
authors.initials: M
authors.lastname: Paldor
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldenberg
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Sonnenblick
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Goldyne Savad Institute of Gene Therapy.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Axelrod
mesh_terms: D000818:Animals; D042822:Genomic Instability; D006498:Hepatectomy; D006521:Hepatitis, Chronic / Q000150:complications*; D006965:Hyperplasia; D006984:Hypertrophy; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D008115:Liver Regeneration; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C577686:interleukin-6, mouse