C3 - IL-6, STAT3 and gender disparity in the development of inflammation-associated HCC in the Mdr2-knockout mouse

Team C3_2014-2017

Leiter:

Prof. Eithan Galun, M.D.
Director, Goldyne Savad Institute of Gene Therapy
Hadassah Hebrew University Hospital
Jerusalem, 91120
Israel
Tel.: +972-2-6777762
Fax: +972-2-6430982
E-mail: eithang@hadassah.org.il
Skype: eithangalun1

Projektbeschreibung

The cytokine Interleukin 6 (IL-6) has two faces: On the one hand, it is a major driving signaling pathway for regeneration processes in the liver. On the other hand, IL-6 expression has been linked to increased risk for the development and progression of liver cancer, particularly in patients suffering from chronic viral hepatitis. Consequently, IL-6 signaling in liver cancer has emerged as a potential target for cancer immunotherapy. Our aim is to determine the role of IL-6 in chronic hepatitis-associated hepatocarcinogenesis (HCG) as the exact mechanism remains unclear. First results from a mouse model are promising: Upon administration of an anti-IL6 antibody, thereby preventing IL-6 signaling, we were able to show a clinical beneficial effect of reducing HCG.

C3 in 60 SekundenVideoarchiv

online seit 02.11.2012

In the first funding period, we have investigated the role of the H19 non-coding RNA imprinting gene in liver cancer development. Our results are quite surprising: We had found that H19 is actually a pluripotent factor which controls both Nanog and Oct4. In embryos and induced pluripotent stem cells, Nanog, together with other factors such as Oct4, sets the ground state of pluripotency. The reduction of H19 levels in our human embryonic carcinoma cells is associated with early differentiation, and the reduction of pluripotent markers. Interestingly, in the mouse model, the Mdr2-IL-6 double KO mice, H19 is very significantly increased. We are currently investigating the molecular mechanism behind this observation as it possibly explains the increase in hepatocarcinogenesis.

Aktuelles aus der Arbeitsgruppe:

Rivkin M, Simerzin A, Zorde-Khvalevsky E, Chai C, Yuval JB, Rosenberg N, Harari-Steinfeld R, Schneider R, Amir G, Condiotti R, Heikenwalder M, Weber A, Schramm C, Wege H, Kluwe J, Galun E, Giladi H

Inflammation-Induced Expression and Secretion of MicroRNA 122 Leads to Reduced Blood Levels of Kidney-derived Erythropoietin and Anemia
Gastroenterology. 2016 Jul 28. pii:S0016-5085(16)34827-2. doi: 10.1053/j.gastro.2016.07.031. [Epub ahead of print]

Geiger-Maor A, Guedj A, Even-Ram S, Smith Y, Galun E, Rachmilewitz J

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism
Cancer Res. 2015 Jul 1;75(13):2663-73. doi:10.1158/0008-5472.CAN-14-3635. Epub 2015 May 14.

Rozenblum N, Zeira E, Bulvik B, Gourevitch S, Yotvat H, Galun E, Goldberg SN

Radiofrequency Ablation: Inflammatory Changes in the Periablative Zone Can Induce Global Organ Effects, Including Liver Regeneration
Radiology. 2015 Aug;276(2):416-25. doi: 10.1148/radiol.15141918. Epub 2015 Mar 30.

Rozenblum N, Zeira E, Scaiewicz V, Bulvik B, Gourevitch S, Yotvat H, Galun E, Goldberg SN

Oncogenesis: An “Off-Target” Effect of Radiofrequency Ablation
Radiology. 2015 Aug;276(2):426-32. doi: 10.1148/radiol.2015141695.

Stoyanov E, Ludwig G, Mizrahi L, Olam D, Schnitzer-Perlman T, Tasika E, Sass G, Tiegs G, Jiang Y, Nie T, Kohler J, Schinazi RF, Vertino PM, Cedar H, Galun E, Goldenberg D

Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis
Oncotarget. 2015 May 10;6(13):11047-60.

Zahavi T, Lanton T, Divon MS, Salmon A, Peretz T, Galun E, Axelrod JH, Sonnenblick A

Sorafenib treatment during partial hepatectomy reduces tumorgenesis in an inflammation-associated liver cancer model
Oncotarget. 2015 Dec 17. doi: 10.18632/oncotarget.6638. [Epub ahead of print]