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:

Lanton T, Shriki A, Nechemia-Arbely Y, Abramovitch R, Levkovitch O, Adar R, Rosenberg N, Paldor M, Goldenberg D, Sonnenblick A, Peled A, Rose John S, Galun E, Axelrod JH

Interleukin 6-dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis
Hepatology. 2017 May;65(5):1600-1611. doi: 10.1002/hep.29004. Epub 2017 Mar 23

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]

Galun E

Liver inflammation and cancer: The role of tissue microenvironment in generating the tumor-promoting niche (TPN) in the development of hepatocellular carcinoma
Hepatology. 2016 Feb;63(2):354-6. doi: 10.1002/hep.28344. Epub 2015 Dec 18.

Simerzin A, Zorde-Khvalevsky E, Rivkin M, Adar R, Zucman-Rossi J, Couchy G, Roskams T, Govaere O, Oren M, Giladi H, Galun E

The liver-specific microRNA-122*, the complementary strand of microRNA-122, acts as a tumor suppressor by modulating the p53/mouse double minute 2 homolog circuitry
Hepatology. 2016 Jun 15. doi: 10.1002/hep.28679. [Epub ahead of print]