Characterization of the erythropoietin-erythropoietin receptor axis in a rat model of liver damage and cholangiocarcinoma developmentReport as inadecuate

Characterization of the erythropoietin-erythropoietin receptor axis in a rat model of liver damage and cholangiocarcinoma development - Download this document for free, or read online. Document in PDF available to download.

Histochemistry and Cell Biology

, Volume 139, Issue 3, pp 473–485

First Online: 04 October 2012Accepted: 10 September 2012DOI: 10.1007-s00418-012-1037-x

Cite this article as: Moriconi, F., Ramadori, P., Schultze, F.C. et al. Histochem Cell Biol 2013 139: 473. doi:10.1007-s00418-012-1037-x


It has been recently shown that the biological effects of erythropoietin EPO are not limited to the hematopoietic compartment but, as pleiotropic glycoprotein, this hormone can exert pro-angiogenic and tissue-protective functions also in a wide range of non-hematopoietic organs. The role of EPO and the effective functionality of its receptor in solid tumors are still a controversial point of debate. In the present work we analyzed the gene expression of EPO and its cognate receptor EpoR in a rat model of thioacetamide-induced damage and tumor. An analysis of the EPO-EpoR axis was also performed on human cholangiocarcinoma CC cell lines. A progressive increase of EPO and EpoR mRNA can already be observed during the fibrotic–cirrhotic development with a peak of expression rising at tumor formation 24.7 ± 9.9-fold increase and 15.5 ± 1.1-fold increase, respectively, for the two genes. Co-localization studies by immunofluorescence revealed hepatocytes in the regenerative cirrhotic nodules Hep Par-1 and in the dysplastic bile duct cells CK19 as the major EPO producers in this specific condition. The same cell populations, together with endothelial cells, exhibited an increased expression of EpoR, although all the non-parenchymal cell populations in the liver exhibited modest basal mRNA levels. Challenging human CC cells, Mz-Cha-2, with a combination of EPO and SCF resulted in a synergistic effect on the gene expression of EPO, CyclinD1 and PCNA. This study suggests that the autocrine and paracrine release of endogenous EPO in the microenvironment may contribute to the development and maintenance of the CC possibly in cooperation with other signaling pathways.

KeywordsCholangiocarcinoma CC Chronic liver injury Erythropoietin EPO Erythropoietin receptor EpoR Thioacetamide TAA F. Moriconi and P. Ramadori contributed equally to the work.

Electronic supplementary materialThe online version of this article doi:10.1007-s00418-012-1037-x contains supplementary material, which is available to authorized users.

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Author: Federico Moriconi - Pierluigi Ramadori - Frank C. Schultze - Martina Blaschke - Ahmad Amanzada - Sajjad Khan - Giuliano Ra


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