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Am J Physiol Gastrointest Liver Physiol 290: G624-G632, 2006. First published December 1, 2005; doi:10.1152/ajpgi.00128.2005
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TRANSLATIONAL PHYSIOLOGY

Cell proliferation and drug resistance in hepatocellular carcinoma are modulated by Rho GTPase signals

Paola Sterpetti,1,* Luca Marucci,1,* Cinzia Candelaresi,1 Deniz Toksoz,2 Gianfranco Alpini,3 Laura Ugili,1 Gianluca Svegliati Baroni,1 Giampiero Macarri,1 and Antonio Benedetti1

1Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy; 2Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts; and 3Department of Internal Medicine and Medical Physiology, The Texas A&M University System Health Sciences Center, and Central Texas Veterans Health Sciences Center, Temple, Texas

Submitted 31 March 2005 ; accepted in final form 1 November 2005

ABSTRACT

Hepatocellular carcinoma is highly resistant to chemotherapeutic agents, thus the need to discover effective therapeutic molecules to suppress cancer cell growth and to overcome drug resistance is urgent. The Rho GTPase is implicated in cancer and metastasis and is directly activated by the Lymphoid blast crisis (Lbc) protooncogene, a Rho guanine-nucleotide exchange factor. The aim of the study was to analyze the expression of Lbc in hepatocarcinoma and to determine the effect of Lbc-induced Rho signaling on expression, growth rate and resistance to genotoxic stress. We found, by immunohistochemical analysis of biopsy samples and Northern and Western blot analyses of cell lines, that Lbc is absent in normal adult liver but is abundantly expressed in hepatocarcinoma, implying an increased Rho pathway signaling. Lbc stably transfected hepatocarcinoma cells exhibit increased proliferation and levels of ERK and cyclin D1 activation, which are blocked by a Rho inhibitor. In contrast, AKT activation was not altered. Moreover, Lbc expression confers increased resistance to genotoxic stress induced by doxorubicin, which is associated with upregulation of Bcl-2 and BAD phosphorylation, and this is reversed by a Rho inhibitor. In conclusion, these data support a role for Rho in liver cancer progression and resistance to therapy and may provide a basis for developing effective treatment for hepatocarcinoma.

cell cycle; oncogenes


Address for reprint requests and other correspondence: P. Sterpetti, Dept. of Gastroenterology; Polytechnic Univ. of Marche, Polo Didattico, Via Tronto 10, 60020 Torrette, Ancona, Italy (e-mail: clingastro{at}univpm.it)






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