TGF-beta inactivation and TGF-alpha overexpression cooperate in an in vivo mouse model to induce hepatocellular carcinoma that recapitulates molecular features of human liver cancer.

Publication Type:

Journal Article


International journal of cancer. Journal international du cancer, Volume 127, Issue 5, p.1060-71 (2010)


2010, Animals, Blotting, Western, Carcinoma, Hepatocellular, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Experimental Histopathology Core Facility, Female, Flow Cytometry Core Facility, Gene Expression Regulation, Neoplastic, Humans, Immunoenzyme Techniques, Integrases, Liver Neoplasms, Male, MICE, Mice, Inbred C57BL, Mice, Transgenic, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Scientific Imaging Core Facility, Shared Resources, Signal Transduction, Transforming Growth Factor alpha, Transforming Growth Factor beta, Translational Bioimaging Center Core Facility


Hepatocellular carcinoma (HCC) results from the cumulative effects of deregulated tumor suppressor genes and oncogenes. The tumor suppressor and oncogenes commonly affected include growth factors, receptors and their downstream signaling pathway components. The overexpression of transforming growth factor alpha (TGF-alpha) and the inhibition of TGF-beta signaling are especially common in human liver cancer. Thus, we assessed whether TGF-alpha overexpression and TGF-beta signaling inactivation cooperate in hepatocarcinogenesis using an in vivo mouse model, MT1/TGFa;AlbCre/Tgfbr2(flx/flx) mice ("TGFa;Tgfbr2(hepko)"), which overexpresses TGF-alpha and lacks a TGF-beta receptor in the liver. TGF-beta signaling inactivation did not alter the frequency or number of cancers in mice with overexpression of TGF-alpha. However, the tumors in the TGFa;Tgfbr2(hepko) mice displayed increased proliferation and increased cdk2, cyclin E and cyclin A expression as well as decreased Cdkn1a/p21 expression compared to normal liver and compared to the cancers arising in the TGF-alpha overexpressing mice with intact TGF-beta receptors. Increased phosphorylated ERK1/2 expression was also present in the tumors from the TGFa;Tgfbr2(hepko) mice and correlated with downregulated Raf kinase inhibitor protein expression, which is a common molecular event in human HCC. Thus, TGF-beta signaling inactivation appears to cooperate with TGF-alpha in vivo to promote the formation of liver cancer that recapitulates molecular features of human HCC.