Dr. Jekyll and Mr. Hyde: A paradoxical oncogenic and tumor suppressive role of signal transducer and activator of transcription 3 in liver cancer

U nrestrained activation of the signal transducer and activator of transcription (Stat) signaling cascade frequently occurs in a wide variety of tumor types. In this pathway, binding of extracellular ligands such as cytokines, hormones, and growth factors to their specific receptors leads to the activation of Janus tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2). These tyrosine kinases are able to phosphorylate a single tyrosine residue of each Stat protein. Similarly, nonreceptor tyrosine kinase such as Abelson murine leukemia viral oncogene homolog (c-ABL) and Schmidt-Ruppin A-2 viral oncogene homolog (c-SRC) can directly phosphorylate Stat proteins in the absence of ligand-induced receptor signaling. Once phosphorylated, Stat proteins homodimerize or heterodimerize and translocate into the nucleus, where they activate a number of target genes involved in cell proliferation, survival, angiogenesis, invasion, and metastasis. Nuclear localization of Stat proteins also results in the transcriptional activation of three families of inhibitory proteins, namely, the protein inhibitors of activated Stats (PIAS), the SH2-containing phosphatases (SHP), and the suppressors of cytokine signaling (SOCS). Induction of PIAS, SHP, and SOCS proteins following Stat activation represents an efficient negative feedback loop mechanism limiting the magnitude of Stat effects on target cells. In the liver, the best-characterized member of the Stat pathway is Stat3. Under physiological conditions, Stat3 is required for liver regeneration due to its ability to stimulate hepatic cell proliferation and survival. In hepatocellular carcinoma (HCC), presumably due to the loss of PIAS, SHP, and SOCS genes via promoter hypermethylation and/or the elevated synthesis of cytokines and growth factors that are able to activate the Stat cascade, Stat3 activity is almost ubiquitously elevated and unconstrained. Of note, high levels of Stat3 were detected in a vast HCC collection regardless of the liver tumor etiology, indicating that uncontrolled activation of Stat3 is a universal event in hepatocarcinogenesis. Also, it has been found that Stat3 levels are directly correlated with HCC biological aggressiveness and inversely with survival of patients with HCC, pointing to an important role of Stat3 in liver cancer prognosis. Subsequent in vitro and in vivo studies have shown that suppression of Stat3 enhances the chemosensitivity of HCC cells and suppresses the growth and metastatic properties of human HCC in xenograft models. Also, hepatocyte-specific Stat3-deficient mice were found to exhibit more than a six-fold reduction in HCC load compared to Stat3 wild-type mice when subjected to diethylnitrosamine treatment. In the latter model, disruption of the inhibitor of nuclear factor kappa-B kinase subunit beta– nuclear factor kappa-B (NF-jB) axis was the causative event leading to aberrant Stat3 activation, suggesting that the NF-jB pathway is a major negative regulator of Stat3 in HCC. Furthermore, carcinogen-induced HCC development in mice was significantly enhanced by heterozygous deletion of the Stat3 inhibitor SOCS1. Similarly, genetic knockout of the SOCS3 gene in the mouse liver resulted in prolonged Stat3 phosphorylation and increased expression of Stat3 target genes, ultimately leading to rapid HCC development when SOCS3 knockout mice were subjected to chemically induced hepatocarcinogenesis. Altogether, these data establish Stat3 as a bona fide oncogene in the liver and suggest that Stat3 might be a critical target for innovative therapeutical approaches in HCC. In this issue of HEPATOLOGY, the report by Schneller et al. provides new, significant experimental data on the role of Stat3 in liver carcinogenesis. In particular, the authors investigate the function of Stat3 in HCC progression in the presence of other molecular alterations, namely the activation of the rat sarcoma viral oncogene homolog (Ras) oncogenic cascade and the loss of expression of the p14/p19 tumor Abbreviations: HCC, hepatocellular carcinoma; Jak, Janus tyrosine kinase; NF-jB, nuclear factor kappa-B; PIAS, protein inhibitors of activated Stats; SHP, SH2-containing phosphatases; SOCS, suppressors of cytokine signaling; Stat, signal transducer and activator of transcription. Address reprint requests to: Diego F. Calvisi, M.D., Institut für Pathologie, Ernst-Moritz-Arndt-Universität, Friedrich-Löffler-Straße 23e, 17489 Greifswald, Germany. E-mail: diego.calvisi@uni-greifswald.de; fax: 0049-3834-865701. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24435 Potential conflict of interest: Nothing to report.