Pro- and anti-oncogenic functions of Stat3 in HCC progression

Signal transducer and activator of transcription 3 (Stat3) is frequently activated in HCC. We addressed the role of Stat3 in Ras-dependent HCC progression in the presence and absence of p19ARF/p14ARF. Surprisingly, we found that constitutive active (ca) Stat3 is tumor-suppressive in Ras-transformed p19ARF-/- hepatocytes, while expression of Stat3 lacking Tyr705 phosphorylation (U-Stat3) enhances tumor formation. These data demonstrate a novel tumor suppressor activity of Stat3 in cells lacking p19ARF. Notably, endogenous expression of p19ARF in Ras-transformed hepatocytes executes oncogenic Stat3 functions, resulting in augmented or reduced HCC progression after expression of caStat3 or U-Stat3, respectively. Accordingly, the knock-down of p14ARF (human homologue of p19ARF) in Hep3B hepatoma cells associates with reduced pY-Stat3 levels during tumor growthin order to circumvent the tumor-suppressive effect of Stat3. Inhibition of Janus kinases (Jaks) revealed that Jak1 predominantly causes pY-Stat3 activation independently of p14ARF levels, indicating that p14ARF controls the oncogenic function of pY-Stat3 downstream of Jaks (Figure 3). These data show evidence that p19ARF/p14ARF determines the pro- or anti-oncogenic activity of U-Stat3 and pY-Stat3 in HCC progression, which is of prognostic and therapeutic value for HCC intervention (see also: www.jak-stat.at).

Figure 3. Model of Stat3 actions in HCC. (A) In the presence of p14ARF, Jak1 activated Stat3 or ca Stat3 promotes tumorigenesis (red arrows). p14ARF sequesters an unknown factor termed ARF-X. (B) In the absence of p14ARF, U-Stat3 interacts with ARF-X to drive oncogenesis (red arrow). U-Stat3 is generated by suppression of Jak-mediated Stat3 activation. CaStat3 causes tumor suppression (brown-colored arrow) by modulating alternative Stat3 targets.