Mikula Mario, Gotzmann Josef, Fischer Alexandra N M, Wolschek Markus F, Thallinger Christiane, Schulte-Hermann Rolf, Beug Hartmut, Mikulits Wolfgang
Institute of Cancer Research, University of Vienna, Borschke-Gasse 8a, A-1090 Vienna, Austria.
Oncogene. 2003 Oct 2;22(43):6725-38. doi: 10.1038/sj.onc.1206781.
Hepatocytes adopt an invasive and metastatic phenotype caused by the cooperation of transforming growth factor (TGF)-beta and oncogenic Ha-Ras. In the initial phase of this process, c-Fos is rapidly induced by TGF-beta, but then decreases to undetectable levels. Here, we investigated the functional implications of c-Fos activation and its contribution to hepatocellular tumorigenesis. By employing conditional c-Fos expression, we observed that continuous activation of c-Fos and consequently AP-1 activity leads to depolarization of differentiated murine epithelial hepatocytes. Most remarkably, this change in morphology was associated with inhibition of proliferation and induction of cell death. Coexpression of antiapoptotic Bcl-XL or scavenging of reactive oxygen species was sufficient to prevent the c-Fos-mediated phenotype. In contrast, the cooperation of c-Fos with oncogenic Ha-Ras or a Ras mutant selectively activating the MAPK pathway even enhanced c-Fos-induced effects. Showing the negative role in hepatocellular tumorigenesis, c-Fos repressed oncogenic Ras-driven anchorage-independent growth in vitro and strongly suppressed tumour formation in vivo. Taken together, we demonstrate that c-Fos modulates plasticity of epithelial hepatocytes and acts tumour suppressive in neoplastic hepatocytes by stimulating cell cycle inhibition and cell death.
肝细胞呈现出由转化生长因子（TGF）-β与致癌性Ha-Ras协同作用所导致的侵袭性和转移性表型。在此过程的初始阶段，TGF-β能迅速诱导c-Fos表达，但随后其表达水平会降至无法检测到的程度。在此，我们研究了c-Fos激活的功能意义及其对肝细胞肿瘤发生的作用。通过采用条件性c-Fos表达，我们观察到c-Fos的持续激活以及由此导致的AP-1活性会使分化的小鼠上皮肝细胞发生去极化。最显著的是，这种形态学变化与增殖抑制和细胞死亡诱导相关。共表达抗凋亡蛋白Bcl-XL或清除活性氧足以预防c-Fos介导的表型。相反，c-Fos与致癌性Ha-Ras或选择性激活MAPK途径的Ras突变体协同作用，甚至会增强c-Fos诱导的效应。c-Fos在体外抑制致癌性Ras驱动的非锚定依赖性生长，并在体内强烈抑制肿瘤形成，表明其在肝细胞肿瘤发生中起负性作用。综上所述，我们证明c-Fos调节上皮肝细胞的可塑性，并通过刺激细胞周期抑制和细胞死亡在肿瘤性肝细胞中发挥肿瘤抑制作用。
