近日，国际著名期刊Nature communication在线发表了奥地利科学家的一项最新研究成果，他们发现在KRAS突变的肺腺癌细胞中，STAT3的低表达会促进肺腺癌的进一步发展，表明STAT3在KRAS突变的肺腺癌细胞中具有肿瘤抑制性作用。

        一直以来科学家们都认为STAT3在肺癌等恶性肿瘤中均发挥癌基因作用，因此靶向STAT3成为肿瘤干预治疗的一种重要手段。但这项研究发现STAT3在KRAS突变的肺腺癌(AC)中发挥了令人意想不到的肿瘤抑制性作用。STAT3在小鼠肺部组织特异性失活会导致KrasG12D驱动的肺腺癌起始以及恶性化进展增加，显著降低小鼠生存率，在异种移植的人类AC细胞中敲低STAT3也会促进肿瘤生长。

        在临床研究中发现，有吸烟史的AC病人容易发生KRAS突变，而STAT3的低表达与这类病人恶劣的生存情况以及病情进一步恶化呈现相关性。同时，KRAS突变的肺部肿瘤也呈现出STAT3的低表达。研究人员在机制上的进一步研究发现STAT3能够通过抑制NF-κB入核，控制NF-κB诱导的IL-8表达，并进一步抑制IL-8介导的髓系肿瘤浸润以及肿瘤血管生成，从而抑制肿瘤发展。

        这项研究阐述了KRAS突变型肺腺癌中一条新的STAT3-NF-κB-IL-8途径，为治疗KRAS突变型AC提供了新的见解，并且对这类肿瘤治疗方法的开发具有重要意义。

        doi:10.1038/ncomms7285

        Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

        Beatrice Grabner,Daniel Schramek,Kristina M. Mueller,Herwig P. Moll,Jasmin Svinka,Thomas Leander Blaas,Natascha Hruschka,Katalin Zboray,Patricia Stiedl,Harini Nivarthi,Edith Bogner,Wolfgang Ralf Harun Zwick,Lukas Kenner,Valeria Poli,Fritz Aberger,Dagmar Stoiber,Gerda Egger,Harald Esterbauer,Johannes Zuber,Richard Moriggl,Robert Eferl,Balázs Gy?rffy,Josef M. Penninger,Helmut Popper& Emilio Casanova

        STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3-NF-κB-IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.