近日，國際著名期刊Nature communication在線發表了奧地利科學家的一項最新研究成果，他們發現在KRAS突變的肺腺癌細胞中，STAT3的低表達會促進肺腺癌的進一步發展，表明STAT3在KRAS突變的肺腺癌細胞中具有腫瘤抑製性作用。

        一直以來科學家們都認為STAT3在肺癌等惡性腫瘤中均發揮癌基因作用，因此靶向STAT3成為腫瘤幹預治療的一種重要手段。但這項研究發現STAT3在KRAS突變的肺腺癌(AC)中發揮了令人意想不到的腫瘤抑製性作用。STAT3在小鼠肺部組織特異性失活會導致KrasG12D驅動的肺腺癌起始以及惡性化進展增加，顯著降低小鼠生存率，在異種移植的人類AC細胞中敲低STAT3也會促進腫瘤生長。

        在臨床研究中發現，有吸煙史的AC病人容易發生KRAS突變，而STAT3的低表達與這類病人惡劣的生存情況以及病情進一步惡化呈現相關性。同時，KRAS突變的肺部腫瘤也呈現出STAT3的低表達。研究人員在機製上的進一步研究發現STAT3能夠通過抑製NF-κB入核，控製NF-κB誘導的IL-8表達，並進一步抑製IL-8介導的髓係腫瘤浸潤以及腫瘤血管生成，從而抑製腫瘤發展。

        這項研究闡述了KRAS突變型肺腺癌中一條新的STAT3-NF-κB-IL-8途徑，為治療KRAS突變型AC提供了新的見解，並且對這類腫瘤治療方法的開發具有重要意義。

        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.