Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis.
Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis.
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DOI：
10.1038/ncomms7285
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发表时间：
2015-03-03
影响因子：
16.6
通讯作者：
Casanova, Emilio
中科院分区：
文献类型：
--
作者：
Grabner, Beatrice;Schramek, Daniel;Mueller, Kristina M.;Moll, Herwig P.;Svinka, Jasmin;Hoffmann, Thomas;Bauer, Eva;Blaas, Leander;Hruschka, Natascha;Zboray, Katalin;Stiedl, Patricia;Nivarthi, Harini;Bogner, Edith;Gruber, Wolfgang;Mohr, Thomas;Zwick, Ralf Harun;Kenner, Lukas;Poli, Valeria;Aberger, Fritz;Stoiber, Dagmar;Egger, Gerda;Esterbauer, Harald;Zuber, Johannes;Moriggl, Richard;Eferl, Robert;Gyorffy, Balazs;Penninger, Josef M.;Popper, Helmut;Casanova, Emilio
STAT3被认为在包括肺癌在内的几种恶性肿瘤中起致瘤作用；因此，靶向STAT3目前被认为是一种治疗干预措施。在这里，我们证明了STAT3在KRAS突变型肺腺癌（AC）中发挥了意想不到的肿瘤抑制作用。事实上，小鼠肺组织特异性Stat3失活导致krasg12d驱动的AC启动和恶性进展增加，导致生存率显著降低。在异种移植的人类AC细胞中敲低STAT3可促进肿瘤生长。临床上，有吸烟史的人肺AC患者易发生KRAS突变，STAT3低表达水平与生存率差和恶性肿瘤进展相关。KRAS突变型肺肿瘤始终表现出STAT3水平的降低。在机制上，我们证明STAT3通过在细胞质内隔离NF-κB来控制NF-κB诱导的IL-8表达，从而抑制IL-8介导的髓系肿瘤浸润和肿瘤血管化，从而抑制肿瘤进展。这些结果阐明了KRAS突变AC中新的STAT3-NF -κB-IL-8轴与治疗和预后的相关性。STAT3是细胞内细胞因子信号的换能器，在肿瘤形成过程中与Ras合作，在肺癌中经常被激活。在这里，作者表明STAT3在kras驱动的肺腺癌小鼠模型中作为肿瘤抑制因子。
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. STAT3 is an intracellular transducer of cytokine signals that cooperates with Ras in tumour formation and is often activated in lung cancer. Here the authors show that STAT3 acts as a tumour suppressor in a mouse model of Kras-driven lung adenocarcinoma.
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影响因子：
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通讯作者：
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