Zhou Jingjiao, Qu Zhaoxia, Yan Shapei, Sun Fan, Whitsett Jeffrey A, Shapiro Steven D, Xiao Gutian
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Oncogene. 2015 Jul;34(29):3804-3814. doi: 10.1038/onc.2014.318. Epub 2014 Oct 6.
Signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including pulmonary adenocarcinoma. However, the role of STAT3 in lung cancer pathogenesis has not been determined. Using lung epithelial-specific inducible knockout strategies, we demonstrate that STAT3 has contrasting roles in the initiation and growth of both chemically and genetically induced lung cancers. Selective deletion of lung epithelial STAT3 in mice before cancer induction by the smoke carcinogen, urethane, resulted in increased lung tissue damage and inflammation, K-Ras oncogenic mutations and tumorigenesis. Deletion of lung epithelial STAT3 after establishment of lung cancer inhibited cancer cell proliferation. Simultaneous deletion of STAT3 and expression of oncogenic K-Ras in mouse lung elevated pulmonary injury, inflammation and tumorigenesis, but reduced tumor growth. These studies indicate that STAT3 prevents lung cancer initiation by maintaining pulmonary homeostasis under oncogenic stress, whereas it facilitates lung cancer progression by promoting cancer cell growth. These studies also provide a mechanistic basis for targeting STAT3 to lung cancer therapy.
信号转导及转录激活因子3（STAT3）与包括肺腺癌在内的多种癌症相关。然而，STAT3在肺癌发病机制中的作用尚未明确。利用肺上皮特异性诱导敲除策略，我们证明STAT3在化学诱导和基因诱导的肺癌起始和生长过程中具有相反的作用。在通过烟雾致癌物乌拉坦诱导小鼠患癌之前，选择性敲除肺上皮细胞中的STAT3会导致肺组织损伤和炎症增加、K-Ras致癌突变及肿瘤发生。肺癌形成后敲除肺上皮STAT3会抑制癌细胞增殖。在小鼠肺中同时敲除STAT3并表达致癌性K-Ras会加剧肺损伤、炎症及肿瘤发生，但会减缓肿瘤生长。这些研究表明，STAT3通过在致癌应激下维持肺内稳态来预防肺癌起始，而通过促进癌细胞生长来推动肺癌进展。这些研究还为将STAT3作为肺癌治疗靶点提供了机制基础。
