Vestergaard Janni, Pedersen Mikkel W, Pedersen Nina, Ensinger Christian, Tümer Zeynep, Tommerup Niels, Poulsen Hans Skovgaard, Larsen Lars Allan
Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Biochemistry and Genetics, University of Copenhagen, and Department of Radiation Biology, The Finsencenter, Copenhagen University Hospital, Denmark.
Lung Cancer. 2006 Jun;52(3):281-90. doi: 10.1016/j.lungcan.2005.12.014. Epub 2006 Apr 17.
The hedgehog (HH) signaling pathway plays multiple roles during embryonic development and increasing evidence suggests that this embryonic pathway is involved in development and progression of several human cancers including those of the brain, skin, lung and gastrointestinal tract. To investigate HH signaling activity in small-cell lung cancer (SCLC), we have performed gene expression analysis on members of the HH pathway on a panel of 20 SCLC cell lines. Sonic hedgehog (SHH) expression was detected in only DMS79 and GLC16 and only DMS114 expressed detectable protein levels of GLI1, one of the key transcription factors of the pathway. Involvement of HH signaling in SCLC proliferation was investigated in a subset of cell lines using the HH signaling inhibitor cyclopamine or small interfering RNA (siRNA) against GLI1. Cells expressing GLI1 responded only weakly to both cyclopamine and RNA interference, suggesting that HH signaling plays only a minor role in the growth of SCLC cell lines. To investigate HH pathway activity in vivo, GLI1 immunohistochemistry was performed on SCLC tumors. Interestingly, GLI1 was expressed in most SCLC tumors studied, indicating that HH signaling is important for in vivo growth of SCLC but establishment of cell lines from SCLC tumors may lead to loss of expression of key HH pathway members. Thus, the data support the idea that the HH pathway may be a therapeutic target in SCLC. However, the data also suggest that the SCLC cells can circumvent the apparent in vivo requirement of HH signaling.
刺猬信号通路（HH）在胚胎发育过程中发挥多种作用，越来越多的证据表明，这条胚胎信号通路参与了包括脑、皮肤、肺和胃肠道癌症在内的多种人类癌症的发生和发展。为了研究小细胞肺癌（SCLC）中的HH信号活性，我们对20个SCLC细胞系组成的细胞组进行了HH信号通路成员的基因表达分析。仅在DMS79和GLC16中检测到音猬因子（SHH）表达，并且仅在DMS114中检测到该信号通路关键转录因子之一GLI1的可检测蛋白水平。使用HH信号抑制剂环杷明或针对GLI1的小干扰RNA（siRNA），在一部分细胞系中研究了HH信号在SCLC增殖中的作用。表达GLI1的细胞对环杷明和RNA干扰的反应均较弱，这表明HH信号在SCLC细胞系生长中仅起次要作用。为了研究体内HH信号通路的活性，我们对SCLC肿瘤进行了GLI1免疫组织化学检测。有趣的是，在大多数研究的SCLC肿瘤中均检测到GLI1表达，这表明HH信号对SCLC的体内生长很重要，但从SCLC肿瘤建立细胞系可能导致关键HH信号通路成员的表达缺失。因此，这些数据支持HH信号通路可能是SCLC治疗靶点的观点。然而，数据也表明SCLC细胞可以规避HH信号在体内的明显需求。
