Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, Division of Thoracic Surgery, Institute of Surgical Pathology, University Hospital Zürich, Zurich, Switzerland.
Clin Cancer Res. 2012 Sep 1;18(17):4646-56. doi: 10.1158/1078-0432.CCR-12-0599. Epub 2012 Jun 25.
The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM).
The expression of hedgehog signaling components was assessed by quantitative PCR and in situ hybridization in 45 clinical samples. Primary MPM cultures were developed in serum-free condition in 3% oxygen and were used to investigate the effects of smoothened (SMO) inhibitors or GLI1 silencing on cell growth and hedgehog signaling. In vivo effects of SMO antagonists were determined in an MPM xenograft growing in nude mice.
A significant increase in GLI1, sonic hedgehog, and human hedgehog interacting protein gene expression was observed in MPM tumors compared with nontumoral pleural tissue. SMO antagonists inhibited GLI1 expression and cell growth in sensitive primary cultures. This effect was mimicked by GLI1 silencing. Reduced survivin and YAP protein levels were also observed. Survivin protein levels were rescued by overexpression of GLI1 or constitutively active YAP1. Treatment of tumor-bearing mice with the SMO inhibitor HhAntag led to a significant inhibition of tumor growth in vivo accompanied by decreased Ki-67 and nuclear YAP immunostaining and a significant difference in selected gene expression profile in tumors.
An aberrant hedgehog signaling is present in MPM, and inhibition of hedgehog signaling decreases tumor growth indicating potential new therapeutic approach.
本研究旨在评估 Hedgehog 信号通路在恶性胸膜间皮瘤（MPM）中的活性。
通过定量 PCR 和原位杂交技术，在 45 例临床样本中评估 Hedgehog 信号成分的表达。在 3%氧气的无血清条件下培养原发性 MPM 培养物，并用于研究 smoothened (SMO) 抑制剂或 GLI1 沉默对细胞生长和 Hedgehog 信号的影响。在裸鼠中生长的 MPM 异种移植模型中确定 SMO 拮抗剂的体内效应。
与非肿瘤性胸膜组织相比，MPM 肿瘤中 GLI1、sonic Hedgehog 和 human Hedgehog interacting protein 基因表达显著增加。SMO 拮抗剂抑制敏感原代培养物中的 GLI1 表达和细胞生长。GLI1 沉默模拟了这种作用。还观察到 survivin 和 YAP 蛋白水平降低。过表达 GLI1 或组成型激活 YAP1 可挽救 survivin 蛋白水平。用 SMO 抑制剂 HhAntag 治疗荷瘤小鼠可显著抑制体内肿瘤生长，同时 Ki-67 和核 YAP 免疫染色减少，肿瘤中部分基因表达谱存在显著差异。
异常的 Hedgehog 信号存在于 MPM 中，抑制 Hedgehog 信号可降低肿瘤生长，表明可能有新的治疗方法。
