Thoracic Oncology Program, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
PLoS One. 2013;8(3):e57346. doi: 10.1371/journal.pone.0057346. Epub 2013 Mar 6.
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. Current treatment is rarely curative, thus novel meaningful therapies are urgently needed. Inhibition of Hedgehog (Hh) signaling at the cell membrane level in several cancers has shown anti-cancer activity in recent clinical studies. Evidence of Hh-independent Gli activation suggests Gli as a more potent therapeutic target. The current study is aimed to evaluate the potential of Gli as a therapeutic target to treat MPM. The expression profiles of Gli factors and other Hh signaling components were characterized in 46 MPM patient tissue samples by RT-PCR and immunohistochemistry. Cultured cell lines were employed to investigate the requirement of Gli activation in tumor cell growth by inhibiting Gli through siRNA or a novel small molecule Gli inhibitor (Gli-I). A xenograft model was used to evaluate Gli-I in vivo. In addition, a side by side comparison between Gli and Smoothened (Smo) inhibition was conducted in vitro using siRNA and small molecule inhibitors. Our study reported aberrant Gli1 and Gli2 activation in a large majority of tissues. Inhibition of Gli by siRNAs or Gli-I suppressed cell growth dramatically both in vitro and in vivo. Inhibition of Gli exhibited better cytotoxicity than that of Smo by siRNA and small molecule inhibitors vismodegib and cyclopamine. Combination of Gli-I and pemetrexed, as well as Gli-I and vismodegib demonstrated synergistic effects in suppression of MPM proliferation in vitro. In summary, Gli activation plays a critical role in MPM. Inhibition of Gli function holds strong potential to become a novel, clinically effective approach to treat MPM.
恶性胸膜间皮瘤（MPM）是一种高度侵袭性肿瘤，预后不良。目前的治疗方法很少能治愈，因此迫切需要新的有意义的治疗方法。最近的临床研究表明，在几种癌症中抑制细胞膜水平的 Hedgehog（Hh）信号传导具有抗癌活性。Hh 非依赖性 Gli 激活的证据表明 Gli 是更有效的治疗靶点。本研究旨在评估 Gli 作为治疗 MPM 的治疗靶点的潜力。通过 RT-PCR 和免疫组织化学法对 46 例 MPM 患者组织样本中的 Gli 因子和其他 Hh 信号传导成分的表达谱进行了表征。通过 siRNA 或新型小分子 Gli 抑制剂（Gli-I）抑制 Gli 来研究抑制 Gli 激活对肿瘤细胞生长的必要性。利用异种移植模型评估 Gli-I 的体内活性。此外，通过 siRNA 和小分子抑制剂在体外进行了 Gli 与 Smoothened（Smo）抑制的平行比较。我们的研究报告称，在大多数组织中存在异常的 Gli1 和 Gli2 激活。通过 siRNA 和 Gli-I 抑制 Gli 在体外和体内均能显著抑制细胞生长。与 Smo 相比，siRNA 和小分子抑制剂 vismodegib 和 cyclopamine 抑制 Gli 表现出更好的细胞毒性。在体外，联合使用 Gli-I 和培美曲塞，以及联合使用 Gli-I 和 vismodegib 均显示出协同抑制 MPM 增殖的作用。总之，Gli 激活在 MPM 中起关键作用。抑制 Gli 功能具有成为治疗 MPM 的一种新的、有效的临床方法的巨大潜力。
