Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer.
Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer.
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DOI：
10.1158/1078-0432.ccr-13-2195
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Onaitis M
中科院分区：
文献类型：
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作者：
Huang L;Walter V;Hayes DN;Onaitis M
肺鳞状细胞癌（LSCC）目前缺乏有效的靶向治疗。先前的研究报道了HEDGEHOG（HH）-GLI信号成分在LSCC中的过表达。然而，他们既没有解决肿瘤异质性，也没有解决HH-GLI信号传导的要求。在此，我们研究了HH-GLI信号在喉鳞状细胞癌中的作用，并研究了HH-GLI抑制的治疗潜力。分析两个独立的LSCC患者组群的基因表达数据集以研究HH-GLI信号传导的激活。检查四种人LSCC细胞系的HH-GLI信号传导组分。在通过慢病毒-shRNA敲低或小分子抑制剂阻断HH-GLI通路后，在这些细胞中测定细胞增殖和凋亡。使用免疫缺陷小鼠中的异种移植物来确定GLI抑制剂GANT 61的体内功效。在这两个队列中，HH-GLI信号的激活与LSCC的经典亚型显著相关。在细胞系中，基因敲低SMO对细胞存活产生轻微影响，而GLI 2敲低显著降低增殖并诱导广泛的凋亡。因此，SMO抑制剂GDC-0449在LSCC细胞中导致有限的细胞毒性，而GLI抑制剂GANT 61非常有效。重要的是，GANT 61在GLI阳性细胞系的异种移植模型中表现出特异性的体内抗肿瘤活性。我们的研究表明GLI 2在喉鳞状细胞癌中的重要作用，并建议GLI抑制作为一种新的和有效的策略来治疗喉鳞状细胞癌患者的子集。
Lung squamous cell carcinoma (LSCC) currently lacks effective targeted therapies. Previous studies reported overexpression of HEDGEHOG (HH)-GLI signaling components in LSCC. However, they addressed neither the tumor heterogeneity nor the requirement for HH-GLI signaling. Here, we investigated the role of HH-GLI signaling in LSCC, and studied the therapeutic potential of HH-GLI suppression. Gene expression datasets of two independent LSCC patient cohorts were analyzed to study the activation of HH-GLI signaling. Four human LSCC cell lines were examined for HH-GLI signaling components. Cell proliferation and apoptosis were assayed in these cells after blocking the HH-GLI pathway by lentiviral-shRNA knockdown or small molecule inhibitors. Xenografts in immunodeficient mice were used to determine the in vivo efficacy of GLI inhibitor GANT61. In both cohorts, activation of HH-GLI signaling was significantly associated with the classical subtype of LSCC. In cell lines, genetic knockdown of SMO produced minor effects on cell survival, while GLI2 knockdown significantly reduced proliferation and induced extensive apoptosis. Consistently, the SMO inhibitor GDC-0449 resulted in limited cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective. Importantly, GANT61 demonstrated specific in vivo anti-tumor activity in xenograft models of GLI-positive cell lines. Our studies demonstrate an important role for GLI2 in LSCC, and suggest GLI inhibition as a novel and potent strategy to treat a subset of LSCC patients.