Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China.
Oral Oncol. 2011 Jun;47(6):504-9. doi: 10.1016/j.oraloncology.2011.03.027. Epub 2011 May 4.
Aberrant activation of HH/GLI has recently been reported in multiple cancer types, yet its role in oral squamous cell carcinoma (OSCC) has not been investigated. In this study, we aimed to determine the role of HH/GLI in OSCC. Expression of GLI1 and GLI2 was examined in OSCC samples from 136 patients by immunohistochemistry and correlated with clinicopathology parameters and clinical outcomes of the patients. Two HH/GLI specific small molecule inhibitors cyclopamine and GANT61, were used to test the potential role of HH/GLI in OSCC. We found that GLI2, one of the main transcriptional activators of HH/GLI signalling, was expressed in 60 (44%) of the 136 OSCC samples and the expression was significantly associated with poor clinical outcomes. Only 44% of the patients whose tumours expressed GLI2 survived at 5years after surgery compared to 77% of those whose tumours lacked the GLI2 expression (P<0.0001). Both cyclopamine and GANT61 effectively inhibited GLI expression, slowed cell growth, promoted G1 arrest, increased apoptosis and inhibited migration of OSCC cells. Our results demonstrate that activation of HH/GLI pathway plays an important role in OSCC progression. Together with the finding that expression of GLI2 is strongly associated with a poor clinic outcome of OSCC patients, the data suggest that a subset of OSCC patients may benefit from anti-HH/GLI therapies.
HH/GLI 的异常激活最近在多种癌症类型中被报道，但它在口腔鳞状细胞癌（OSCC）中的作用尚未被研究。在这项研究中，我们旨在确定 HH/GLI 在 OSCC 中的作用。通过免疫组织化学检测了 136 例 OSCC 样本中 GLI1 和 GLI2 的表达，并与患者的临床病理参数和临床结果相关联。我们使用两种 HH/GLI 特异性小分子抑制剂 cyclopamine 和 GANT61 来测试 HH/GLI 在 OSCC 中的潜在作用。我们发现，HH/GLI 信号通路的主要转录激活因子之一 GLI2 在 136 例 OSCC 样本中的 60 例（44%）中表达，其表达与不良临床结果显著相关。与肿瘤缺乏 GLI2 表达的患者相比（P<0.0001），肿瘤表达 GLI2 的患者在手术后 5 年内仅有 44%的患者存活。环巴胺和 GANT61 均可有效抑制 GLI 表达，减缓细胞生长，促进 G1 期阻滞，增加细胞凋亡，抑制 OSCC 细胞迁移。我们的结果表明，HH/GLI 通路的激活在 OSCC 进展中起重要作用。结合 GLI2 表达与 OSCC 患者不良临床结果密切相关的发现，数据表明，一部分 OSCC 患者可能受益于抗 HH/GLI 治疗。
