Miyazaki Ken-Ichi, Saika Shizuya, Yamanaka Osamu, Okada Yuka, Ohnishi Yoshitaka
Department of Ophthalmology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Jpn J Ophthalmol. 2006 Jul-Aug;50(4):305-311. doi: 10.1007/s10384-006-0341-1.
To evaluate the effect of cyclopamine, an inhibitor of the Sonic hedgehog (Shh) signal, on the growth of an epithelial neoplasm.
Chemically induced eyelid tumors in XPC-null mice (n=40) were treated daily with a subcutaneous injection of cyclopamine (1 mg/animal) for 7 days. The animals were killed after bromodeoxyuridine (BrdU) labeling, and the tumors were histologically examined. An in vitro study was conducted by using a squamous cell carcinoma (SCC) cell line. The SCC cells were treated with 0, 12.5, or 25.0 microg/ml recombinant Shh (rShh) and either 0 or 100 microM cyclopamine, and cell proliferation was evaluated by using an MTT assay. Cells from this cell line were also implanted subcutaneously in nude mice (n=8) to develop tumors, and the effect of cyclopamine administration was examined in the developed tumors.
Histology showed that cyclopamine treatment suppressed BrdU incorporation and induced apoptosis in the majority of cells in tumors chemically induced in the eyelid of the XPC-null mice. Cell proliferation of the SCC cell line was enhanced by adding rShh, and this effect was abolished by adding cyclopamine. Proliferation of the SCC cell line was not affected by adding cyclopamine in the absence of rShh. On the other hand, the SCC cells expressed Shh in vivo in tumors developed in nude mice, but cyclopamine suppressed cell proliferation in the tumors, and the Shh-signaling pathway was inhibited by cyclopamine-induced apoptosis.
Cyclopamine inhibits proliferation and induces apoptosis in epithelial tumor cells in vivo. The Shh-signaling pathway may be a potential therapeutic target for patients with eyelid tumors.
评估音猬因子（Shh）信号抑制剂环杷明对上皮性肿瘤生长的影响。
对XPC基因缺失小鼠（n = 40）化学诱导的眼睑肿瘤，每天皮下注射环杷明（1毫克/只动物），持续7天。在溴脱氧尿苷（BrdU）标记后处死动物，对肿瘤进行组织学检查。使用鳞状细胞癌（SCC）细胞系进行体外研究。将SCC细胞用0、12.5或25.0微克/毫升重组Shh（rShh）以及0或100微摩尔环杷明处理，通过MTT法评估细胞增殖。该细胞系的细胞也皮下植入裸鼠（n = 8）以形成肿瘤，并检查环杷明给药对已形成肿瘤的影响。
组织学显示，环杷明治疗抑制了XPC基因缺失小鼠眼睑化学诱导肿瘤中大多数细胞的BrdU掺入并诱导凋亡。添加rShh可增强SCC细胞系的细胞增殖，而添加环杷明可消除这种作用。在没有rShh的情况下，添加环杷明不影响SCC细胞系的增殖。另一方面，SCC细胞在裸鼠体内形成的肿瘤中表达Shh，但环杷明抑制肿瘤中的细胞增殖，并且环杷明诱导的凋亡抑制了Shh信号通路。
环杷明在体内抑制上皮肿瘤细胞的增殖并诱导凋亡。Shh信号通路可能是眼睑肿瘤患者潜在的治疗靶点。
