Sonic hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas
Sonic hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas
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DOI：
10.4161/cbt.5.11.3458
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发表时间：
2006-11-01
影响因子：
3.6
通讯作者：
Ishikura, Hiroshi
中科院分区：
文献类型：
--
作者：
Shida, Takashi;Furuya, Mitsuko;Ishikura, Hiroshi
胃肠道神经内分泌癌(NECS)是一种侵袭性极强、预后极差的肿瘤。我们先前的研究表明，人无毛同源基因1(HASH1)是一种受Notch调控的碱性螺旋-环-螺旋转录因子，在NECS中异常表达。到目前为止，还没有对NECS有效的治疗策略进行研究。Noch、Wnt和Hedgehog(HH)信号对干细胞的自我更新和胃肠道上皮的癌变非常重要。在这项研究中，我们发现HH信号在NECS中以Gli1依赖的方式明显上调。环丙胺对神经内皮细胞的特异性治疗作用也得到证实。RT-PCR结果显示，在8例冰冻标本(3例NECS、1例类癌、3例腺癌和1例正常粘膜)中，Gli1的条带强度在NECS中最强，在类癌中中等强，在腺癌中很弱，在正常粘膜中检测不到。实时荧光定量RT-PCRGli1的表达水平分别是腺癌的108.4倍、28.6倍和16.3倍。在25例石蜡包埋组织的免疫组织化学中，12例NEC和6例类癌中3例Gli1阳性，而7例腺癌中6例为阴性。体外逆转录聚合酶链式反应(RT-PCR)显示NEC细胞系显著表达Gli1mRNA。给予环丙胺可抑制NECs的增殖和侵袭，并诱导其凋亡。在环丙胺处理的NECs中，Gli1、ptch1、Snail和hASH1基因表达下调，E-cadherin基因表达上调。在Gli1阴性的结肠腺癌细胞系或对照生物碱处理的NECs中没有观察到这种作用。HH信号可能在NECS的病理生理过程中起重要作用。用环多巴胺或其合成的衍生物阻断HH通路可能为NECS开辟一种有效的治疗策略，不仅通过抑制肿瘤的存活，而且还通过改变肿瘤细胞的性质。
Gastrointestinal neuroendocrine carcinomas (NECs) are extremely aggressive and poorly prognostic. We showed previously that human achaete-scute homologue gene 1 (hASH1), a basic helix-loop-helix transcription factor regulated by Notch, was aberrantly expressed in NECs. To date, no effective therapeutic strategies for NECs have been investigated. Notch, Wnt and Hedgehog (Hh) signalings are important for stem cell self-renewal and carcinogenesis in the gastrointestinal epithelium. In this study, we showed that Hh signaling was clearly upregulated in NECs in Gli1-dependent manner. Specific therapeutic effects of cyclopamine on NECs were also demonstrated. RT-PCR showed that among eight frozen samples ( three NECs, one carcinoid tumor, three adenocarcinomas and one normal mucosa), the band intensities of Gli1 were the strongest in NECs, moderately strong in a carcinoid tumor, very weak in adenocarcinomas and undetectable in a normal mucosa. In real-time RT-PCR, the expression levels of Gli1 in NECs were 108.4, 28.6 and 16.3 times higher than that in an adenocarcinoma. In immunohistochemistry using 25 paraffin-embedded tissues, all twelve NECs and three of six carcinoid tumors showed positive stainings for Gli1, whereas six of seven adenocarcinomas were negative. In vitro, RT-PCR showed that NEC cell lines expressed Gli1 mRNA significantly. Administration of cyclopamine suppressed cell proliferation and invasion, and induced apoptosis in NECs. In cyclopamine-treated NECs, downregulation of Gli1, Ptch1, Snail and hASH1, and upregulation of E-cadherin were demonstrated at mRNA levels. Such effects were not observed in a Gli1-negative colonic adenocarcinoma cell line or in control alkaloid-treated NECs. Hh signaling may play a crucial role in the pathophysiology of NECs. Blockade of Hh pathway using cyclopamine or its synthetic derivatives might open an effective therapeutic strategy to NECs, not only by suppressing tumor viability but also by altering tumor cell nature.