Shh and p50/Bcl3 signaling crosstalk drives pathogenesis of BCCs in Gorlin syndrome.
Shh and p50/Bcl3 signaling crosstalk drives pathogenesis of BCCs in Gorlin syndrome.
复制标题
SHH和P50/BCL3信号传导串扰驱动BCC在Gorlin综合征中的发病机理。
DOI：
10.18632/oncotarget.5103
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
Athar M
中科院分区：
文献类型：
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作者：
Chaudhary SC;Tang X;Arumugam A;Li C;Srivastava RK;Weng Z;Xu J;Zhang X;Kim AL;McKay K;Elmets CA;Kopelovich L;Bickers DR;Athar M
Nevoid基底细胞癌综合征（NBCCS）是一种罕见的常染色体显性遗传病，在很大程度上是由于肿瘤抑制基因Ptch1突变引起的Shh信号异常。在这里，我们描述了Ptch1+/−/SKH-1小鼠作为这种疾病的新模型的发展。这些动物表现出NBCCS的许多特征，包括发育异常，对紫外线（UVB）和电离辐射都非常敏感，从而导致多种BCCs的发展。与NBCCS患者一样，Ptch1+/−/SKH-1也会自发发展为bcc和其他肿瘤，如横纹肌瘤/横纹肌肉瘤。给予平滑抑制剂（维莫替吉/伊曲康唑/环巴胺）或非甾体抗炎药（舒林酸/柳氮磺胺吡啶）均可导致这些动物的bcc部分消退。然而，联合使用这些药物可抑制uvb诱导的bcc的生长，抑制率为90%。采用基于小分子和诱饵肽的方法，我们进一步证实，bcc的完全缓解只能通过联合抑制p50-NFκB/Bcl3和Shh信号来实现。我们认为Ptch1+/−/SKH-1小鼠是一种新的相关的NBCCS动物模型。了解bcc遗传易感性的机制有助于我们识别和治疗NBCCS基因携带者，包括那些有散发性bcc风险的人，同时加速开发针对这些患者的新治疗方法。
Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder that is due, in large measure, to aberrant Shh signaling driven by mutations in the tumor suppressor gene Ptch1. Here, we describe the development of Ptch1+/−/SKH-1 mice as a novel model of this disease. These animals manifest many features of NBCCS, including developmental anomalies and are remarkably sensitive to both ultraviolet (UVB) and ionizing radiation that drive the development of multiple BCCs. Just as in patients with NBCCS, Ptch1+/−/SKH-1 also spontaneously develops BCCs and other neoplasms such as rhabdomyomas/rhabdomyosarcomas. Administration of smoothened inhibitors (vismodegib/itraconazole/cyclopamine) or non-steroidal anti-inflammatory drug (sulindac/sulfasalazine) each result in partial resolution of BCCs in these animals. However, combined administration of these agents inhibits the growth of UVB-induced BCCs by >90%. Employing small molecule- and decoy-peptide-based approaches we further affirm that complete remission of BCCs could only be achieved by combined inhibition of p50-NFκB/Bcl3 and Shh signaling. We posit that Ptch1+/−/SKH-1 mice are a novel and relevant animal model for NBCCS. Understanding mechanisms that govern genetic predisposition to BCCs should facilitate our ability to identify and treat NBCCS gene carriers, including those at risk for sporadic BCCs while accelerating development of novel therapeutic modalities for these patients.