Hedgehog Signaling in Human Medullary Thyroid Carcinoma: A Novel Signaling Pathway
Hedgehog Signaling in Human Medullary Thyroid Carcinoma: A Novel Signaling Pathway
复制标题
DOI：
10.1089/thy.2012.0474
复制
发表时间：
2013-09-01
期刊：
影响因子：
6.6
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Bohinc, Brittany;Michelotti, Gregory;Diehl, Anna Mae
背景：局部或广泛转移性甲状腺髓样癌（MTC）难以治疗，治疗选择有限。最近，激酶抑制剂在这种癌症中显示出部分疗效，但仍然需要开发新的治疗方法。在此背景下，Hedgehog (Hh) 通路与多种类型的人类肿瘤有关，并且 Hh 拮抗剂的早期临床试验已验证 Hh 作为一种新的治疗靶点。我们首次评估了 MTC 中的 Hh 通路活性，并检查了 Hh 通路扰动对高度特征化的 MTC 细胞系的影响。方法：我们检测了石蜡包埋的正常人 MTC 组织与组织学特征的人 MTC 组织中 Hh 信号传导介质 Sonic Hedgehog (Shh) 和胶质母细胞瘤 (Gli)2 的免疫组织化学表达。我们使用两种已建立的 MTC 细胞系（TT 和 MZ-CRC-1）在体外检查了 Hh 信号传导的药理学破坏。在 MTC 细胞系中，Hh 信号传导要么被药理学激活（SAG），要么被抑制（GDC-0449）；通过定量实时聚合酶链式反应、蛋白质印迹分析以及细胞生长和凋亡活性的定量来评估 Hh 活性。结果：我们的数据显示，与正常组织相比，人 MTC 中 Hh 信号因子的表达增加。在体外，Hh 通路的激活导致关键 Hh 信号成分 Smoothened (Smo) 和 Gli2 的表达增加。相反，抑制 Hh 途径会降低这些基因的表达，导致细胞生长显着减少并增加细胞凋亡。结论：Hedgehog 信号成分在 MTC 中显着上调。 Hh 通路抑制剂有潜力成为转移性和/或手术不可切除的 MTC 患者的新治疗选择。
Background: Locally or widely metastatic medullary thyroid carcinoma (MTC) is difficult to treat, and therapeutic options are limited. Recently, kinase inhibitors have shown partial efficacy in this cancer, but there is a continued need for the development of novel therapeutics. Within this context, the Hedgehog (Hh) pathway has been implicated in several types of human tumors, and early clinical trials with Hh antagonists have validated Hh as a novel therapeutic target. For the first time, we evaluated Hh pathway activity in MTC, and examined the effect of Hh pathway perturbation in highly characterized MTC cell lines. Methods: We examined immunohistochemical expression of the Hh signaling mediators Sonic Hedgehog (Shh) and Glioblastoma (Gli)2 in paraffin-embedded normal versus histologically characterized human MTC tissue. We examined pharmacologic disruption of Hh signaling in vitro using two established MTC cell lines (TT and MZ-CRC-1). Hh signaling was either pharmacologically activated (SAG) or inhibited (GDC-0449) in MTC cell lines; Hh activity was assessed by quantitative real-time polymerase chain reaction, Western blot analysis, and quantification of cellular growth and apoptotic activity. Results: Our data showed increased expression of Hh signaling factors in human MTC compared to normal tissue. In vitro, activation of the Hh pathway resulted in increased expression of key Hh signaling components Smoothened (Smo) and Gli2. Conversely, inhibition of the Hh pathway decreased expression of these genes, leading to significantly reduced cellular growth and increased apoptosis. Conclusions: Hedgehog signaling components are markedly upregulated in MTC. Hh pathway inhibitors have potential as novel therapeutic options in patients with metastatic and/or surgically unresectable MTC.