中国肿瘤临床2011年第38卷第9期
Hedgehog 信号通路在胃癌中的研究进展
郝亚琴综述王立审校
摘要Hedgehog 信号通路是来自内胚层的信号分子之一，在个体胚胎发育诱导、模式的形成和细胞命运的决定中起着关键的作用，信号紊乱会导致各种组织器官畸形。在个体发育成熟后，Hedgehog 信号通路只在特定的部位表达，与器官正常功能的维持、机体内环境的稳定有着密切的关系。然而，越来越多的研究显示Hedgehog 信号通路与肿瘤的发生发展有着密切的关联。已有研究报道胃癌中也明显存在Hedgehog 信号通路的异常活化。本文从Hedgehog 信号通路过度表达的机制、成员突变、非经典Hedgehog 信号通路、胃癌干细胞、上皮间质转化等方面出发，将近几年来Hedgehog 信号通路与胃癌发生发展关联方面的研究进展进行报道。
关键词
胃癌Hedgehog 信号通路干细胞上皮间质转换doi:10.3969/j.issn.1000-8179.2011.09.015Research Advances in the Hedgehog Signaling Pathway in Gastric Cancer
Yaqin HAO,Li WANG
Correspondence to:Li WANG,E-email:wangli380@https://www.doczj.com/doc/854058722.html,
Department of Gastroenterology,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China Abstract The Hedgehog signaling pathway involves cells originating from the endoderm.It plays a crucial role in embryonic de-velopment,pattern formation and cell fate.Its mutation or abnormal expression can result in malformations of various tissues and or-gans.After maturation of the individual,the Hedgehog signaling pathway is either not expressed,has low expression or is only ex-pressed in a few specific parts.This pathway is important for maintaining normal organ function and a stable internal environment.However,many studies have revealed that abnormal expression of the Hedgehog signaling pathway is found in carcinogenesis.These studies also determined that this pathway can be activated by mutations or other mechanisms,leading to abnormal expression in adult tissue.It appears to play a crucial role in the development of tumors,including basal cell cancer,lung cancer,prostate cancer,colorectal cancer,and pancreatic cancer.A special inhibitor of the Hedgehog signaling pathway can inhibit the proliferation of these tumor cells.Gastric cancer is a significant threat to human health;as a malignant disease,it ranks second worldwide and first in China in incidence and mortality.It has been reported that there is an abnormal activation of the Hedgehog signaling pathway in gastric cancer.How does the Hedgehog signaling pathway lead to gastric cancer?This review summarizes the relationship between the Hedgehog signaling path-way and the development of gastric cancer by examining the mechanism of activation of the hedgehog signaling pathway,mutations,the non-canonical Hedgehog signaling pathway,gastric cancer stem cells,and epithelial-mesenchymal transition.Keywords Gastric neoplasms;Hedgehog signaling pathway;Stem cells;Epithelial-mesenchymal transition
作者单位：重庆医科大学附属第一医院消化内科（重庆市400016）
通信作者：王立wangli380@https://www.doczj.com/doc/854058722.html, Hedgehog 基因最早是在1980年由Nusslein-Voll ?hard 和Wieschaus 在研究果蝇基因突变时发现的。后来研究人员在脊椎动物中也发现了Hh 基因家族的存在，并对Hedgehog 信号通路进行了系统研究。认为Hedgehog 信号通路至少包括以下各个部分hedgehog （Hh ）、patched （Ptc ）、smoothened （Smo ）、丝氨酸/苏氨酸激酶fused （Fu ）、suppressor of fused ［Su （Fu ）］、costal 2（cos2是一种具有动力素样功能蛋白）和锌指转录因子cubitus interruptus （Ci ）。1Hedgehog 信号通路Hedgehog 是由Hedgehog 基因编码的一种高度保守的分泌型糖蛋白，其分子量约45kDa 。Hedgehog 蛋
白家族成员由两个结构域组成：氨基端结构域（Hh-N ）及羧基端结构域（Hh-C ），其中Hh-N 有Hh 蛋白的信号活性，而Hh-C 则具有自身蛋白水解酶活性
及胆固醇转移酶功能。Hh 前体蛋白在内质网中通过
自身催化分裂成Hh-N 片段及Hh-C 片段两部分，其
中Hh-C 共价结合胆固醇分子、并将其转移到Hh-N
的氨基端，随后在酰基转移酶的作用下，Hh-N 氨基
端的半胱氨酸发生棕榈酰化，通过这些翻译后的修
饰过程，Hh 即变成功能蛋白。Ptc 和Smo 均是位于细胞膜上的跨膜蛋白，其中Ptc 是Hh 的受体，是一种含胆固醇敏感区（SSD ）的12次跨膜蛋白，脊椎动物至少表达两种Ptc 蛋白：·综述·536