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浙江大学学报（医学版）
浙江大学学报（医学版）  2021, Vol. 50 Issue (2): 245-260    DOI: 10.3724/zdxbyxb-2021-0048
综述     
原纤毛及其在肿瘤发生发展中的作用
毛红美1,2(),孙毅1,2,*()
１.浙江大学医学院附属第二医院肿瘤研究所，浙江 杭州 310009
２.浙江大学转化医学研究院，浙江 杭州 310029
Primary cilium and its role in tumorigenesis
MAO Hongmei1,2(),SUN Yi1,2,*()
1. Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
2. Department of Translation Medicine, Zhejiang University, Hangzhou 310029, China
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摘要：

原纤毛是一个突出于大多数真核细胞表面的感觉细胞器，其重要功能是接收和转导细胞内外各种关键信号，从而在机体的正常发育和稳态中发挥不可替代的作用。原纤毛结构和/或功能异常会导致一系列包括肿瘤在内的疾病。原纤毛与细胞周期具有双向调控作用，可能可以作为一个细胞周期的检查点来抑制肿瘤的发生和发展；与细胞自噬相互调控，可能通过调控自噬活性从而在肿瘤的进展中发挥作用；与 Shh、Wnt、Notch 和血小板源性生长因子受体（PDGFR）等多个致癌性信号通路相互调控，参与肿瘤的发生发展。本综述总结了纤毛在肿瘤发生发展中的作用以及该领域所面临的挑战。
关键词： 原纤毛;  细胞周期;  纤毛相关信号通路;  自噬;  肿瘤发生    
Abstract:

The primary cilium, a sensory organelle that protrudes from the surface of most eukaryotic cells, receives and transduces various critical signals that are essential for normal development and homeostasis. Structural or functional disruption of primary cilia causes a number of human diseases, including cancer. Primary cilia has cross talks with cell cycle and it may act as a cell cycle checkpoint to suppress cancer development. Moreover, primary cilia has cross-regulation with autophagy, which may affect tumor progression. We then discuss the association of the primary cilia with several oncogenic signaling pathways, including Shh, Wnt, Notch and platelet-derived growth factor receptor (PDGFR). Since these signaling pathways are often over-activated in many types of human cancers, primary cilia are likely to play a role in the tumorigenesis by modulating these pathways. Finally, we summarize current progress on the role of cilia during tumorigenesis and the challenges that the cilia-cancer field faces.
Key words: Primary cilia    Cell cycle    Cilia-related signaling pathways    Autophagy    Tumorigenesis
收稿日期: 2020-10-29 出版日期: 2021-06-18
基金资助: 国家重点研发计划（2016YFA0501800）
通讯作者: 孙毅     E-mail: mhm@zju.edu.cn;yisun@zju.edu.cn
作者简介: 毛红美，博士后，主要从事原纤毛形成机制的研究；E-mail：mhm@zju.edu.cn；https://orcid.org/0000-0002-5565-5587
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引用本文:

毛红美,孙毅. 原纤毛及其在肿瘤发生发展中的作用[J]. 浙江大学学报（医学版）, 2021, 50(2): 245-260.

MAO Hongmei,SUN Yi. Primary cilium and its role in tumorigenesis. J Zhejiang Univ (Med Sci), 2021, 50(2): 245-260.

链接本文:

http://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0048    或    http://www.zjujournals.com/med/CN/Y2021/V50/I2/245

图 1  原纤毛的基本结构及形成原纤毛由基体、轴丝和纤毛膜组成，轴丝的基本结构为九组二联微管（9+0）.IFTA：鞭毛内运输复合物 A；IFTB：鞭毛内运输复合物 B.
图 2  原纤毛与细胞周期的双向调控细胞周期相关蛋白调控原纤毛的形成和解聚.细胞周期相关激酶促进原纤毛的形成.极样激酶 1 通过正向调控极光激酶 A、磷酸化HDAC6 和磷酸化 KIF2A 促进原纤毛的解聚；极光激酶 A 通过磷酸化HDAC6 促进原纤毛的解聚；NEK2 通过磷酸化 KIF24 促进原纤毛的解聚.HDAC：组蛋白脱乙酰酶；KIF：驱动蛋白家族；NEK：NIMA 相关激酶.
图 3  自噬与原纤毛的相互调控原纤毛可通过上调 Shh 信号通路的活性或下调 mTOR 信号通路的活性促进自噬的发生；而自噬可通过降解 IFT20 抑制原纤毛的形成或通过降解 OFD1 促进原纤毛的形成.mTOR：哺乳动物雷帕霉素靶蛋白；IFT20：鞭毛内运输蛋白 20.
图 4  定位在原纤毛的信号通路A：原纤毛调控 Shh 信号通路.当无 Shh 配体时，Shh 信号通路处于失活状态；当 Shh 配体存在时，Smo 蛋白使全长的 Gli 不被降解，随后全长 Gli、Sufu 和驱动蛋白家族 7（KIF7）形成复合物并朝原纤毛的顶端移动，一旦到达纤毛顶端，Gli 分离并被修饰成 GliA.B：原纤毛调控 Wnt 信号通路. 原纤毛调控平面细胞极性（PCP）的活性，但具体分子机制未明确.经典 Wnt 信号通路中，当 Wnt 与 FZD 及低密度脂蛋白受体相关蛋白 5/6（LRP5/6）结合时，散乱蛋白（DVL）被激活且将 APC/酪蛋白激酶 1（CK1）复合物招募至细胞膜，抑制β-Catenin 降解使得细胞质以及细胞核的β-Catenin 增多，进而转录激活下游靶基因；而无 Wnt 配体时，β-Catenin 被招募至由腺瘤性息肉病蛋白（APC）和 Axin 组成的复合物上，被 CK1 和糖原合成激酶（GSK）磷酸化，最终在蛋白酶体被降解.C：原纤毛调控 Notch 信号通路.Notch 受体和 Presenilin-2 定位在纤毛上，原纤毛可以正向调控 Notch 信号通路的活性，被水解切割的 Notch 释放出其细胞内结构域 NICD，后者从细胞膜转移至细胞核转录激活下游靶基因.D：原纤毛调控血小板源性生长因子受体（PDGFR）-α信号通路.PDGFR-α定位于某些细胞的原纤毛上，原纤毛可以通过 MEK-胞外信号调节激酶（ERK）及磷脂酰肌醇 3 激酶（PI3K）-蛋白激酶 B（AKT）正向调控血小板源性生长因子（PDGF）信号通路的活性.
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