Hedgehog信号通路与肿瘤

Hedgehog信号通路在胚胎发育中细胞的生长分化、组织器官形成以及成体干细胞的维持和自稳态的保持等方面具有重要作用。同时,Hedgehog信号通路与Wnt信号通路、Notch信号通路等相互作用、密切联系,在肿瘤的发生、发展过程中也起到关键作用。论文综述了Hedgehog信号通路的作用机理,与其他信号通路、蛋白质因子的相互联系,以及在肿瘤研究中所关注的靶位点和小分子化合物抑制剂,对于癌症的预防和治疗具有一定的参考价值。     

Hedgehog信号通路的作用机制及研究进展

HH(Hedgehog)信号通路参与多种生物学过程,包括细胞分化、细胞增殖、细胞衰老、肿瘤的发生、肿瘤恶性转化以及肿瘤耐药,HH信号通路相关基因的异常表达或突变会在生物发生发展的不同阶段引起各种疾病的发生。而HH信号通路通过复杂的机制调控诸多信号通路,进一步影响生物体的功能。所以深入了解HH信号通路在各种遗传疾病、肿瘤发生发展以及化疗耐药发展过程中的作用,将有利于进一步发现和研究疾病治疗靶点。该文中,我们概述了HH信号通路,以及HH信号通路在癌症发生发展、发育以及衰老中的作用机制,可为针对HH信号通路的治疗方法研究提供理论依据。     

肿瘤细胞Hedgehog信号通路及其抑制剂

越来越多的证据显示, 肿瘤的发生、生长、转移、复发以及耐药等均与肿瘤干细胞密切相关.Hedgehog (Hh)信号通路调节胚胎发育和成体许多组织器官干细胞的自我更新与增殖.然而, 那些在正常发育过程中受到Hh信号通路调节的组织器官, 在该信号通路异常时常常发生肿瘤.这些肿瘤包括肝癌、神经胶质瘤、基底细胞癌、横纹肌肉瘤、胰腺癌、小细胞肺癌、胃癌、结肠癌、前列腺癌、黑色素瘤和多发性骨髓瘤等.介绍了近年来Hh信号通路在肿瘤发生和发展过程中的机制、在维持肿瘤干细胞自我更新方面的作用, 以及该通路的特异性抑制剂, 以显示其在肿瘤治疗中潜在的重要意义.最后, 提出了今后肿瘤干细胞Hh通路研究的重点和新思路.     

Gli1与β-catenin相互作用促进二者在结肠癌细胞中的协同核输入（英文）

Wnt信号通路和Hedgehog(Hh)信号通路在胚胎和干细胞的发育中发挥重要作用.此外,这两条信号途径在结肠癌复发和浸润的过程也至关重要.然而,Wnt信号通路、Hedgehog信号通路二者之间具体的交互作用机制目前仍不清楚.本文发现,这两条途径的关键分子Gli1和β-联蛋白之间存在蛋白质相互作用.Gli1与β-联蛋白之间的分子相互作用有助于二者的核输入.同时发现,在肠癌细胞系中,Gli1与β-联蛋白协同上调表达.Li Cl激活细胞Wnt信号通路使Gli1表达水平增加,RNA干扰抑制Wnt信号通路,Gli1的表达水平下降.同时,Gli1的过表达也提高了细胞内β-联蛋白的表达水平,并且用Hedgehog信号通路抑制剂GANT61处理细胞,降低Gli1的表达后细胞内β-联蛋白的表达相应下降.本研究揭示了Gli1和β-联蛋白的相互作用及二者协助核输入在Wnt、Hedgehog信号通路交互调节中发挥重要作用,Wnt、Hedgehog信号通路交互作用为大肠癌发生发展研究提供了细胞水平交互调控机制.     

Gli1与β-catenin相互作用促进二者在结肠癌细胞中的协同核输入

Wnt信号通路和Hedgehog（Hh）信号通路在胚胎和干细胞的发育中发挥重要作用.此外,这两条信号途径在结肠癌复发和浸润的过程也至关重要.然而,Wnt信号通路、Hedgehog信号通路二者之间具体的交互作用机制目前仍不清楚.本文发现,这两条途径的关键分子Gli1和β-联蛋白之间存在蛋白质相互作用.Gli1与β-联蛋白之间的分子相互作用有助于二者的核输入.同时发现,在肠癌细胞系中,Gli1与β-联蛋白协同上调表达. LiCl激活细胞Wnt信号通路使Gli1表达水平增加, RNA干扰抑制Wnt信号通路,Gli1的表达水平下降.同时,Gli1的过表达也提高了细胞内β-联蛋白的表达水平,并且用Hedgehog信号通路抑制剂GANT61处理细胞,降低Gli1的表达后细胞内β 联蛋白的表达相应下降.本研究揭示了Gli1 和 β-联蛋白的相互作用及二者协助核输入在Wnt、Hedgehog信号通路交互调节中发挥重要作用,Wnt、Hedgehog信号通路交互作用为大肠癌发生发展研究提供了细胞水平交互调控机制.     

乳腺癌相关的细胞内信号通路

乳腺癌是女性中常见的恶性肿瘤之一.乳腺癌的发生、发展、转移及耐药性的产生与细胞内的信号通路密切相关,其中雌激素受体(estrogen receptor,ER)信号通路、胰岛素样生长因子受体（insulin-like growth factor receptor,IGFR)信号通路和表皮生长因子受体（epidermal growth factor receptor,EGFR）信号通路尤为重要．深入了解ER、IGFR和EGFR三条信号通路的作用机制及它们之间的交叉对话对于寻找新的更有效的肿瘤治疗靶点至关重要．本文综述了近年来有关ER、IGFR和EGFR三条信号通路研究进展及这三条通路与乳腺癌关系．     

POMP与SuFu相互作用调控Hedgehog信号通路的活性

Hedgehog信号通路在胚胎发育、组织再生中发挥重要的作用,且与癌症发生发展密切相关. 其胞内调控组分Suppressor of Fused（SuFu）蛋白通过结合转录因子Gli(s),负调控该信号通路,但其作用的分子机制仍不甚清楚. 在本项研究中,以人SuFu作为诱饵蛋白,利用酵母双杂交技术成功地筛选到1个新的相互作用因子-蛋白酶体成熟蛋白（POMP）. 通过免疫共沉淀、体外GST pull-down和免疫细胞化学实验验证其相互作用. 为了探究POMP与SuFu的相互作用对Hedgehog信号通路的影响,构建了POMP的过表达质粒和干扰质粒（miR-RNAi）以及转录因子Gli活性检测系统,即荧光素酶报告基因法,结果显示,过表达SuFu蛋白时POMP正调控Hedgehog信号通路,而下调POMP的表达则抑制Gli的活性. 该研究结果揭示了POMP新的生物学功能,为阐明Hedgehog信号通路的具体分子机制提供了新的线索.     

雌激素受体信号通路在乳腺癌发生和治疗中的作用

雌激素受体信号通路在调控乳腺细胞增殖和凋亡等生理机能中发挥重要功能,该通路出现调控异常时可导致乳腺癌发生。雌激素受体在乳腺癌发生中的作用机制包括核受体介导的基因组信号通路和膜受体介导的非基因组信号通路以及二者的相互作用。基于雌激素受体信号通路及其关键信号分子的靶向治疗是开展乳腺癌治疗的重要策略与有效途径。对雌激素受体结构以及雌激素受体信号通路在乳腺癌发生和治疗中的作用作一综述。     

Hedgehog信号通路与动物骨骼肌发育调控

Hedgehog信号通路在动物胚胎期及出生后骨骼肌的生长发育过程中发挥着重要作用。本文综述了Hedgehog信号通路对骨骼肌细胞增殖分化及肌纤维特性的调控作用及其在骨骼肌发育过程中与其它信号通路交互作用最新研究进展,为畜禽肉品质改良和肌肉相关疾病治疗提供理论基础。     

Hedgehog信号通路在胚胎发育过程中的调控作用

Hedgehog信号通路首次在果蝇体内被发现,进化上呈高度保守状态。该通路在胚胎发育、机体组织器官的形成过程中发挥了重要作用,它的异常调节会导致一系列严重的疾病。本文主要就Hedgehog信号通路对神经系统、骨骼系统、消化系统、肺、颅面部发育的调控作用作一综述。     

A directed mutagenesis screen in Drosophila melanogaster reveals new mutants that influence hedgehog signaling

The Hedgehog signaling pathway has been recognized as essential for patterning processes in development of metazoan animal species. The signaling pathway is, however, not entirely understood. To start to address this problem, we set out to isolate new mutations that influence Hedgehog signaling. We performed a mutagenesis screen for mutations that dominantly suppress Hedgehog overexpression phenotypes in the Drosophila melanogaster wing. We isolated four mutations that influence Hedgehog signaling. These were analyzed in the amenable wing system using genetic and molecular techniques. One of these four mutations affects the stability of the Hedgehog expression domain boundary, also known as the organizer in the developing wing. Another mutation affects a possible Hedgehog autoregulation mechanism, which stabilizes the same boundary.     

Triparanol suppresses human tumor growth in vitro and in vivo

Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.     

Epigenetic gene silencing in the Wnt pathway in breast cancer

Breast cancer is one of the most common malignancies in women. Despite advances in treatment of endocrine-dependent tumors, the complete molecular basis of transformation is still unknown. What is clear is that a variety of genetic lesions and epigenetic modifications are present in the neoplasm. Disregulation of several signaling pathways is known to be associated with breast cancer development, among them is the wingless and integration site growth factor (Wnt) pathway. While genetic mutations of certain components of this pathway, such as APC, are significant contributing factors for colorectal cancers, they are typically not the predominate mechanism associated with breast cancer. Instead, it appears that DNA hypermethylation leads to aberrant regulation of the Wnt pathway in breast cancer, and as such, this review focuses on the epigenetic regulation of Wnt pathway components in breast cancer.     

经典Wnt信号通路与人类肿瘤

近年来,随着对肿瘤的深入研究,Wnt信号的研究也受到了高度的关注．Wnt信号通路是一条在进化上保守的信号途径,在控制胚胎发育,调节细胞生长、迁移、分化,调控正常组织重建等生命活动中发挥重要的作用,其异常活化与众多人类肿瘤的发生、发展密切相关．Wnt信号途径异常的核心是β-catenin在细胞内累积,并通过其下游途径引起特异靶基因的转录．本文着重介绍Wnt/β-catenin信号转导通路的研究进展及其与肿瘤的关系,了解该通路在肿瘤发生过程中的具体分子机制有助于为临床诊断提供依据,为早期干预治疗提供方法．     

Regulation of Hedgehog signaling by ubiquitination

The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult stem cell function. The timing, duration and location of Hh signaling activity need to be tightly controlled. Abnormalities of Hh signal transduction lead to birth defects or malignant tumors. Recent data point to ubiquitination-related posttranslational modifications of several key Hh pathway components as an important mechanism of regulation of the Hh pathway. Here we review how ubiquitination regulates the localization, stability and activity of the key Hh signaling components.     

Hedgehog signaling: networking to nurture a promalignant tumor microenvironment

In addition to its role in embryonic development, the Hedgehog pathway has been shown to be an active participant in cancer development, progression, and metastasis. Although this pathway is activated by autocrine signaling by Hedgehog ligands, it can also initiate paracrine signaling with cells in the microenvironment. This creates a network of Hedgehog signaling that determines the malignant behavior of the tumor cells. As a result of paracrine signal transmission, the effects of Hedgehog signaling most profoundly influence the stromal cells that constitute the tumor microenvironment. The stromal cells in turn produce factors that nurture the tumor. Thus, such a resonating cross-talk can amplify Hedgehog signaling, resulting in molecular chatter that overall promotes tumor progression. Inhibitors of Hedgehog signaling have been the subject of intense research. Several of these inhibitors are currently being evaluated in clinical trials. Here, we review the role of the Hedgehog pathway in the signature characteristics of cancer cells that determine tumor development, progression, and metastasis. This review condenses the latest findings on the signaling pathways that are activated and/or regulated by molecules generated from Hedgehog signaling in cancer and cites promising clinical interventions. Finally, we discuss future directions for identifying the appropriate patients for therapy, developing reliable markers of efficacy of treatment, and combating resistance to Hedgehog pathway inhibitors.     

Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm

Medulloblastomas often activate Hedgehog signaling inappropriately. The finding that mutations in components of this pathway are present only in few tumors suggests that additional genetic or epigenetic lesions can also lead to Hedgehog dysregulation. Chromosome 17p deletion, the most frequently detected genetic lesion in medulloblastoma, has recently been identified as a cause of unrestrained Hedgehog signaling. Such a deletion leads to the loss of REN(KCTD11), a novel Hedgehog antagonist, thus removing a checkpoint of Hedgehog-dependent events during cerebellum development and tumorigenesis. The disruption of additional Hedgehog modulators that map to 17p suggests a rationale for a multitargeted therapeutic strategy aimed at interrupting the cooperative activation of the Hedgehog pathway.