Notch信号通路相关基因与乳腺癌发生发展的研究新进展

Notch信号通路是一条进化上十分保守的信号转导途径,广泛存在于生物进化过程中,相邻细胞间通过Notch受体与配体的相互作用转导细胞信号,调节细胞的增殖、分化和凋亡,影响器官形成和形态的发生。近年大量研究表明Notch信号分子的异常表达在乳腺癌发生过程中起着重要的调控作用,但该基因表达异常的内在机制还不清楚,本文就Notch基因表达及其表达机制与乳腺癌的发生关系进行综述。     

Notch信号转导通路与乳腺癌靶向治疗

Notch信号转导通路参与调控细胞增生、分化及凋亡.异常的Notch信号转导通路可以诱导转基因鼠乳腺癌的发生,而在乳腺癌患者中,高表达Notch受体和(或)配体则与预后不良相关,因此靶向抑制Notch信号转导通路可能对乳腺癌治疗有益.     

Notch3在肿瘤发生发展中的作用

Notch信号通路是一个高度保守的信号通路,在脊椎动物发育过程中扮演重要角色。研究发现Notch受体介导的信号通路在多种肿瘤中异常表达。近年来研究表明Notch3与多种肿瘤的发生发展有着密切的联系,Notch3在调控肿瘤细胞的凋亡、增殖和分化中起着重要作用,本文就Notch3在各类常见肿瘤中的研究进展进行综述,重点探讨Notch3异常表达与肿瘤形成、发展的分子机制,以期推动Notch3作为药物作用靶点的研究。     

Notch3信号通路与卵巢癌发生发展关系的研究北大核心CSCD

Notch信号传导通路是影响细胞命运的重要通路之一,相邻细胞间通过Notch受体传递信号可以调节多种细胞的分化、增殖和凋亡,影响器官形成和形态变化。Notch信号传导的变化与肿瘤的发生发展密切相关,如脑肿瘤、乳腺癌、肝癌等。近年来研究表明,Notch异常通路介导卵巢癌的发生发展,尤其Notch3及其信号传导分子参与肿瘤的化疗耐药与复发。文章对新近有关Notch3信号通路的重要分子调控卵巢癌的发生发展进行综述。     

Notch信号通路与乳腺肿瘤发生关系的研究进展

目的：探讨Notch信号通路的组成，及近年来Notch通路与乳腺肿瘤形成关系的研究进展。方法：PubMed全文数据库和雏普资讯-中文科技期刊数据库中搜索关键字为“Notch”，截选并通读2004年至今的综述以全面了解Notch信号系统的基本概念，并由此追溯至Notch的首次发现；分别以“Notch and mammary tumor”和“Notch、乳腺癌”为检索词，搜索PubMed和维普科技期刊数据库中近10年间国内外学者在乳腺癌的形成与Notch信号的联系这一领域的研究报道，按Notch受体家族不同成员在乳腺癌中所发挥的作用归类为“Notch4与乳腺癌”、“Notch1与乳腺癌”等。结果：Notch4作为首次证明乳腺肿瘤发生与Notch信号相关的证据，研究的较多，转基因小鼠实验验证了其在乳腺癌发生过程中的致癌作用；后来鉴定出Notch1也可以作为MMTV的插入位点，其在乳腺肿瘤发生中的作用越来越受关注；Notch受体家族其他成员在乳腺癌发生中发挥作用的证据较少，Notch3可能在肿瘤发生时血管形成中起一定作用。Notch信号在乳腺癌形成过程中与其他信号发生对话。结论：Notch信号通路与乳腺癌的发生存在着密切的联系并且可能在乳腺癌发生过程中与其他信号产生协同作用。     

Notch信号转导通路与原发性肝癌

Notch信号转导通路由一组在进化上高度保守的细胞膜配体、受体及下游分子组成。细胞间受体配体作用可激活Notch信号转导过程,从而直接调节基因转录,使细胞基因表达受相邻细胞调控,Notch信号在细胞分化、胚胎发育、组织自我更新过程中均发挥了重要的作用,许多病理过程（包括肿瘤）都有Notch信号参与。Notch信号多作为癌基因促进肿瘤生长,但在某些组织也可起到诱导细胞分化、抑制肿瘤增殖的作用。肿瘤干细胞中Notch信号的改变可能发挥了关键性作用。目前认为,Notch在肝癌中作为抑癌基因抑制肿瘤的生长,其机制初步被认为是Notch1使JNK活化、p53高表达以及Bcl2表达下调,从而诱导肝癌细胞凋亡,但尚待更加深入的研究。鉴于针对Notch信号通路的干预措施已经成为治疗肿瘤的新方式,该通路也有望成为肝癌的生物治疗新的靶点。     

Notch信号在人类乳腺癌中的作用

目的观察Notch1和JAG1在乳腺癌中的表达及其与乳腺癌相关因素的关系,探讨Notch信号在人类乳腺癌中的作用。方法应用逆转录聚合酶链反应(RT-PCR)检测62例乳腺癌组织及22例癌旁正常乳腺组织中Notch1和JAG1的表达,对乳腺癌组织与癌旁正常乳腺组织进行表达率和表达强度标准化系数的统计学比较,并在不同的腋窝淋巴结转移情况间、不同的临床分期间进行Notch1表达强度标准化系数的统计学比较。结果乳腺癌组织Notch1的表达率和标准化系数分别为98.0%和0.91,均明显高于癌旁正常乳腺组织,乳腺癌组织中JAG1的表达率为15.0%,癌旁组织中无JAG1表达;伴腋窝淋巴结转移的病例Notch1标准化系数高于无腋窝淋巴结转移的病例;乳腺癌Ⅰ期病例Notch1标准化系数(0.66)低于Ⅱ期(1.20),Ⅱ期高于Ⅲ期(0.62),Ⅰ期与Ⅲ期差异无统计学意义。结论人类乳腺癌中存在Notch1和JAG1的异常高表达,提示Notch1的异常表达与活化人能与人类乳腺癌的形成有关,Notch1在人类乳腺癌不同发展阶段的作用可能不同。     

PTEN和Nocth信号通路与非小细胞肺癌的关系

肺癌是一种基因性疾病,癌基因激活或抑癌基因失活是导致细胞异常增殖和凋亡障碍从而导致肺癌发生的关键。PTEN 是第一个被发现的具有双重特异性磷酸酶活性的抑癌基因,它与肿瘤发生关系密切。Notch 信号通路在决定细胞分化方向,细胞增殖和凋亡过程中起重要作用,其异常表达常参与肿瘤的发生、发展和血管生成等。因此,针对 PTEN 及 Notch 信号通路的研究有助于对非小细胞肺癌的预防和治疗。本文结合国内外最新报道,对 PTEN 及 Notch 信号通路与非小细胞肺癌相关性研究进展作一综述。     

Notch信号通路在乳腺癌干细胞中的研究进展

乳腺癌干细胞是一群具有自我更新及多向分化潜能的细胞,在乳腺癌的发生、发展以及转移、复发中起着极其重要的作用。正常情况下,乳腺干细胞的分化、更新能力受相关信号转导通路的严格调控,当这些信号通路发生异常干细胞将会异常分化,形成乳腺癌干细胞,并无限增殖形成肿瘤。随着人们对乳腺癌干细胞的深入研究,Notch信号通路与其他信号通路的相互作用对乳腺癌干细胞的调控逐渐被人们所重视。本文为进一步了解Notch信号通路在乳腺癌的发生、发展以及靶向治疗中的重要意义,结合乳腺癌干细胞信号通路的最新研究进展进行综述。      

miR-139-5p通过调节Notch信号通路对乳腺癌细胞增殖和凋亡的影响

目的:探讨miR-139-5p通过靶向抑制Notch信号通路调控乳腺癌细胞的增殖和凋亡。方法:通过实时定量PCR法检测miR-139-5p以及Notch1在乳腺癌和乳腺上皮细胞中的表达;采用双荧光素酶报告基因法验证miR-139-5p对Notch1的调控作用;通过CCK8和流式细胞术分别检测miR-139-5p与Notch1对乳腺癌细胞MDA-MB-231增殖和凋亡的影响,并通过Western blot法检测miR-139-5p对Notch1及相关凋亡蛋白表达的影响。结果:miR-139-5p在人乳腺癌细胞中表达显著下调（P<0.05）,尤其在乳腺癌MDA-MB-231细胞中下调更为显著（P<0.01）;双荧光素酶报告基因实验证实miR-139-5p能与Notch1 3’ UTR结合;同时miR-139-5p过表达能够显著抑制细胞活力,促进细胞凋亡（P<0.01）,显著抑制Notch1蛋白表达（P<0.01）,进而降低相关凋亡蛋白Bcl-2的表达,增强Bax的表达。 结论:miR-139-5p能够通过抑制靶基因Notch1的表达,抑制乳腺癌细胞的增殖,促进细胞凋亡。     

miR-129对乳腺癌肿瘤干细胞自我更新能力的调控作用及其机制探讨

目的:探究miR-129在乳腺癌中对肿瘤干细胞自我更新能力的调控作用及其机制。方法:应用免疫组化检测乳腺癌肿瘤干细胞在肿瘤组织与癌旁组织中的数量及其与乳腺癌肿瘤分期的关系,验证miR-129和Numb与乳腺癌肿瘤干细胞之间的相关关系。在体外实验中应用Western Blotting及RT-PCR验证miR-129通过阻断雌激素受体alpha（ER alpha,ESR1）对Notch信号通路的调节作用及其调节的具体机制;应用裸鼠成瘤实验验证miR-129在裸鼠体内水平对乳腺癌肿瘤干细胞的影响。结果:肿瘤组织中乳腺癌肿瘤干细胞的比例高于癌旁组织并与肿瘤分期具有相关性;乳腺癌肿瘤干细胞比例与临床样本中miR-129和Numb的表达水平呈负相关;乳腺癌肿瘤干细胞中miR-129的过表达与Notch信号通路的抑制直接相关,这种作用很可能是miR-129通过调控ESR1所引起的Let-7b的表达下调进而导致Numb的释放来实现的;miR-129在裸鼠体内实验中可以抑制乳腺癌肿瘤干细胞的成瘤。结论:miR-129在乳腺癌组织中可以通过调控Notch信号通路影响乳腺癌肿瘤干细胞自我更新的能力,具体的调节机制可能是通过调控ESR1所引起的Let-7b的表达下调进而导致Numb的释放来最终抑制Notch信号通路的激活。     

Aberrant activation of notch signaling in human breast cancer

A role for Notch signaling in human breast cancer has been suggested by both the development of adenocarcinomas in the murine mammary gland following pathway activation and the loss of Numb expression, a negative regulator of the Notch pathway, in a large proportion of breast carcinomas. However, it is not clear currently whether Notch signaling is frequently activated in breast tumors, and how it causes cellular transformation. Here, we show accumulation of the intracellular domain of Notch1 and hence increased Notch signaling in a wide variety of human breast carcinomas. In addition, we show that increased RBP-Jkappa-dependent Notch signaling is sufficient to transform normal breast epithelial cells and that the mechanism of transformation is most likely through the suppression of apoptosis. More significantly, we show that attenuation of Notch signaling reverts the transformed phenotype of human breast cancer cell lines, suggesting that inhibition of Notch signaling may be a therapeutic strategy for this disease.     

Breast cancer stem cells: something out of notching?

We and others have established that the developmental Notch receptor signaling pathway is active in breast cancer cell lines, as well as in preinvasive and invasive primary samples. Recently, a role for Notch in regulating the hierarchy of stem and progenitor cells in both normal and cancer epithelium has been elucidated. Because inhibiting the Notch receptor signaling pathway is a possible future breast cancer therapy, here, we review the expression and activity of the different ligands and receptors and summarize the various ways in which the pathway's activity can be inhibited, and the likely effects of inhibition on different tumor cell subpopulations.     

Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis

Background  

Recent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression.     

Notch信号通路与消化系统肿瘤相关性的研究进展

Notch信号是一种遗传进化上高度保守,反映相邻细胞间通信作用的一种信号通路,其不仅在细胞正常发育、分化增殖和凋亡中起着重要的作用,而且与多种肿瘤的发生和发展具有相关性.食管鳞状细胞癌的发生常伴随Notch-1的低表达,但食管腺癌的发生却与Notch信号的高表达相关,且高表达的Notch信号对胃癌形成具有促进作用,其表达量提高的程度预示胃癌形成风险的高低.结肠癌中Notch-1表达的升高与病理分级、淋巴转移和病程相关,而Nctch配体Dll-4可促进结肠癌中新生血管的生成有助于癌细胞的转移和远端浸润,与之相反的是Notch-2却可能起到抑制结肠癌生长的作用.总之,目前Notch信号多被视为致癌因素,可促进肿瘤的生长,但在某些肿瘤中也能够诱导肿瘤细胞分化、抑制肿瘤细胞的增殖,表现为致癌与抑癌两种截然相反的作用.应用γ-分泌酶抑制剂(γ-secretase inhibitor,GSI)、小RNA干扰技术和单克隆抗体等方法阻断Notch信号通路,将成为肿瘤治疗的一个新方向.     

Notch Activation Is Associated with Tetraploidy and Enhanced Chromosomal Instability in Meningiomas

The Notch signaling cascade is deregulated in diverse cancer types. Specific Notch function in cancer is dependent on the cellular context, the particular homologs expressed, and cross-talk with other signaling pathways. We have previously shown that components of the Notch signaling pathway are deregulated in meningiomas. However, the functional consequence of abnormal Notch signaling to meningiomas is unknown. Here, we report that exogenous expression of the Notch pathway effector, HES1, is associated with tetraploid cells in meningioma cell lines. Activated Notch1 and Notch2 receptors induced endogenous HES1 expression and were associated with tetraploidy in meningiomas. Tetraploid meningioma cells exhibited nuclear features of chromosomal instability and increased frequency of nuclear atypia, such as multipolar mitotic spindles and accumulation of cells with large nuclei. FACS-sorted tetraploid cells are viable but have higher rates of spontaneous apoptosis when compared with diploid cells. We have used spectral karyotyping to show that, in contrast to diploid cells, tetraploid cells develop a higher number of both numerical and structural chromosomal abnormalities. Our findings identify a novel function for the Notch signaling pathway in generating tetraploidy and contributing to chromosomal instability. We speculate that abnormal Notch signaling pathway is an initiating genetic mechanism for meningioma and potentially promotes tumor development.     

HBV激活Notch1信号通路上调GP73的表达

目的:探索HBV上调GP73表达的相关机制.方法:通过real-time PCR和Western blot检测HepG2和整合HBV的HepG2.2.15细胞中Notch1及其下游分子Hes1的表达.分别转染Notch1过表达载体和干扰载体,观察Notch1对GP73表达的影响.免疫组织化学法检测GP73、Notch1在肝癌组织中的表达,分析两者的相关性.结果:HBV可引起Notch1的表达升高;Notch1可引起GP73的表达升高,两者在肝癌组织中呈正相关.结论:HBV可通过激活Notch1通路上调GP73的表达,这可能是GP73在肝癌组织中表达升高的原因之一.     

MicroRNA‐34a suppresses the breast cancer stem cell‐like characteristics by downregulating Notch1 pathway

MicroRNAs play pivotal roles in cancer stem cell regulation. Previous studies have shown that microRNA‐34a (miR‐34a) is downregulated in human breast cancer. However, it is unknown whether and how miR‐34a regulates breast cancer stem cells. Notch signaling is one of the most important pathways in stem cell maintenance and function. In this study, we verified that miR‐34a directly and functionally targeted Notch1 in MCF‐7 cells. We reported that miR‐34a negatively regulated cell proliferation, migration, and invasion and breast cancer stem cell propagation by downregulating Notch1. The expression of miR‐34a was negatively correlated with tumor stages, metastasis, and Notch1 expression in breast cancer tissues. Furthermore, overexpression of miR‐34a increased chemosensitivity of breast cancer cells to paclitaxel (PTX) by downregulating the Notch1 pathway. Mammosphere formation and expression of the stemness factor ALDH1 were also reduced in the cells treated with miR‐34a and PTX compared to those treated with PTX alone. Taken together, our results indicate that miR‐34a inhibited breast cancer stemness and increased the chemosensitivity to PTX partially by downregulating the Notch1 pathway, suggesting that miR‐34a/Notch1 play an important role in regulating breast cancer stem cells. Thus miR‐34a is a potential target for prevention and therapy of breast cancer.     

Visfatin promotes cell and tumor growth by upregulating Notch1 in breast cancer

Overexpression of Notch1 has been associated with breast cancer. We recently showed that visfatin stimulates breast cancer cell proliferation and invasion. The present study was undertaken to determine whether Notch1 signaling is affected by visfatin and to characterize the functional role of the visfatin-Notch1 axis in breast cancer. Visfatin and Notch1 were expressed at higher levels in breast tumors than in matched control tissues. Visfatin induced Notch1 expression in MDA-MB-231 breast cancer cell line and in nontransformed MCF10A mammary epithelial cells, whereas visfatin depletion reduced Notch1 mRNA and protein levels. Depletion of Notch1 in MDA-MB-231 cells attenuated cell growth in vitro and in vivo; visfatin depletion produced similar effects, but was less potent. Additionally, Notch1 depletion inhibited cell proliferation induced by visfatin. Analysis of the signaling pathways underlying visfatin-mediated Notch1 upregulation revealed that visfatin activated NF-κB p65. Blockade of NF-κB signaling suppressed the effects of visfatin on Notch1 upregulation and breast cancer cell proliferation. Breast tumors expressing high levels of NF-κB p65 exhibited increased expression of Notch1. Our results demonstrate that the visfatin-Notch1 axis contributes to breast tumor growth through the activation of the NF-κB pathway. Study of the visfatin-Notch1 axis may offer new therapeutic directions for breast cancer.