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。     

Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy

Notch signaling pathway is evolutionarily conserved in mammals, which plays an important role in cell development and differentiation. In recent years, increasing evidence has shown that aberrant activation of Notch is associated with tumor process. Aberrant activation of Notch signaling pathway has been found in many different solid tumors can induce cell proliferation, metastasis and epithelial-mesenchymal transition. Notch receptor and its ligand are both single transmembrane protein, and Notch is activated when it binds to the Notch ligand of neighbor cells. The signal transduction of Notch signaling pathway is only between cells that are in contact with each other, which is independent of second messengers. Thus, Notch needs to cross talk with other signaling pathways, including PI3K/AKT, NF-κB, integrin and miRNAs, to precisely regulate cell fate. In this review, we summarize the roles of Notch signaling pathway in tumor metastasis and its regulatory mechanisms and discuss the current treatment strategies targeting Notch signal pathway.     

Notch信号通路调控肿瘤细胞凋亡机制研究进展

Notch信号通路在许多肿瘤细胞中异常表达,因其高表达相关性,表现为原癌或抑癌基因作用。当肿瘤细胞因外部刺激或细胞内信号影响Notch信号表达后,Notch信号通过与其他细胞信号通路的“串扰”,或直接调控凋亡蛋白,从而促进或抑制肿瘤细胞凋亡。本文综述了Notch信号通路促进和抑制肿瘤细胞凋亡及其作用机制,通过Notch信号通路在各种凋亡途径中的不同作用机制,为Notch信号通路抗肿瘤治疗提供理论支持。     

An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell line EC9706

Previous studies have demonstrated that Notch1 signaling pathway plays a major role in maintaining the balance of cell proliferation, differentiation and apoptosis, and is closely associated with tumorigenesis. However, roles of Notch1 signaling pathway in esophageal squamous cell carcinoma (ESCC), which is a common cause of mortality in China, remain poorly understood. Therefore, a novel strategy for seeking a rational molecular therapeutic target for ESCC is urgently needed. The purpose of this study is to examine the effect of the active Notch1 signaling pathway on the proliferation and apoptosis of ESCC cells and to investigate the underlying molecular mechanisms in carcinogenesis of the esophagus. The results revealed that a constitutively activated Notch1 signaling pathway was observed in ESCC cell line EC9706, through a pcNICD vector mediated expression system. Clearly, the activated Notch1 signaling pathway gave rise to proliferation suppression of the cells, accompanied with a cell cycle inhibition at the G0/G1 phase and apoptosis. In contrast to the expression of CDK2, cyclin D1 and cyclin E observed in EC9706 cells untreated and transfected with pcDNA3.1, there was a markedly decrease in the cells stably expressing Notch1 NICD. Up- and down-regulations of GSK3 beta and beta-catenin, respectively, indicated that Notch1 inhibited proliferation and induced apoptosis of EC9706 cells through Wnt-mediated signaling pathway. These findings suggest that Notch1 signaling pathway may participate in carcinogenesis of the esophagus.     

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.     

Downregulation of the Notch signaling pathway inhibits hepatocellular carcinoma cell invasion by inactivation of matrix metalloproteinase-2 and -9 and vascular endothelial growth factor

Hepatocellular carcinoma (HCC) is one of the most common malignancies. The main cause of death in HCC patients is tumor progression with invasion and metastasis. However, the underlying mechanisms of HCC invasion and metastasis are still not fully understood. Some studies show that the Notch signaling pathway may participate in tumor invasion and metastasis. However, the mechanisms by which the Notch signaling pathway mediates tumor cell invasion, especially in hepatocellular carcinoma, are not yet known. In the current study, we investigated the anti-invasion effect of the downregulation of the Notch signaling pathway by DAPT in HCC cells. The Notch signaling pathway inhibitor could suppress invasion of HCC cells via the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathways, resulting in the downregulation of matrix metalloproteinase-2 and -9 (MMP-2 and -9) and vascular endothelial growth factor (VEGF). These observations suggested that inhibition of the Notch signaling pathway by DAPT would be useful for devising novel preventive and therapeutic strategies targeting invasion of HCC.     

Notch signaling drives multiple myeloma induced osteoclastogenesis

Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors.The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance.Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact.Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.     

Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors

The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of gamma-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify such tumor-forming cells. We found that Notch blockade reduced the CD133-positive cell fraction almost 5-fold and totally abolished the side population, suggesting that the loss of tumor-forming capacity could be due to the depletion of stem-like cells. Notch signaling levels were higher in the stem-like cell fraction, providing a potential mechanism for their increased sensitivity to inhibition of this pathway. We also observed that apoptotic rates following Notch blockade were almost 10-fold higher in primitive nestin-positive cells as compared with nestin-negative ones. Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway.     

Critical role of notch signaling in osteosarcoma invasion and metastasis.

PURPOSE: Notch signaling is an important mediator of growth and survival in several cancer types, with Notch pathway genes functioning as oncogenes or tumor suppressors in different cancers. However, the role of Notch in osteosarcoma is unknown. EXPERIMENTAL DESIGN: We assessed the expression of Notch pathway genes in human osteosarcoma cell lines and patient samples. We then used pharmacologic and retroviral manipulation of the Notch pathway and studied the effect on osteosarcoma cell proliferation, survival, anchorage-independent growth, invasion, and metastasis in vitro and in vivo. RESULTS: Notch pathway genes, including Notch ligand DLL1, Notch1 and Notch2, and the Notch target gene HES1, were expressed in osteosarcoma cells, and expression of HES1 was associated with invasive and metastatic potential. Blockade of Notch pathway signaling with a small molecule inhibitor of gamma secretase eliminated invasion in Matrigel without affecting cell proliferation, survival, or anchorage-independent growth. Manipulation of Notch and HES1 signaling showed a crucial role for HES1 in osteosarcoma invasiveness and metastasis in vivo. CONCLUSION: These studies identify a new invasion and metastasis-regulating pathway in osteosarcoma and define a novel function for the Notch pathway: regulation of metastasis. Because the Notch pathway can be inhibited pharmacologically, these findings point toward possible new treatments to reduce invasion and metastasis in osteosarcoma.     

Notch signaling from tumor cells: a new mechanism of angiogenesis

Notch signaling is an evolutionarily conserved pathway and plays key roles in embryonic vascular development and angiogenesis. Multiple components of the Notch pathway are expressed in vasculature, and mice deficient for a variety of these components display embryonic lethality with vascular remodeling defects. Alteration of Notch signaling in various endothelial cells generates profound effects on angiogenesis in vitro. New evidence shows that Notch signaling from tumor cells is able to activate endothelial cells and trigger tumor angiogenesis in vitro and in a xenograft mouse tumor model. Selective interruption of Notch signaling within tumors may provide an antiangiogenic strategy.