Notch信号通路与恶性肿瘤侵袭、转移关系的研究进展

恶性肿瘤细胞具有侵袭、转移的生物学特性,近年来研究发现Notch信号通路与肿瘤侵袭、转移及肿瘤新生血管等过程关系密切,了解其在恶性肿瘤生长过程中的作用及机制有助于寻找相应的阻断途径,对遏制恶性肿瘤发展有重要作用,本文对Notch信号通路与恶性肿瘤侵袭转移关系及相关机制的研究进展作一概述。     

Notch信号通路与原发性肝癌关系的研究进展

Notch信号通路作为一种相对保守的细胞信号,对细胞命运起决定性作用。迄今已基本阐明Notch信号通路的主要成员及核心转导过程,随着研究的深入,人们逐渐认识到该信号通路影响肿瘤的生长和转移。原发性肝癌是临床上常见的消化系统恶性肿瘤之一,具有较高的发病率和病死率。目前研究表明Notch信号通路与肝癌的关系密切。本文除回顾Notch信号通路组件、转导过程及调控外,主要就肝癌中Notch信号通路组件的异常表达,调控Notch信号通路对肝癌细胞增殖、凋亡和转移的影响,以及Notch信号通路介导乙肝病毒HBx蛋白促进肝癌的发生等方面作一综述。     

肿瘤干细胞在肿瘤侵袭转移中的作用机制及功能相关信号通路研究进展

肿瘤干细胞是肿瘤组织中存在的少量具有自我更新能力和分化潜能的细胞。目前可通过一些干细胞分子标志物(CD177、CD133、CD44等)对其进行识别。肿瘤干细胞可通过上皮间叶转变途径诱导肿瘤细胞侵袭,通过趋化因子诱导肿瘤细胞迁移,并能够诱导肿瘤组织血管生成。肿瘤干细胞可通过多种信号转导通路如Wnt/β-catenin信号通路、Notch通路、Patched通路等参与肿瘤的侵袭和转移。     

DLL4/NOTCH通路与肿瘤血管生成关系研究进展

Notch信号通路是进化保守的影响胚胎和出生后发育分化进程和细胞命运的细胞间信号通路[1].许多研究证明其对血管的发生发展有重要的调控功能,其在脉管系统不同发育阶段均有表达.研究发现Notch信号通路配体Dll4在人类许多肿瘤血管中呈现高表达.因此对Dll4深入研究可为肿瘤新生血管分子靶向治疗提供新的策略和靶标.现就Notch 信号通路组成,传导,调控与肿瘤血管生成关系做一综述.     

Notch信号通路在胃肠道肿瘤发生中的作用

Notch信号通路是影响细胞命运的重要通路之一,相邻细胞之间通过Notch受体与配体的相互作用传递信号,可调节包括干细胞在内的多种细胞的分化、增殖和凋亡。除在正常组织、细胞的分化、发育中发挥重要作用外．Notch信号通路还参与了肿瘤的发生、发展,并在不同肿瘤中呈现促癌或抑癌作用。深入研究Notch信号通路可能为胃肠道肿瘤的基因治疗提供新的靶点。     

Notch信号通路和神经内分泌肿瘤

Notch信号通路既简单又复杂,表达于多个物种且高度保守.在不同的细胞类型中,Notch信号通路可促进或抑制细胞增殖、分化和凋亡.Notch信号通路与肿瘤的关系比较复杂,既可以作为癌基因,也可以作为抑癌基因,它的作用与细胞类型有关.在神经内分泌肿瘤(NETs)如类癌、小细胞肺癌(SCLC)和甲状腺髓样癌(MTC)中Notch信号通路失活,若激活Notch信号通路可抑制肿瘤细胞生长、减少NETs标志物,证明Notch信号通路在NETs中发挥肿瘤抑制作用.因此,Notch信号通路激活剂可能会成为NETs患者的一个潜在治疗药物.     

Hedgehog和TGF-β/Smads信号通路与胰腺癌发生发展的关系

正Hedgehog(HH)信号和TGF-β信号通路在肿瘤的发生发展中起着重要的作用,近年来不断有研究指出HH信号通路中的主要效应因子Gli2也是TGF-β/Smads信号通路的靶基因。HH信号通路的异常与胰腺癌的发生密切相关,而TGF-β通路中的信号异常也参与胰腺癌肿瘤的生长、侵袭和转移。该文就这2个信号通路及其与胰腺癌的关系的研究进展作一综述。1总论胰腺癌在世界范围内呈增多趋势,已成为癌症     

Notch1在人肝细胞癌组织的表达及其临床意义

Notch信号通路在肿瘤形成中所起的重要作用已成为近年来研究的热点问题,前期实验结果显示在大鼠肝癌前病变模型中Notch1的表达是上调的[1].其在人肝癌发生和发展中的具体作用机制目前尚不清楚.本实验检测了Notch信号通路中的主要分子Notch1在人肝细胞癌的表达,并分析其与肝癌临床病理学参数的相关性,以期为深入理解Notch信号通路在肝癌发生和发展中的作用提供进一步的实验依据.     

整合素与肿瘤转移

肿瘤侵袭和转移是肿瘤的恶性标志和特征，也是导致肿瘤患者治疗失败和死亡的主要原因。阻断肿瘤细胞的侵袭和转移为治疗肿瘤患者提供了一条新途径。肿瘤转移是一个复杂的多步骤多环节的过程，它需要几条信号传导通路的协调工作，包括肿瘤细胞增生、周围环境改变、侵袭和转移及分化四个步骤。在肿瘤转移过程中发生许多肿瘤细胞和细胞外基质(ECM)的相互作用，整合素在此过程中发挥主要作用。因此，近年来对整合素的关注也越来越多。本文就整合素与肿瘤及肿瘤转移的关系结合近几年的研究作一综述。     

Notch信号通路在风湿性心脏病炎症相关发病机制中的研究进展

风湿性心脏病是一种以长期、反复发作的风湿性心瓣膜炎导致慢性心瓣膜损害的疾病.炎症在风湿性心脏病的发生和发展中起到了重要作用.通过近年来的研究发现,Notch信号通路与高血压、先天性心脏病如二叶式主动脉瓣、心瓣膜钙化以及室间隔缺损等疾病的发生和发展相关.Notch信号通路与淋巴细胞发育和增殖及炎症过程有密切关系,考虑Notch信号通路在风湿性心脏病的发生和发展中起的重要作用.     

KIFC3 Regulates the progression and metastasis of gastric cancer via Notch1 pathway

IntroductionKIFC3 is a member of the kinesin family which has shown great promise in cancer therapy recently. In this study, we sought to elucidate the role of KIFC3 in the development of GC and its possible mechanisms.MethodsTwo databases and a tissue microarray were used to explore the expression of KIFC3 and its correlation with patients’ clinicopathological characteristics. Cell proliferation was examined by cell counting kit-8 assay and colony formation assay. Wound healing assay and transwell assay were performed to examine cell metastasis ability. EMT and Notch signaling related proteins were detected by western blot. Additionally, a xenograft tumor model was established to investigate the function of KIFC3 in vivo.ResultsThe expression of KIFC3 was upregulated in GC, and was associated with higher T stage and poor prognosis in GC patients. The proliferation and metastasis ability of GC cells were promoted by KIFC3 overexpression while inhibited by KIFC3 knockdown in vitro and in vivo. Furthermore, KIFC3 might activate the Notch1 pathway to facilitate the progression of GC, and DAPT, an inhibitor of Notch signaling, could reverse this effect.ConclusionTogether, our data revealed that KIFC3 could enhance the progression and metastasis of GC by activating the Notch1 pathway.     

Role of Notch signaling pathway in gastric cancer: A meta-analysis of the literature

AIM: To perform a meta-analysis to quantitatively summarize the evidence for the association between the Notch signaling pathway and gastric cancer (GC).METHODS: An electronic search of the MEDLINE, EMBASE and Chinese National Knowledge Infrastructure, which contain articles published from 1966 onwards, was conducted to select studies for this meta-analysis.RESULTS: Fifteen studies with a total of 1547 gastric cancer cases and 450 controls were included in this meta-analysis. Overall, the expression of Notch1, Notch2, Delta-like 4 and Hes1 was significantly higher in tumor tissues of GC compared to normal tissues. Specifically, stratified analyses showed that significantly increased expression of Notch1 was associated with non-cardia location, > 5 cm size, diffuse type, positive lymphovascular invasion and distal metastasis. Statistically significant higher expression of Notch3 was found in diffuse type GC. Jagged1 was also significantly over-expressed in diffuse type and poor differentiation type of GC. DLL4 was significantly over-expressed in advanced T stage, N stage and TNM stage in GC patients. However, the stratified analysis showed that there was no statistically significant difference in Hes1 expression between different subgroups. Sporadic reports showed that Notch1 and Jagged1 were independent poor prognostic predictors in GC.CONCLUSION: The Notch signaling pathway plays an important role in tumor progression of gastric cancer.     

Notch signaling pathway and new strategies in cancer treatment

The Notch signaling pathway plays a crucial role at different stages of cell development, such as proliferation, growth, differentiation, and apoptosis. Recent studies demonstrate that depending on the expression level and cellular context, the Notch receptors play a role in apoptosis resistance in malignant cells. These findings suggest that Notch signaling components may be a potential target in the development of new cancer therapies. This review describes the function of the Notch pathway and new strategies in the modulation of its signal.     

miR-577通过介导Notch信号通路抑制肺癌细胞的增殖、侵袭和耐药性

目的研究miR-577通过介导Notch信号通路抑制肺癌细胞的增殖、侵袭和耐药性。方法RT-PCR检测肺癌组织和细胞以及配对的正常组织和细胞中miR-577的表达量;CCK-8测定miR-577对肺癌细胞A549增殖的影响;荧光素酶报告实验验证miR-577和Notch是否结合;Western blot检测A549细胞中Notch、DSL以及耐药蛋白P-gp和MRP1的蛋白表达水平。结果RT-PCR结果显示,miR-577在肺癌组织和细胞中的表达量显著低于正常组织和细胞中的表达量;过表达miR-577能够显著抑制肺癌细胞A549的增殖和侵袭,并降低细胞的耐药性;荧光素酶报告实验结果表明miR-577能够靶向结合Notch的启动子序列;Western blot结果显示miR-577能够抑制Notch和DSL的蛋白表达水平;进一步的机制探究结果表明miR-577可通过下调Notch和DSL的蛋白表达抑制A549细胞增殖、侵袭以及耐药性。结论miR-577能够抑制肺癌细胞A549增殖、侵袭以及耐药性的产生,其作用机制是通过介导Notch信号通路来实现的。     

Notch信号通路在肺部疾病中的研究进展

Notch信号通路存在于多种动物体内,无论是在无脊椎动物还是在脊椎动物中均可影响发育过程中多种细胞的分化、增殖和凋亡,在细胞命运的决定中起重要作用.新近研究发现,Notch信号通路参与多种肺部疾病的发生发展,阻断或激活这一途径可影响某些肺部疾病的进展,从而推断这一信号通路的抑制剂或激活剂可预防和治疗肺部疾病;因而近年来...     

Notch1信号通路对胃癌细胞增殖的影响

目的探讨Notch1信号通路对体外培养的胃癌细胞(BGC-823)增殖的影响,为胃癌的治疗提供新思路。方法将体外培养的胃癌细胞株BGC-823分为三组,空白组加入PBS缓冲液,激活剂组加入Notch1通路激活剂rh-NF-κB,抑制剂组加入Notch1通路抑制剂γ-secretase inhibitorⅡ。Western blot法检测各组Notch-1和Hes-1蛋白表达;MTT法检测细胞增殖情况;流式细胞仪检测细胞周期分布。结果与空白组比较,激活剂组Notch-1和Hes-1呈高表达、抑制剂组呈低表达;激活剂组细胞增殖减低,抑制剂组增殖旺盛;激活剂组S期胃癌细胞所占比例低,抑制剂组所占比例高。P均<0.05。结论 Notch1信号通路激活能抑制胃癌细胞增殖。     

Primers on Molecular Pathways — Notch

Notch, initially discovered and well characterized in Drosophila due to the notches apparent in the wing blades of mutant strains, and its signaling pathway play a key role in cell-cell communication, which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life, including timely cell lineage specification of both the endocrine and exocrine pancreas. This pathway serves as an excellent model signaling cascade for the regulation of the transition from normal ductal epithelium to metaplasia to cancer. In human pancreatic cancer, the change in epithelial differentiation programming is an early hallmark. Several of these changes, including activation of the Notch pathway, which are observed in pathological scenarios, are also seen during normal embryonic development of the pancreas. Notch receptors, ligands as well as downstream targets have been identified to be upregulated in preneoplastic lesions to invasive pancreatic cancers in humans and mice, suggesting that Notch signaling may be an early event leading to accumulation of undifferentiated precursor cells in pancreatic cancers.     

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular metabolism. Both hyper- and hypoactivated Notch induce a glycolytic phenotype in breast tumor cells, although by distinct mechanisms: hyperactivated Notch signaling leads to increased glycolysis through activation of the phosphatidylinositol 3-kinase/AKT serine/threonine kinase pathway, whereas hypoactivated Notch signaling attenuates mitochondrial activity and induces glycolysis in a p53-dependent manner. Despite the fact that cells with both hyper- and hypoactivated Notch signaling showed enhanced glycolysis, only cells with hyperactivated Notch promoted aggressive tumor growth in a xenograft mouse model. This phenomenon may be explained by that only Notch-hyperactivated, but not -hypoactivated, cells retained the capacity to switch back to oxidative phosphorylation. In conclusion, our data reveal a role for Notch in cellular energy homeostasis, and show that Notch signaling is required for metabolic flexibility.     

Contactin 1: A potential therapeutic target and biomarker in gastric cancer

Despite advances in diagnosis and treatment,gastric cancer remains one of the most common malignant tumors worldwide,and early diagnosis remains a challenge.The lack of effective methods to detect these tumors early is a major factor contributing to the high mortality in patients with gastric cancer,who are typically diagnosed at an advanced stage.Additionally,the early detection of metastases and the curative treatment of gastric cancer are difficult to achieve,and the detailed mechanisms remain to be fully elucidated.Thus,the identification of valuable predictive biomarkers and therapeutic targets to improve the prognosis of patients with gastric cancer is becoming increasingly important.Contactin 1(CNTN1),a cell adhesion molecule,is a glycosylphosphatidylinositolanchored neuronal membrane protein that plays an important role in cancer progression.The expression of CNTN1 is upregulated in primary lesions,and its expression level correlates with tumor metastasis in cancer patients.The current evidence reveals that the functions of CNTN1 in the development and progression of cancer likely promote the invasion and metastasis of cancer cells via the VEGFC/FLT4 axis,the RHOAdependent pathway,the Notch signaling pathway and the epithelial-mesenchymal transition progression.Therefore,CNTN1 may be a novel biomarker and a possible therapeutic target in cancer treatment in the near future.