Notch信号通路在肿瘤免疫中对巨噬细胞的调控作用

巨噬细胞依据不同的肿瘤微环境发挥促癌或抑癌作用,肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs往往与大部分肿瘤的不良预后相关。巨噬细胞如何成为TAMs以及TAMs如何与肿瘤细胞相互作用并影响肿瘤的发生发展是肿瘤研究中的热点问题之一。已证实Notch信号通路参与调控TAMs的分化和功能,但Notch信号如何调控TAMs并使其发挥促癌或抑癌的功能仍有待挖掘。因此,本综述总结了目前Notch信号通路对TAMs分化和功能调控以及对肿瘤微环境的影响,讨论了TAMs、肿瘤细胞以及肿瘤微环境中其他细胞之间通过Notch信号介导的直接或间接的相互作用。对巨噬细胞中Notch信号通路的深入研究将有助于研发出更有效的治疗肿瘤的免疫干预方法。     

Wnt与Notch信号通路的串话与肿瘤发生、发展的关系

肿瘤是危害人类健康与生命的常见疾病之一,其发病机制至今尚未完全探明.Wnt与Notch信号通路在生物体的生长发育中起着重要的调控作用,同时也都被证实与肿瘤相关.两条通路之间存在着许多直接或间接的串话.在肿瘤的发生发展中,二者间的相互作用取决于不同的组织背景,既可以表现为相互协同,也可以表现为相互拮抗.Wnt与Notch信号通路的串话与肿瘤的关系,在基础与临床肿瘤研究中都具有重大意义.本文对两条信号通路的组成、作用机制、相互作用,以及其串话与肺癌、皮肤癌、乳腺癌、白血病、黑色素瘤等肿瘤疾病间的关系进行了阐述与分析.     

Notch通路介导的microRNAs对肝癌干细胞的调节作用

肝癌干细胞(hepatic cancer stem cells,HSCs)是存在于肝细胞癌中的一类具有干细胞特性的细胞,与肝癌的形成、 生长、 转移、 药物耐受和复发有密切关系.microRNAs(miRNAs)是一种长约19~22 nt的短链非编码RNA,在细胞众多的生化活动中起着重要的调节作用,通过作用于细胞中关键信号通路的重要节点分子调控肿瘤的发生发展.而Notch信号通路是调控肿瘤干细胞自我更新、 增殖和分化过程的最重要的信号通路之一.miRNAs在Notch信号通路中的作用如何?miRNAs通过靶向作用于Notch信号通路进而发挥调控肝癌干细胞的自我更新、 分化及致癌性作用的机制是什么?这均是本文重点阐述的问题.     

长链非编码H19靶向调节miR-107通过Notch通路对肺癌的侵袭迁移的影响

目的：探讨长链非编码H19靶向调节miR-107通过Notch通路对肺癌的侵袭迁移的影响情况。方法：qPCR检测肺癌和癌旁组织、不同肺癌细胞中H19的表达情况;Transwell侵袭实验检测沉默H19后肺癌细胞侵袭能力的变化;划痕实验检测沉默H19后肺癌细胞迁移能力的变化;双荧光素酶报告基因检测H19与miR-107的相互作用;qPCR检测肺癌和癌旁组织、不同肺癌细胞中miR-107的表达情况;Transwell侵袭实验检测沉默H19后miR-107对肺癌细胞侵袭能力的影响;划痕实验检测沉默H19后miR-107肺癌细胞迁移能力的影响;裸鼠皮下成瘤检测沉默H19后miR-107对肺癌成瘤大小以及体积的影响。Western blot检测沉默H19后Notch通路蛋白的表达情况。结果：与癌旁组织相比,肺癌组织中H19表达明显增高;肺癌细胞A549中H19表达水平最高;沉默H19可以抑制肺癌细胞侵袭和迁移能力;H19能与miR-107的3′UTR特异性结合;与癌旁组织相比,肺癌组织中miR-107表达明显降低;沉默H19后,抑制miR-107可以促进肺癌细胞侵袭和迁移能力;与H19-siRNA组相比,H19-siRNA+miR-107-inhibitor组荷瘤小鼠肿瘤体积和重量都明显增大。沉默H19后Notch通路蛋白表达情况相应下调。结论：H19在肺癌发生发展过程中起重要作用,H19可以靶向调节miR-107通过Notch信号通路调控肺癌细胞的侵袭和迁移能力。     

Wnt和Notch信号通路在肿瘤干细胞自我更新中的作用

肿瘤干细胞是一类能够导致肿瘤发生的具有自我更新能力的细胞，它与干细胞具有很多相似性，其中最重要的一点是自我更新能力。它们具有相似的自我更新调节通路，如：Wnt，Notch和Shh(Sonic hedgehog)。Wnt和Notch信号通路通过其受体和配体的相互作用在自我更新的增殖和分化中都起着重要的作用，两者均能促进干细胞增殖而抑制其分化，但各自侧重不同。此外，Wnt和Notch信号通路之间相互作用、协调共同完成干细胞的自我更新。对肿瘤干细胞的Wnt和Notch信号通路研究将为未来肿瘤的靶向治疗提供新的方向。     

肿瘤细胞间相互作用:Notch-1信号转导与调控机制

Notch-1信号通路在细胞分化、发育以及增殖、凋亡方面起重要作用,并参与肿瘤的发生发展,与肿瘤的侵袭、运动和转移过程密切相关。活化的Notch-1信号通路能够直接或间接调控细胞的增殖和迁移,促进肿瘤细胞发生上皮细胞间充质转换,并维持其间充质特性,增强肿瘤细胞的黏附能力。同时,Notch信号通路与PI3K/Akt、NF-κB等途径交互作用,将信号级联放大,从而加强调控肿瘤细胞的恶性行为。多种实体瘤中存在异常活化的Notch-1信号通路。从Notch的结构和功能、Notch-1信号通路与肿瘤发生和转移的关系、Notch-1调控肿瘤转移的分子机制与调控网络和以Notch为靶点的肿瘤治疗5个方面进行综述。阐明Notch-1信号通路在肿瘤转移过程中的作用与调控机制以及目前针对Notch-1信号通路的治疗策略,能够为肿瘤的病理机制和临床治疗研究提供参考信息。     

Notch信号通路在骨重建中的作用

Notch信号通路在胚胎发育、神经系统、血管系统、内分泌系统及肿瘤等领域具有广泛的影响。近年来的研究表明,Notch对于骨组织代谢尤其是骨重建有着重要的调控作用,而骨重建的调节紊乱和骨质疏松、骨关节炎等疾病的进展密切相关。Notch信号通路可以通过调控骨组织不同细胞的功能从而影响骨重建过程,但其在不同细胞中具体的参与方式仍然未知。综述近年来Notch信号通路在骨重建中的作用研究进展。     

Notch信号通路与消化道肿瘤（文献综述）

一直以来，肿瘤严重危害着人类的健康，有关肿瘤发病机制、治疗靶标的研究也成为科学研究的重点和热点之一。自1919年Notch基因在对果蝇的研究中被发现以来，越来越多的研究表明，Notch信号通路的异常激活或构成性活化与多种组织的肿瘤形成有关。而作为常见的消化道肿瘤，其与Notch信号通路的研究也越来越多。现就目前Notch信号通路与消化道肿瘤关系的研究状况作一综述。     

肿瘤Notch信号通路的研究进展

Notch基因编码一类高度保守的细胞表面受体,决定胚胎发育和成熟组织中的细胞命运,是相邻细胞之间通讯进而调控细胞发育、增殖和凋亡的重要通路。多种肿瘤的发生与进展和Notch信号通路异常有关。针对不同肿瘤,有效调控靶向Notch的参与者与靶分子,对抗肿瘤治疗具有重要研究意义。     

Notch与Ras/MAPK信号通路在胚胎发育及肿瘤发生中的串话

Notch和Ras信号在生物进化过程中高度保守,参与细胞增殖、分化和凋亡等的调控。Notch和Ras信号通路的失调可导致胚胎发育异常和细胞的恶性转化等。在果蝇、线虫的发育及哺乳动物的肿瘤发生中这两条信号通路都存在大量串话,彼此之间可相互调节、协同或制约。在生物体发育过程中二者相互调节,经信号网络整合作用精确地调节细胞命运的选择,而在肿瘤发生中Notch与Ras可以促癌也可共同发挥抑癌作用。     

miR-34a通过Notch1信号通路对肺癌干细胞的抑制

BACKGROUND:It has been proved that miR-34a plays an inhibitory role in the growth of lung cancer stem cells, but the underlying mechanism remains unclear. OBJECTIVE:To explore the inhibitory effect of miR-34a on lung cancer stem cells and the underlying mechanism. METHODS:The CD133⁺ lung cancer stem cells were separated from lung cancer A549 cell lines using magnetic activated cell sorting method. And miR-34a-overexpressing CD133⁺ lung cancer stem cells were established by liposome transfection technology. Besides, the targeted relationship between miR-34a and Notch1 was analyzed by the dual-luciferase reporter. Afterwards, Notch1 silencing was performed by gene knockout, and its effect on lung cancer stem cells was determined. RESULTS AND CONCLUSION:After sorted and detected by immunomagetic selection and flow cytometry assay respectively, a high rate of CD133⁺ lung cancer stem cell was obtained. And qRT-PCR detected that the expression level of miR-34a in CD133⁺ lung cancer stem cells was significantly lower than that in CD133^- lung cancer stem cells. Moreover, miR-34a-overexpressing CD133⁺ lung cancer stem cells were successfully constructed and miR-34a significantly inhibited proliferation and induced apoptosis of lung cancer stem cells. Dual-luciferase reporter assay indicated that Notch1 mRNA was a target of miR-34a. In addition, Notch1 silencing obviously inhibited proliferation and induced apoptosis of lung cancer stem cells. These findings suggest that miR-34a can inhibite lung cancer stem cells via the Notch1 signaling pathway.     

BCYRN1 调控miR-503 通过Notch1 信号通路对肺癌迁移和侵袭的影响

目的:探讨BCYRN1 调控miR-503 通过Notch1 信号通路对肺癌迁移和侵袭的影响机制。方法:qPCR 检测不同肺癌细胞株中BCYRN1 和miR-503 的表达情况;免疫荧光和qPCR 检测慢病毒BCYRN1+siRNA 转染肺癌细胞的转染效率;双荧光素酶报告基因检测BCYRN1 与miR-503 的相互作用;Transwell 侵袭实验和划痕实验检测沉默BCYRN1 后肺癌细胞侵袭和迁移能力的变化;Western blot 检测沉默BCYRN1 后Notch1 信号通路蛋白的表达情况;裸鼠皮下成瘤检测沉默BCYRN1后肺癌细胞裸鼠体内成瘤能力的影响。结果:在肺癌细胞H1299 中BCYRN1 表达水平最高,miR-503 的表达水平相对较高;免疫荧光及mRNA 水平证明BCYRN1+siRNA 慢病毒可以有效转染进入H1299 细胞内;BCYRN19 能与miR-503 的3’-UTR 特异性结合;沉默BCYRN1 可以抑制肺癌H1299 细胞的侵袭和迁移能力;沉默BCYRN1 后Notch1 通路蛋白表达情况相应下调;与NC 组相比,BCYRN1-siRNA 组荷瘤小鼠肿瘤体积和重量都明显减小。结论:BCYRN1 可以靶向调节miR 503 通过Notch1 信号通路影响肺癌H1299 细胞的侵袭和迁移能力。     

miR-107 靶向NID2 通过Notch 信号通路调控肺癌细胞的增殖侵袭

目的:miR-107 靶向NID2 调控Notch 信号通路影响肺癌的侵袭和增殖。方法:免疫组化检测NID2 在肺癌组织和正常肺组织中的表达;PCR 检测miR-107 在肺癌组织中的表达;双荧光素酶报告基因系统检测miR-107 对NID2 转录活性的影响;肿瘤细胞成球实验检测miR-107 的表达对肺癌细胞A549 的增殖能力的影响;Transwell 侵袭实验检测miR-107 的表达对肺癌A549 细胞的侵袭能力的影响;划痕试验检测miR-107 的表达对肺癌A549 细胞的迁移能力的影响;Western blot 检测过表达miR-107 后Notch 信号通路的蛋白表达水平。结果:和正常肺组织比较,NID2 在肺癌组织中表达较高;miR-107 在肺癌组织中表达明显降低;双荧光素酶报告基因系统检测结果显示,miR-107 可以直接调控NID2 的转录活性;过表达miR-107 后,肺癌细胞A549 的增殖、侵袭和迁移能力明显降低;过表达miR-107 后,Notch1、hes-1、presenilin1 蛋白表达下调。结论:miR-107靶向NID2 的表达,通过Notch 通路调控肺癌细胞的增殖和侵袭能力。     

Notch1和Bmi-1蛋白在肺癌组织中的表达及意义

BACKGROUND: Studies have found that Notch pathway and Bmi-1 gene both have the ability to regulate stem cell self-renew. Functional dysfunction of the both may have a great relationship with tumorigenesis. OBJECTIVE: To investigate the expression and clinical significance of Notch1 and Bmi-1 protein in lung tissue. METHODS: Eighty-seven lung cancer tissue samples (lung cancer group) and forty pathologically confirmed normal lung tissue samples (normal group) were obtained from related surgeries and included as research objects. The protein expression of Notch1 and Bmi-1 in specimens of these two groups was measured by immunohistochemistry SP method. The relationship between Notch1 and Bmi-1 protein expression and clinicopathological features of lung cancer patients was analyzed. RESULTS AND CONCLUSION: The positive rate of Notch1, Bmi-1 protein expression was respectively 61% and 47%, which was significantly higher in the lung cancer group than that in the normal group (P < 0.05). In the lung cancer group, Notch1 protein expression was significantly positively correlated with Bmi-1 protein expression (r=0.567, P < 0.001). There were no significant differences in Notch1 and Bmi-1 protein expression rates between different genders and different pathological types of patients (P < 0.05). The Notch1 and Bmi-1 protein positive expression rates in poorly-differentiated, TNM stage III-IV lung cancer patients with lymph node metastasis were significantly higher than those in well- and moderately-differentiated, TNM stage I-II lung cancer patients without lymph node metastasis (P < 0.05). These results demonstrate that Notch1 and Bmi-1 protein may have certain relationship with the occurrence and development of lung cancer.       

Mechanisms of neuroendocrine differentiation in pulmonary neuroendocrine cells and small cell carcinoma

We review the significance of a network of proneural basic helix-loop-helix (bHLH) factors. Immunohistochemically, pulmonary neuroendocrine cells (PNECs) are positive for Mash1, one of the activator bHLHs, and non-PNECs such as Clara cells are positive for Hes1, one of the repressor bHLHs. Since mice deficient for the Mash1 gene do not possess PNEC and mice deficient for the Hes1 gene have many PNECs, it is suggested that a network of bHLHs work in cell fate determination of lung epithelium. Moreover, the Notch pathway could play a role in cell differentiation mechanisms in the lung because this signaling pathway has been reported to work in various tissues. PNECs have been reported to modulate various nonneoplastic human lung diseases. We demonstrate that PNECs in usual interstitial pneumonia and hASH1 (human homolog of Mash1) are upregulated in diseased lung tissues. Moreover, studies of small cell carcinoma and non-small cell carcinoma suggest that neuroendocrine differentiation could be regulated by hASH1. In non-small cell carcinoma, Hes1 and Notch signaling may have roles in maintaining cell differentiation. Thus, a network of bHLHs and Notch signaling are important in cell differentiation of normal and pathologic lung epithelial cells.     

Notch signaling pathway and human placenta

Notch signaling was evolutionarily conserved and critical for cell-fate determination, differentiation and many other biological processes. Growing evidences suggested that Notch signaling pathway played an important role in the mammalian placental development. All of the mammalian Notch family proteins had been identified in human placenta except Delta-like 3, which appeared to affect the axial skeletal system. However the molecular mechanisms that regulated the Notch signaling pathway remained largely unknown in human placenta. Therefore, additional research was needed to investigate expression pattern of Notch family members and the mechanisms for activation of Notch signaling pathway in human placenta, which might help elucidate the roles of Notch signaling pathway in human placentation. This review would focus on the roles of Notch receptors and ligands in the human placental trophoblasts function and placental angiogenesis. It might hopefully provide perspectives for future research about human placentation of pregnancy complicated by preeclampsia and other placenta associated diseases.     

Dichotomy of Notch signalling in regulating tumour immune surveillance

Notch signalling is an evolutionarily conserved multifaceted pathway that controls diverse cellular processes. Its role in regulating development and tissue homeostasis is well established. Aberrant activation of the Notch pathway has been implicated in the initiation and progression of many types of cancers. However, although in some cancers Notch signalling acts as a tumour‐promoter, in others it is reported to suppress tumour growth and progression. Accumulating evidence suggests the involvement of both the innate and adaptive immune system in the development of various tumours. Currently, extensive studies on investigating the effects of Notch signalling in tumour immune surveillance are being carried out. Interestingly, recent literature shows how the changing expression of Notch genes in different T cell subsets like CD4 and CD8 helps in controlling anti‐tumour immune responses. In this review, we discuss in depth the roles of Notch signalling molecules and different immune cells in the context of the tumour microenvironment. We also outline how current knowledge can be exploited to develop novel therapies in order to control the propagation of cancer stem cells.     

Notch signaling in stem cell systems

The Notch signaling pathway is among the most commonly used communication channels in animal cells. Recent studies have demonstrated that this pathway is indispensable for cells in various stages of maturation, including terminal differentiation. One main focus in mammalian studies is the role of Notch in embryonic and postembryonic stem cell systems. In this review, the roles of Notch signaling in various mammalian stem and early progenitor cells are summarized.     

Expression and significance of notch signaling pathway in salivary adenoid cystic carcinoma

Notch signaling plays a role in stem cell biology, tumor formation, angiogenesis, and cell death. Targeting Notch pathway could serve as a therapeutic strategy in cancer. Little is known about the differential role of various components of the Notch pathway in salivary adenoid cystic carcinoma (AdCC). To investigate the association of the Notch pathway in AdCC carcinogenesis, we analyzed the Notch receptor (Notch-1, Notch-2, Notch-4) and Notch ligand (Jagged-1, Delta) expressions. The results showed elevated expression levels of all 5 proteins in AdCC tissue relative to normal salivary gland tissues. Jagged-1/Notch-2 coexpression was significantly associated with increased patient survival rate. The elevated expression level of these Notch receptors and ligands in AdCC points to Notch signaling as a key player in AdCC pathogenesis. Our data provide evidence for a relationship between Jagged-1/Notch-2 coexpression and better overall patient survival with AdCC. Targeting Notch signaling pathway may provide therapeutic benefits for these patients.