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.     

Notch信号通路与乳腺癌发生关系的研究进展

1983年Artavanis Tsakonas研究组首次克隆了Notch基因,并发现其编码一类大的跨膜受体,即Notch受体.随后相继在线虫、爪蟾、鼠和人等多个物种体内发现其家族不同成员~([1]).Notch信号不仅影响细胞的增殖、分化、凋亡、黏附和上皮细胞-间叶细胞转变(epithelial-mesenchy maltransition,EMT)等活动,在胚胎发育、造血、血细胞发育、血管生成、某些神经系统疾病及肿瘤形成等生理病理过程中起着重要的作用~([1]).     

Notch信号通路在脑缺血的研究进展

Notch信号通路对中枢神经系统、血管细胞及免疫细胞生长分化发挥重要的调节作用.脑血管疾病引起的脑缺血激活Notch信号通路,活化的Notch信号通路调控神经前体细胞增殖和分化、介导炎症介质释放和促进血管细胞生成等在神经损伤修复、炎症反应、血管缺血区血管生成等起重要的调节作用.此外,Notch还与遗传性疾病CADASIL发病有关.本文就Notch信号通路在脑血管病中的作用及机制进行了分析.     

Notch信号通路研究进展

1917年,Morgan及其同事在果蝇体内发现一种基因,因其功能部分缺失可导致果蝇翅缘出现缺口,故命名该基因为Notch。随后的研究发现,Notch从无脊椎动物到脊椎动物的多个物种中表达,其家族成员的结构具有高度保守性,在细胞分化、发育中起着关键作用。迄今研究己阐明Notch信号通路的主要成员及核心转导过程,然而随着研究的深入,人们逐渐认识到该通路实际上处于十分复杂的调控网络之中,而这与其在发育过程中功能的多样性相符合。本文结合最新进展,系统阐述Notch信号通路的组成,功能,作用机制及调控,并揭示该通路异常与疾病的联系。     

Notch信号通路与神经干细胞的增殖分化

Notch信号通路是调节细胞增殖分化的一条古老的途径，传统观点认为它是通过“旁侧抑制”发挥作用的，近来许多研究表明，Notch系统也有激活和指导细胞分化的作用。神经干细胞是一种有自新能力的多能干细胞，是神经元和神经胶质细胞的共同前体细胞，对于它的研究是一个全新的领域。这一老一新的结合可使我们从一个不同以往的角度看待一些神经系统疾病，如Alzheimer′s病等疾病的发病机制和治疗方案。     

Notch 信号通路在银屑病发病机制中的研究进展

Notch 信号通路是一种高度保守的信号转导通路,在细胞的分化、发育和功能调节中发挥重要作用。近来研究表明,Notch 信号通路在银屑病的发生发展中扮演重要的角色。了解Notch 信号通路在银屑病中的作用将有助于阐明其发病机制,并为治疗提供新的选择。     

肝再生过程中Notch信号通路的研究进展

肝脏再生能力在各种病理状态下会受到不同程度影响,因此研究肝再生有助于解决肝源短缺的问题。肝再生过程受到多种信号通路的调控,其中Notch信号通路是进化中高度保守的信号转导通路,其调控细胞增殖、分化和凋亡的功能涉及几乎所有组织和器官。已有研究证实Notch信号通路在肝再生过程中可能具有重要作用,现就Notch信号通路在肝再生作用中的研究进展进行综述。     

Notch信号通路调控Th9的研究进展

Notch信号通路是一条高度保守的信号转导通路。该通路通过配体与受体之间的相互联系及与其他通路之间的相互影响,来调控Th9的分化、发育和IL-9的分泌。研究Notch信号通路对Th9的调控为恶性肿瘤、毛细支气管炎、哮喘等疾病的治疗及预防拓宽了思路,提供了新的方法。该文就近几年Notch信号通路对Th9的发育、分化及IL-9的产生等过程中的调控研究进展进行综述。     

Notch信号通路调控调节性T细胞分化与功能的研究进展

Notch信号通路在进化上十分保守,通过介导细胞之间的相互作用贯穿于机体的各项生命活动,精细地调控生长、发育、凋亡等过程的进行。调节性T细胞是一类表型和功能特异的T细胞亚群,通过与靶细胞直接接触或分泌抑制性细胞因子的方式在维持机体免疫稳态中起重要作用。本文重点对Notch信号通路调控调节性T细胞分化与功能的研究进展进行综述。     

Notch信号通路与神经干细胞的增殖分化

Notch信号通路是调节细胞增殖分化的一条古老的途径,传统观点认为它是通过“旁侧抑制”发挥作用的,近来许多研究表明,Notch系统也有激活和指导细胞分化的作用。神经干细胞是一种有自新能力的多能干细胞,是神经元和神经胶质细胞的共同前体细胞,对于它的研究是一个全新的领域。这一老一新的结合可使我们从一个不同以往的角度看待一些神经系统疾病,如Alzheimer's病等疾病的发病机制和治疗方案。     

Association of Notch1 with vasculogenic mimicry in human hepatocellular carcinoma cell lines

Background and aims: According to recent findings, some tumor cells function as endothelial progenitor cells to initiate tumor vasculogenesis, known as “vasculogenic mimicry” (VM). Notch1, the key regulator of vasculogenesis and embryonic differentiation, has shown a correlation with a poor prognosis in hepatocellular carcinoma (HCC). We attempted to elucidate the relationship between Notch1 and the vascularization of HCC. Materials and methods: HCC cell lines were assayed for tube formation and low-density lipoprotein (LDL) absorption. The translation level of targets of interest was verified using western blot. Notch1 was silenced in HepG2, BEL-7402 and HCCLM6 using lentivirus shRNA. A hypoxic culture was conducted in an anaerobic culture chamber to induce VM in HepG2. Samples from 53 patients with HCC, i.e., 5 with metastasis and 48 without were tested for Notch1⁺ cells and CD34 negative plus Periodic Acid-Schiff (PAS) positive structures, respectively. Results: BEL-7402 and HCCLM6 were capable of tube formation and LDL absorption in vitro, while HepG2 was negative for both. Notch1 down-regulation suppressed endothelial marker expression and greatly impaired tube formation. After hypoxic culture, the tube formation capacity of HepG2 was significantly enhanced, along with an increase in Notch1 expression. Notch1 was strongly and profusely expressed in all 5 cases of distant metastasis, while 19 of the 48 cases without metastasis were sparsely positive (P < 0.05). Notch1 positivity was mainly seen in the cytoplasm and nuclei. VM structures were only found in 2 cases from the metastasis group (P < 0.05). Conclusions: HCC is capable of VM. Notch1 might serve as a potential target for VM development in HCC.     

Gamma-secretase complex-dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

The γ-secretase complex is a presenilin-dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ-secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ-secretase complex inhibitor and CD147-directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ-secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Notch signaling in lymphocyte development

Cytokine and antigen receptor signals play well-characterized roles in promoting the survival and maturation of T and B lymphocyte progenitors through sequential developmental stages. Emerging studies suggest equally important roles for more ancient signaling pathways that evolved prior to the adaptive immune system in jawed vertebrates. In particular, there are at least two essential functions for the highly conserved Notch signaling pathway in lymphocyte development. First, Notch signals are essential for the development of T cell progenitors in the thymus and intestinal epithelium. Second, Notch signals are required to suppress B cell development in the thymus. This review will focus on focus on recent advances in our understanding of how Notch signaling regulates this developmental switch, as well as how Notch might regulate subsequent survival and cell fate decisions in developing T cells.     

Notch signaling in oral squamous neoplasia

Notch signaling is involved in cell–cell communication. It is an evolutionarily ancient mechanism and plays a fundamental role in development. The typical function of Notch signaling is the regulation of cell fate segregation at asymmetric division; however, a role in tumorigenesis has also been suggested. Inactivating mutations of NOTCH1 are present in about 10 % of cases of squamous cell carcinoma of the skin, oral cavity, esophagus, and lung, rendering it one of the most frequently mutated genes in squamous cell carcinoma. Mouse knockout studies have demonstrated that Notch1 is imperative for early development but is dispensable for formation of the squamous epithelium. However, loss of Notch signaling predisposes the epidermis to hyperplasia and increases tumor incidence. This tumor‐inducing effect resulting from the loss of Notch signaling is associated with non‐cell‐autonomous effects that are elicited by subtle alteration of epithelial cell features, generating a wound‐like microenvironment in the underlying stroma. We found that Notch1 was expressed specifically in the basal cells of the oral squamous epithelium. In cancer and oral epithelial dysplasia, it was significantly downregulated, suggesting that reduced Notch activity plays a distinct role in oral neoplasia.     

细胞外基质刚度在肝细胞癌中的研究进展

肿瘤微环境在肿瘤的发生发展中起着重要的作用,其主要的组成部分是细胞外基质,这是一个复杂的大分子网络,具有独特的物理、生化和生物力学特性。越来越多的证据表明刚度作为细胞外基质的重要生物力学属性,对肝癌细胞的生物学行为产生重要影响。具体表现在高基质刚度增强肝癌细胞的化疗耐药性、增殖及侵袭转移的能力,但是低基质刚度促进肝癌细胞干性相关标志物的表达,并且增强化疗后细胞克隆启动能力。了解基质刚度是如何影响肿瘤进展有助于开发针对肿瘤微环境的治疗干预手段。     

Notch信号通路与心血管发育的关系

Notch信号通路在脊椎动物和无脊椎动物中高度保守,它在决定细胞的分化上起重要作用。Notch信号通路由受体、配体和核效应物三部分组成。它对正常心血管系统的发育有重要作用,Notch信号表达不足或者过量都会造成动物因心血管异常而死亡。正常情况下,Notch信号抑制胚胎干细胞向心肌细胞的分化。此外,Notch信号在动静脉分化中也具有重要作用,它能促进前体细胞向动脉细胞发育。     

Notch1通过非经典的Notch信号通路调节胰腺星形细胞的活化

目的:探讨Notch1在胰腺星形细胞(pancreatic stellate cells,PSCs)活化中的作用。方法:利用免疫组织化学法与免疫荧光双标法检测Notch1在人胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDAC)组织的表达情况;原代分离培养小鼠PSCs,利用油红O染色、Western blot及RT-qPCR法对其进行鉴定,并利用Western blot及RT-qPCR检测Notch1及其下游关键分子HES1的表达情况;转染Notch1小干扰RNA(Notch1 siRNA)至小鼠PSCs后,利用Western blot检测α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)、纤连蛋白(fibronectin)、I型胶原(collagen typeⅠ,ColⅠ)、Notch1及HES1的表达情况;利用划痕实验与CCK-8实验检测Notch1 siRNA对小鼠PSCs迁移与细胞活力的影响。结果:免疫组化与免疫荧光双标染色结果显示,Notch1表达在α-SMA阳性的PDAC间质细胞中;成功培养了小鼠PSCs细胞,且...     

Mechanisms of ligand‐mediated inhibition in Notch signaling activity in Drosophila

The transmembrane proteins Delta and Serrate act as ligands for the signaling receptor Notch. In addition to this activating role, Delta and Serrate can also inhibit Notch signaling activity. This inhibitory effect is concentration‐dependent and appears to be evolutionarily conserved. In characterizing the underlying cellular mechanisms of the ligand inhibitory effect, we can confirm that ligand‐mediated inhibition of Notch signaling can occur as a cell autonomous process (cis‐inhibition) and that ligand‐mediated inhibition prevents a step in Notch signaling activation early enough to suppress Notch ectodomain shedding. Developmental Dynamics 239:798–805, 2010. © 2010 Wiley‐Liss, Inc.