mTOR信号通路与肾上腺肿瘤发生发展的关系进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)是一种丝/苏氨酸蛋白激酶,是细胞内调控生长、增殖的中心信号分子,与肿瘤发生、发展关系密切.近年发现,m TOR信号通路在肾上腺肿瘤的发生发展中扮演重要角色.许多研究证实,PI3K/Akt/m TOR信号通路的关键蛋白Akt、m TOR、S6K1、4EB-P1的磷酸化水平在肾上腺皮质癌(adrenocortical carcinoma,ACC)和嗜铬细胞瘤(pheochromocytomas,PCC)中均明显高于正常肾上腺组织,且可能与肾上腺肿瘤的恶性转化相关.胰岛素样生长因子2基因的杂合性缺失、PTEN的生殖系突变、微小RNA表达异常均可激活PI3K/Akt/m TOR信号通路,使得血管内皮生长因子、细胞周期蛋白等分子过表达,从而产生抑凋亡、促增殖、促血管形成等效应,使组织呈现出肿瘤特征,并促进肿瘤的侵袭和转移.目前,细胞和动物模型研究已证实m TOR抑制剂对ACC与PCC有良好的疗效,且联合其他抗癌药物治疗效果更佳,这给肾上腺肿瘤患者的治疗带来了新的希望.本文总结了近年来m TOR信号通路与肾上腺肿瘤发生、发展的关系进展,希望为肾上腺肿瘤的机制研究及临床治疗提供实验室依据.     

mTOR 信号通路在糖代谢中作用

哺乳类动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)是一种高度保守的丝氨酸-苏氨酸类激酶,通过在体内形成两种不同的复合体对机体生长、代谢产生调控作用。m TOR信号分子可对多种营养信号作出应答而成为细胞内重要的能量感受分子。近年来研究发现能量感受分子m TOR与糖代谢关系密切,可以通过影响胰岛素信号通路、胰岛β细胞发育以及调控ghrelin、nesfatin-1等代谢调节激素的合成分泌等多种途径对糖代谢产生影响。本文就m TOR信号通路及其在糖代谢乃至于糖尿病发生过程中作用作一综述。     

miRNA靶向mTOR相关信号通路对肿瘤的影响

miRNA是一类含有22个nt左右的内源性短小非编码RNA,可作用于mRNA使之降解或者抑制翻译来调节靶基因的表达。哺乳动物雷帕霉素靶蛋白(mammals target of rapamycin,mTOR)是一种丝/苏氨酸蛋白激酶,近年来有研究表明mTOR集成了多个信号通路控制着有机体的生长和体内平衡。目前,大量研究表明miRNA能靶向mTOR相关信号通路对肿瘤产生影响。因此,本文主要探讨m TOR相关信号通路与肿瘤的关系,综述miRNA靶向m TOR相关信号通路对肿瘤的影响,旨在为肿瘤的靶向性治疗提供更好的理论依据。     

mTOR信号通路在乳脂合成中的调控作用

乳脂肪含量与组成是构成牛奶重要营养品质的主要物质基础之一。牛乳脂肪的主要成分是甘油三酯,乳腺细胞以细胞内合成和胞外摄取两种形式获得脂肪酸并进一步合成甘油三酯。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)是一个进化上十分保守的蛋白激酶,与其他蛋白一起组成m TOR信号通路,通过感受细胞内外的营养状况进而调控细胞生长和代谢,在乳脂合成中发挥重要作用。综述了m TOR信号通路在乳脂合成中的作用与机制,并结合研究现状展望了未来研究热点。     

PI3K/Akt/mTOR信号通路与自噬及肿瘤的关系北大核心CSCD

自噬是一种以胞质内出现双层膜结构包裹长寿命蛋白和细胞器的自噬体为特征的细胞"自我消化"过程,在维持细胞内稳态、发育、肿瘤发生和感染中发挥重要作用。近来,诸多研究表明,自噬作为一把"双刃剑",对肿瘤的发生发展既有促进作用,也有抑制作用。PI3K/Akt/m TOR通路由PI3激酶(PI3K)、蛋白激酶B(PKB/Akt)和哺乳动物类雷帕霉素靶蛋白(m TOR)3个作用分子组成,是一个中心的调节机构,对肿瘤细胞的生长与增殖有促进作用,同时对自噬进行抑制。本文就PI3K/Akt/m TOR通路与自噬及肿瘤发生发展的关系作一综述。     

Hedgehog信号通路的作用机制及研究进展

HH(Hedgehog)信号通路参与多种生物学过程,包括细胞分化、细胞增殖、细胞衰老、肿瘤的发生、肿瘤恶性转化以及肿瘤耐药,HH信号通路相关基因的异常表达或突变会在生物发生发展的不同阶段引起各种疾病的发生。而HH信号通路通过复杂的机制调控诸多信号通路,进一步影响生物体的功能。所以深入了解HH信号通路在各种遗传疾病、肿瘤发生发展以及化疗耐药发展过程中的作用,将有利于进一步发现和研究疾病治疗靶点。该文中,我们概述了HH信号通路,以及HH信号通路在癌症发生发展、发育以及衰老中的作用机制,可为针对HH信号通路的治疗方法研究提供理论依据。     

结直肠癌中Hedgehog信号通路的研究进展

结直肠癌(colorectal cancer, CRC)是全球最常见的恶性肿瘤之一,其病因复杂且死亡率较高。结直肠癌的发展和转移涉及多个因素和机制。Hedgehog(Hh)信号在胚胎发生和体细胞发育中起重要作用。研究证明,Hh通路的异常激活与几种类型的人类肿瘤有关。然而,Hh信号传导在结直肠癌中的作用仍然是有争议的。在此综述中,我们将介绍近些年关于Hh信号及其在结直肠癌中的相关研究,讨论靶向Hh信号通路在治疗,预后和预防结直肠癌方面的潜力。     

结肠癌干细胞:信号通路抑制剂与肿瘤耐药性

作为当前威胁人类生命的常见癌症之一,结肠癌的复发与转移严重影响了患者的预后,而近年来肿瘤干细胞理论的兴起则为肿瘤治疗提供了全新的思路。在结肠癌中,结肠癌干细胞不仅参与肿瘤的复发与转移,同时,还能引起癌细胞对化疗药产生耐药性。因其生长依赖于多种信号通路的作用,故靶向结肠癌干细胞生长所需的信号通路将成为未来根治结肠癌的重要研究方向。现就目前关于结肠癌干细胞信号通路的分子靶向抑制剂研究进展及结肠癌干细胞与化疗药耐药性的关系作一综述。     

淋巴瘤发病机制与相关信号通路研究

淋巴瘤作为一类原发于淋巴结或结外淋巴组织的恶性肿瘤,其发生和发展机制至今尚未完全阐明。目前的研究表明淋巴瘤的发生、发展、预后和耐药等方面与很多信号通路密切相关。本文对目前淋巴瘤的研究进行系统梳理,剖析归纳与淋巴瘤发病机制密切相关的信号通路,包括经典Wnt/β-catenin信号通路、细胞核转录因子κB(NF-κB)信号通路、JAK-STAT信号通路、PI3K-Akt-m TOR信号通路、PD-1/PD-L信号通路、c AMP信号通路、Notch信号通路、Hedgehog信号通路和MAPK/Erk信号通路,为进一步深入地寻求淋巴瘤的研究和治疗策略提供依据。     

结肠癌干细胞标志物和信号通路的研究进展

结肠癌是一种最常见的消化道恶性肿瘤,世界范围内其发病率位列第三。大部分的结肠癌患者死亡由肿瘤的复发转移和耐药性所致,而这些过程都有肿瘤干细胞的参与。因此,靶向肿瘤干细胞将成为未来根治结肠癌的重要研究方向,而结肠癌干细胞标志物的发现则为其提供了新思路。同时,因结肠癌干细胞的生长依赖多种信号通路的作用,故其相关信号通路靶向药物的研究也将是一大发展方向。该文就目前关于结肠癌干细胞标志物及其相关信号通路抑制剂的研究进展作一综述。     

Wnt/beta-catenin signaling inhibits death receptor-mediated apoptosis and promotes invasive growth of HNSCC

The Wnt/beta-catenin signaling pathway plays a critical role in cell proliferation and oncogenesis. It has been found to be chronically activated in a variety of human cancers, including head and neck squamous cell carcinoma (HNSCC). Previously, we have found that the activation of the Wnt/beta-catenin signaling pathway inhibits mitochondria-mediated apoptosis. In this study, we extended our studies to determine whether the Wnt/beta-catenin signaling pathway inhibited death receptor-mediated apoptosis in HNSCC cells. We found that Wnt/beta-catenin inhibited not only tumor necrosis factor (TNF)/c-Myc-mediated apoptosis, but also cell detachment-mediated apoptosis (anoikis) which is dependent on the death receptor signaling pathway. Interestingly, we also observed that the Wnt/beta-catenin signaling pathway induced HNSCC cell scattering and promoted cell invasion in the Matrigel, both of which are hallmarks for the invasive growth of HNSCC. Consistently, the over-expression of beta-catenin promoted HNSCC tumor growth in nude mice. Taken together, our results suggest that the Wnt/beta-catenin signaling pathway plays dual functions in HNSCC development: promoting both cell survival and invasive growth of HNSCC cells.     

SDF-1alpha promotes invasion of head and neck squamous cell carcinoma by activating NF-kappaB

CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), a chemokine ligand for the G protein-coupled receptor CXCR4, plays an important role in the directed movement of cells. Many studies have documented the importance of CXCR4 in tumor progression and organ-specific metastasis. Recently, several studies have implicated a role for SDF-1alpha in head and neck squamous cell carcinoma (HNSCC) metastasis, but currently there is little information about how SDF-1alpha promotes HNSCC metastasis. In this report we show that the NF-kappaB signaling pathway is activated in response to SDF-1alpha in HNSCC while primary and immortalized keratinocytes show no SDF-1alpha-mediated NF-kappaB activity. We found that SDF-1alpha-mediated NF-kappaB signaling is independent of phosphoinositide 3-kinase/Akt and ERK/MAPK pathways. We observed that SDF-1alpha induces IkappaBalpha phosphorylation and degradation and the nuclear translocation of NF-kappaB in HNSCC cell lines, suggesting that SDF-1alpha activates the classical NF-kappaB signaling pathway. Contrary to previous reports, SDF-1alpha-induced NF-kappaB activation is not mediated by tumor necrosis factor alpha. Furthermore, blocking the NF-kappaB signaling pathway with an IKKbeta inhibitor significantly reduces SDF-1alpha-mediated HNSCC invasion. Taken together, our data suggest SDF-1alpha/CXCR4 may promote HNSCC invasion and metastasis by activating NF-kappaB and that targeting NF-kappaB may provide therapeutic opportunities in preventing HNSCC metastasis mediated by SDF-1alpha.     

Targeting the mTOR Signaling Network for Alzheimer’s Disease Therapy

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that can sense environmental stimuli such as growth factors, energy state, and nutrients. It is essential for cell growth, proliferation, and metabolism, but dysregulation of mTOR signaling pathway is also associated with a number of human diseases. Encouraging data from experiments have provided sufficient evidence for the relationship between the mTOR signaling pathway and Alzheimer’s disease (AD). Upregulation of mTOR signaling pathway is thought to play an important role in major pathological processes of AD. The mTOR inhibitors such as rapamycin have been proven to ameliorate the AD-like pathology and cognitive deficits effectively in a broad range of animal models. Application of mTOR inhibitors indicates the potential value of reducing mTOR activity as an innovative therapeutic strategy for AD. In this review, we will focus on the recent process in understanding mTOR signaling pathway and the vital involvement of this signaling pathway in the pathology of AD, and discuss the application of mTOR inhibitors as potential therapeutic agents for the treatment of AD.     

哺乳动物雷帕霉素靶蛋白（mTOR）在不同发育阶段SD大鼠睾丸中的表达及作用

精子发生是男性生殖中的主要过程,精原细胞的不断分裂增殖又保证了精子发生的顺利进行。随着年龄的不断增长,男性精子的数量、质量出现下降趋势。mTOR信号转导通路在细胞增殖分化中发挥着中心调控作用,因此,mTOR信号通路可能在精子发生过程中有着重要的地位。为了探明mTOR信号通路与精子发生的关系,首先,通过SD大鼠睾丸组织切片的免疫组化,发现mTOR是在生精小管的精原细胞胞浆中表达;其次,采用FQ-PCR检测mTOR mRNA在SD大鼠睾丸中的表达。结果显示,80周龄组mTOR的转录与8周龄组相比差异显著。最后利用Western blot检测出mTOR蛋白的表达及其对下游靶蛋白P70S6K的磷酸化效率均随年龄的增长逐渐下降。同时,在用雷帕霉素处理8周龄SD大鼠中,发现精子数量减少,P70S6K磷酸化效率降低并伴随生精小管萎缩和空泡化。通过这些结果,可以看出mTOR信号转导通路可能在精子发生中发挥着重要作用。     

The exploration of new therapeutic targets for HPV-negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis

Previous studies have shown that human papillomavirus (HPV)-negative patients with head and neck squamous cell cancer (HNSCC) suffer from an unsatisfactory prognosis. Long noncoding RNAs (lncRNAs) have been verified to participate in many biological processes, including regulating gene expression as competing endogenous RNAs (ceRNAs), while few studies focused the ceRNA network regulation mechanism in patients with HPV-negative HNSCC tumor. Meanwhile, the immune microenvironment may be critical in the development and prognosis of HPV-negative tumors. Our study aimed to further investigate the pathogenesis and potential biomarkers for the diagnosis, therapy and prognosis of HPV-negative HNSCC through a ceRNA network. Comprehensively analyzing the sequencing data of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in The Cancer Genome Atlas HNSCC dataset, we constructed a differentially expressed ceRNA network containing 131 lncRNAs, 35 miRNAs and 162 mRNAs. Then, survival analysis in the network was cited to explore the prognostic biomarkers. Eight mRNAs, nine lncRNAs, and one miRNA were identified to be associated with prognosis. Neuropilin (NRP) binding function, retinoid X receptor (RXR) binding, and the vascular endothelial growth factor (VEGF) signaling pathway were associated with the enrichment analysis, and they also related to the immune microenvironment. Combined with the analysis of the immune microenvironment differences, we obtained new targeted therapies using an RXR agonist, or a combination of the VEGF monoclonal antibody and an NRP antagonist, which may provide a promising future for HPV-negative HNSCC patients.     

Mammalian target of rapamycin: master regulator of cell growth in the nervous system

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our current understanding of the mTOR signaling pathway and its role in promoting ribosome biogenesis and cell growth. We suggest that studies of this pathway may prove useful in identifying molecular targets for biologically-based therapies of brain tumors associated with these inherited cancer syndromes as well as sporadic central nervous system tumors.     

Correlation of the AKT/mTOR signaling pathway with the clinicopathological features and prognosis of nasopharyngeal carcinoma

The primary aim of this study was to examine the correlation of the AKT/mTOR signaling pathway with the clinicopathological features and prognostic significance in nasopharyngeal carcinoma (NPC). The study tissues were collected from 285 patients with NPC and normal mucosal tissues were obtained from 289 individuals with normal nasopharynxes. Immunohistochemical staining was used to detected the expression of the AKT, mTOR, and p70 ribosomal S6 kinase (P70S6K) proteins. Follow-up was performed for between 8 and 60 months. Spearman’s rank correlation analysis was performed to evaluate the correlation of the expression of the AKT, mTOR, and P70S6K proteins in NPC tissues. Kaplan-Meier curves were plotted to show the survival of patients with NPC. A Cox proportional hazards model was used to explore the independent risk factors for prognosis. The expression of the AKT, mTOR, and P70S6K proteins in NPC tissues was higher than that in healthy nasopharyngeal mucosal tissues, and was correlated with T-staging, N-staging, clinical stage, distant metastasis, and differentiation. The positive expression of the AKT, mTOR, and P70S6K proteins was higher in patients with stage III/IV NPC, low differentiation, and metastasis. The survival rates of patients with NPC with AKT-positive, mTOR-positive, and P70S6K-positive expression were considerably lower than those without the expression of these proteins. Distant metastasis and the overexpression of the AKT, mTOR, and P70S6K proteins were independent risk factors for the prognosis of patients with NPC. The results obtained from this study indicated an association between the AKT/mTOR signaling pathway and the progression of NPC. The upregulation of the AKT/mTOR pathway in patients with NPC is a predictor of poor prognosis.Key words: AKT, mTOR, P70S6K, nasopharyngeal carcinoma, prognosis     

Knockdown of β-catenin controls both apoptotic and autophagic cell death through LKB1/AMPK signaling in head and neck squamous cell carcinoma cell lines

The Wnt/β-catenin pathway regulates the viability and radiosensitivity of head and neck squamous cancer cells (HNSCC). Increased β-catenin predisposes HNSCC patients to poor prognosis and survival. This study was conducted to determine the mechanism by which β-catenin regulates the viability of HNSCC. AMC-HN-3, -HN-8, UM-SCC-38, and -SCC-47 cells, which were established from human head and neck cancer specimens, and underwent cell death following β-catenin silencing. β-Catenin silencing significantly induced G1 arrest and increased the expression of Bax and active caspase-3, which demonstrates the sequential activation of apoptotic cascades following treatment of HNSCC with targeted siRNA. Intriguingly, β-catenin silencing also induced autophagy. Here, we confirm that the number of autophagic vacuoles and the expression of type II light chain 3 were increased in cells that were treated with β-catenin siRNA. These cell death modes are most likely due to the activation of LKB1-dependent AMPK following β-catenin silencing. The activated LKB1/AMPK pathway in AMC-HN-3 cells caused G1 arrest by phosphorylating p53 and suppressing mTOR signaling. In addition, treating AMC-HN-3 cells with LKB1 siRNA preserved cell viability against β-catenin silencing-induced cytotoxicity. Taken together, these results imply that following β-catenin silencing, HNSCC undergo both apoptotic and autophagic cell death that are under the control of LKB1/AMPK. To the best of our knowledge, these results suggest for the first time that novel crosstalk between β-catenin and the LKB1/AMPK pathway regulates the viability of HNSCC. This study thus presents new insights into our understanding of the cellular and molecular mechanisms involved in β-catenin silencing-induced cell death.