热休克蛋白27 在肿瘤中的研究进展

热休克蛋白27(HSP27)作为热应激蛋白表达于各种生理或是环境损伤之后,保护细胞生存,其具有多种功能包括:分子伴侣,抗凋亡,参与细胞运动等。近年来发现HSP27在多种肿瘤中过度表达,参与肿瘤的发生发展,分化,耐药以及转移等方面,因而抑制HSP27成为一种新的肿瘤治疗策略。本文就相关研究进展进行综述。     

热激蛋白27的性质及生理功能

热激蛋白（heat shock protein,HSP）是广泛存在于生物体内、在生物进化过程中序列高度保守的蛋白质家族。HSP27是HSP家族中的重要一员,在机体应激的情况下表达增加,通过分子伴侣作用、抗细胞凋亡和抗氧化应激等作用保护细胞,同时HSP27与多种临床疾病密切相关。     

HSP27对细胞迁移的调控

细胞迁移是多细胞生物的一项基本生理过程,不仅在血管重建、炎症反应、发育、伤口愈合等方面发挥重要作用,而且还与肿瘤细胞侵袭和转移有关.热休克蛋白27(heat shock protein27,HSP27)是小型热休克蛋白家族中研究最广泛的成员之一,普遍存在于生物体内.HSP27是一种多功能蛋白质,可以通过黏着斑和肌动蛋白调节细胞迁移.另外,HSP27还可调控肿瘤早期的上皮间质转化,影响癌症转移.本文整理了近期关于HSP27参与细胞迁移及相应的肿瘤细胞转移方面的研究,探究HSP27在临床医学研究领域的价值和应用前景.     

热激蛋白27的性质及生理功能

热激蛋白(heat shock protein,HSP)是广泛存在于生物体内,在生物进化过程中序列高度保守的蛋白质家族.HsP27是HSP家族中的重要一员,在机体应激的情况下表达增加,通过分子伴侣作用、抗细胞凋亡和抗氧化应激等作用保护细胞,同时HSP27与多种临床疾病密切相关.     

心血管系统热休克蛋白的研究进展

多种应激因素如热应激,缺血,血流动力学变化能引起细胞内代谢异常,细胞骨架紊乱等一系列的病理改变,同时细胞亦相应合成一系列分子量不同的热休克蛋白分子（HSPs)。研究表明,HSPs通过其分子伴侣功能,对细胞产生保护作用。近年来的研究发现,在心肌缺血,缺血预处理,心肌肥大和血管损伤等病理生理条件下,HSP70,HSP90,HSP47,HSP32,HSP27等热休克蛋白分子均参与心血管系统的保护作用。     

热休克蛋白27增强A型流感病毒NS1对β干扰素的抑制作用

热休克蛋白27(Heat shock protein 27,HSP27)是一种具有多重功能的小热休克蛋白,它在一些病毒的生命周期中也发挥着重要作用。为研究HSP27对流感病毒感染的调节作用,首先在原核及真核细胞中克隆并表达了人源的HSP27蛋白,并验证了HSP27和A型流感病毒NS1蛋白能够相互结合。通过荧光素酶检测试验发现,HSP27可以抑制病毒感染细胞中β干扰素(IFN-β)的表达,但不依赖于其自身的磷酸化状态,而且HSP27与NS1共同对于IFN-β的表达具有叠加抑制效果。进一步的结果表明HSP27可能通过RIG-I样RNA解旋酶(RLH)途径中MDA5因子抑制IFN-β的表达。研究表明,HSP27在被感染细胞的天然免疫中发挥一定作用,有助于进一步阐明宿主因子对于流感病毒感染的调节机理。     

HSP90及其抑制剂对肿瘤免疫反应的影响

HSP90作为一种热休克蛋白参与调控蛋白质的正确折叠、装配和水解等多种生理过程,其在肿瘤组织中异常表达与活化,与恶性肿瘤的发生发展密切相关,是肿瘤药物研发的重要靶标,目前已有多个HSP90抑制剂进入临床研究。近年来研究发现,HSP90在调控机体固有性免疫和适应性免疫反应中也发挥着重要的作用,包括抗原呈递、T细胞、NK细胞活化和DC(树突状细胞)的成熟,以及肿瘤微环境的免疫抑制等。抑制HSP90导致免疫抑制和免疫激活双重反应,因此,HSP90在机体免疫中作用复杂,有待人们进一步研究。本文主要综述了HSP90及其抑制剂与肿瘤免疫之间的联系,为今后相关研究人员的工作提供参考。     

HSP90细胞质亚型的分子结构、功能及与疾病的关系

哺乳动物HSP90蛋白家族是一组高度保守、参与多种细胞进程的蛋白分子。它们广泛分布在各种细胞中,并在维持细胞稳态中发挥重要作用。HSP90有两种细胞质亚型,分别为HSP90α(可诱导型)和HSP90β(组成型)。病理条件下,HSP90表达失常会影响某些疾病的发生与进展,如癌症和神经退行性疾病等。因此,靶向不同的HSP90细胞质亚型在肿瘤和其他疾病的治疗方面具有巨大的潜在价值,本文对HSP90细胞质亚型的分子结构、功能及其在病理生理学中的潜在作用进行综述。     

热休克蛋白对细胞凋亡信号转导途径的调节

细胞凋亡信号转导目前已迅速成为揭示细胞凋亡分子机制的前沿课题. 由于热休克蛋白(HSPs)在细胞生长调控和凋亡中发挥的重要作用, 人们进行了大量关于热休克蛋白与细胞凋亡信号转导途径调节机制的研究. 研究发现, 热休克蛋白家族的多个成员, 如HSP90, HSP70, HSP60, HSP27等能够在Fas死亡受体途径、JNK/SAPK途径、caspase途径等多个水平发挥调节作用, 并且部分依赖于热休克蛋白的“分子伴侣”作用, 控制着细胞生命进程.     

植物热激蛋白70

植物热激蛋白70(HsP70)由多基因家族编码.除热胁迫外,其它环境因素如低温、干旱等也能诱导HSP70基因的大量表达.HSP70主要参与新生肽的成熟与分拣、变性蛋白的复性或降解等细胞活动.该文介绍HSP70的结构、功能和调控的研究现状.     

The neuroprotective effects of heat shock protein 27 overexpression in transgenic animals against kainate-induced seizures and hippocampal cell death

The 27-kDa heat shock protein (HSP27) has a potent ability to increase cell survival in response to a wide range of cellular challenges. In order to investigate the mode of action of HSP27 in vivo, we have developed transgenic lines, which express human HSP27 at high levels throughout the brain, spinal cord, and other tissues. In view of the particular property of HSP27 compared with other HSPs to protect neurons against apoptosis, we have tested these transgenic lines in a well established in vivo model of neurotoxicity produced by kainic acid, where apoptotic cell death occurs. Our results demonstrate for the first time the marked protective effects of HSP27 overexpression in vivo, which significantly reduces kainate-induced seizure severity and mortality rate (>50%) in two independent lines and markedly reduces neuronal cell death in the CA3 region of hippocampus. This reduced seizure severity in HSP27 transgenic animals was associated with a marked attenuation of caspase 3 induction and apoptotic features. These studies clearly demonstrate that HSP27 has a major neuroprotective effect in the central nervous system in keeping with its properties demonstrated in culture and highlight an early stage in the cell death pathway that is affected by HSP27.     

Endothelial barrier dysfunction caused by LPS correlates with phosphorylation of HSP27in vivo

Lung edema during sepsis is triggered by formation of gaps between endothelial cells followed by macrophage infiltration. Endothelial gap formation has been proposed to involve changes in the structure of the actin filament cytoskeleton. Heat shock protein 27 (HSP27) is believed to modulate actin filament dynamics or structure, in a manner dependent on its phosphorylation status. We hypothesized that HSP27 may play a role in endothelial gap formation, by affecting actin dependent events in endothelial cells. As there has been no report concerning HSP27 in lung edema in vivo, we examined induction and phosphorylation of HSP27 in lung following LPS injection, as a model of sepsis. In lung, HSP27 mainly localized in capillary endothelial cells of the alveolus, and in smooth muscle cells of pulmonary arteries. HSP27 became significantly more phosphorylated at 3 h after LPS treatment, while the distribution of HSP27 remained unchanged. Pre-treatment with anti-TNFalpha antibody, which has been shown to reduce lung injury, blocked increases in HSP27 phosphorylation at 3 h. HSP27 phosphorylation was also increased in cultured rat pulmonary arterial endothelial cells (RPAEC) by treatment with TNFalpha, LPS, or H2O2. This phosphorylation was blocked by pre-treatment with SB203580, an inhibitor of the upstream kinase, p38 MAP kinase. Increased endothelial permeability caused by H2O2 in vitro was also blocked by SB203580. The amount of actin associated with HSP27 was reduced after treatment with LPS, or H2O2. In summary, HSP27 phosphorylation temporally correlated with LPS induced pathological endothelial cell gap formation in vivo and in a cell culture model system. This is the first report of increased HSP27 phosphorylation associated with pathological lung injury in an animal model of sepsis.     

Anti-vpr activities of heat shock protein 27

HIV-1 Vpr plays a pivotal role in viral pathogenesis and is preferentially targeted by the host immune system. In this report, we demonstrate that a small heat shock protein, HSP27, exhibits Vpr-specific antiviral activity, as its expression is specifically responsive to vpr gene expression and increased levels of HSP27 inhibit Vpr-induced cell cycle G2 arrest and cell killing. We further show that overexpression of HSP27 reduces viral replication in T-lymphocytes in a Vpr-dependent manner. Mechanistically, Vpr triggers HSP27 expression through heat shock factor (HSF) 1, but inhibits prolonged expression of HSP27 under heat-shock conditions. Together, these data suggest a potential dynamic and antagonistic interaction between HIV-1 Vpr and a host cell HSP27, suggesting that HSP27 may contribute to cellular intrinsic immunity against HIV infection.     

Heat Shock Proteins 27 and 70: Anti-Apoptotic Proteins with Tumorigenic Properties

Heat shock proteins (HSP) HSP27 and HSP70 are expressed in response to a wide variety of physiological and environmental insults including anticancer chemotherapy, thus allowing the cell to survive to lethal conditions. Several mechanisms account for the cytoprotective effect of HSP27 and HSP70. 1) Both proteins are powerful chaperones. 2) They both inhibit key effectors of the apoptotic machinery at the pre- and post-mitochondrial level. 3) They participate in the proteasome-mediated degradation of proteins under stress conditions, thereby contributing to the so called “protein triage”. In cancer cells, the expression of HSP27 and/or HSP70 is abnormally high, and both HSP27 and HSP70 may participate in oncogenesis and in resistance to chemotherapy. In rodent models, HSP27 or HSP70 over-expression increases tumor growth and metastatic potential. The depletion or inhibition of HSP27 and HS70 frequently reduces the size of the tumors and even can cause their complete involution (for HSP70). Therefore, the inhibition of HSP70 and HSP27 has become a novel strategy of cancer therapy.     

Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-beta-activated kinase-1 (TAK1)-mediated signaling

Heat shock protein (HSP) 27 has long been known to be a component of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. p38 MAPK has important functions in the inflammatory response, but the role of HSP27 in inflammation has remained unknown. We have used small interfering RNAs to suppress HSP27 expression in HeLa cells and fibroblasts and found that it is required for pro-inflammatory cell signaling and the expression of pro-inflammatory genes. HSP27 is needed for the activation by interleukin (IL)-1 of TAK1 and downstream signaling by p38 MAPK, JNK, and their activators (MKK-3, -4, -6, -7) and IKKbeta. IL-1-induced ERK activation appears to be independent of HSP27. HSP27 is required for both IL-1 and TNF-induced signaling pathways for which the most upstream common signaling protein is TAK1. HSP27 is also required for IL-1-induced expression of the pro-inflammatory mediators, cyclooxygenase-2, IL-6, and IL-8. HSP27 functions to drive cyclooxygenase-2 and IL-6 expression by augmenting the activation of the kinase downstream of p38 MAPK, MK2, resulting in stabilization of cyclooxygenase-2 and IL-6 mRNAs. The mechanism may not occur in cells of myeloid lineage because HSP27 protein was undetectable in human monocytes and murine macrophages.     

The maximal cytoprotective function of the heat shock protein 27 is dependent on heat shock protein 70

Endogenous heat shock proteins (HSPs) 70 and 25/27 are induced in renal cells by injury from energy depletion. Transfected over-expression of HSPs 70 or 27 (human analogue of HSP25), provide protection against renal cell injury from ATP deprivation. This study examines whether over-expressed HSP27 depends on induction of endogenous HSPs, in particular HSP70, to afford protection against cell injury. LLC-PK1 cells transfected with HSP27 (27OE cells) were injured by ATP depletion for 2 h and recovered for 4 h in the presence of HSF decoy, HSP70 specific siRNA (siRNA-70) and their respective controls. Injury in the presence of HSF decoy, a synthetic oligonucleotide identical to the heat shock element, the nuclear binding site of HSF, decreased HSP70 induction by 80% without affecting the over-expression of transfected HSP27. The HSP70 stress response was completely ablated in the presence of siRNA-70. Protection against injury, provided by over-expression of HSP27, was reduced by treatment with HSF decoy and abolished by treatment with siRNA-70. Immunoprecipitation studies demonstrated association of HSP27 with actin that was not affected by either treatment with HSF decoy or siRNA. Therefore, HSP27 is dependent on HSP70 to provide its maximal cytoprotective effect, but not for its interaction with actin. This study suggests that, while it has specific action on the cytoskeleton, HSP 25/27 must have coordinated activity with other HSP classes, especially HSP70, to provide the full extent of resistance to injury from energy depletion.     

Expression and distribution of HSP27 in response to G418 in different human breast cancer cell lines

Heat shock proteins (HSPs) play an important role in folding, intracellular localization and degradation of cellular proteins. However, the cellular role of HSP27 is not completely understood. The conflicting results have been reported regarding stress-induced nuclear translocation of HSP27. In this study, human breast cancer cells transiently and stably expressing HSP27–EGFP chimera were utilized to observe the intracellular localization of HSP27. The data show that the transient and stable expression of HSP27–EGFP displayed distinguishingly cellular localization. The nuclear translocalization of HSP27–EGFP was correlated with the presence of G418. Experiments carried out with different human breast cancer cell lines revealed clearly different distribution patterns of endogenous HSP27. The subcellular distribution of endogenous HSP27 appeared diffuse throughout the cytoplasm in MDA435 cells. In MCF-7 and SKBR3 cells, the accumulation of the protein was distinctly seen along the cell membrane and around nucleus. Moreover, the nuclear translocation of endogenous HSP27 was stimulated by G418 only in MDA435 cells, but not in MCF-7 and SKBR3 cells. Overexpression of HSP27 has been associated with resistance to cisplatin and doxorubicin. The correlation of the expression pattern of HSP27 with the drug resistance may need to be investigated. Further studies on the intracellular function of HSP27 may take into account its interaction proteins in the cells. It may provide useful information for the identification of sensitivity of carcinoma cells to the chemotherapeutic drugs and development of more specific agents to circumvent HSP27.