热休克蛋白27与恶性肿瘤的研究进展简

热休克蛋白是细胞在受到刺激时产生的一类特殊蛋白质,热休克蛋白27（heat shock protein 27,HSP27）是该家族中的重要成员之一,现已证实HSP27在多种肿瘤细胞中异常高表达,HSP27在肿瘤的发生、发展中的作用及其机制是近年来研究的热点,本文就HSP27与肿瘤的研究进展作一综述.     

热休克蛋白在膀胱肿瘤中的作用

热休克蛋白（HSP）是细胞受各种应激原刺激后诱导产生的一组应激蛋白，具有维持细胞蛋白稳定、促进细胞生存等功能。热休克蛋白在多种肿瘤组织中高表达，与肿瘤细胞的增生、分化、侵袭、转移、凋亡以及免疫系统的识别关系密切。本文就热休克蛋白的结构、生物学功能、致癌机制以及与膀胱癌的关系作一概述。     

HSP70的肿瘤免疫作用及其基因表达调节

热休克蛋白70能够与肿瘤特异性抗原多肽结合,形成热休克蛋白70-多肽复合物,它本身没有抗原性,其抗原性由它结合的多肽所决定,而它是作为"分子伴侣"参与肿瘤免疫作用过程.将这一特性加以应用,可能为肿瘤的治疗和消灭开辟新的途径.     

食管鳞状上皮癌中表达失调蛋白的研究

背景与目的：食管鳞状上皮癌（esophageal squamous cell carcinoma,ESCC)是一种具有高发性和高死亡率疾病,本研究应用蛋白质组学方法分析ESCC中异常表达的蛋白。方法：对ESCC／癌旁组织标本的冰冻切片进行显微切割,分别分离肿瘤细胞和癌旁上皮细胞,提取细胞总蛋白,通过双相电泳得到ESCC及癌旁上皮的蛋白表达谱,采用质谱技术鉴定肿瘤表达异常的蛋白。结果：比较7对食管癌／癌旁组织和蛋白表达谱,并对差异的蛋白进行质谱分析发现：11个蛋白在食管癌中表达明显异常,其中热休克蛋白27（HSP27）在3例ESCC中表达上调,钙依赖磷脂结合蛋白ANNEXINI尖正常食管粘膜存在分子量基本相同、等电点彼此相差约为1的3种变体（isoforms),3种ANNEXINI变体均在5例食管癌中表达下调。结论：双相电泳连接质谱的蛋白质组学方法是快速筛选肿瘤异常表达蛋白的有效手段,HSP27和ANNEXINI的表达失调是食管癌发生过程中的频发事件。     

胰腺癌血清肿瘤标志物研究进展

胰腺癌病程进展迅速,早期诊断困难.目前,糖类抗原19-9(CA19-9)仍是使用最为广泛的胰腺癌诊断及复发监测血清肿瘤标记物.近年来,蛋白质组学研究的发展,为寻找新的肿瘤标志物提供了新的途径.血清中肝癌-小肠-胰腺/胰腺炎相关蛋白(HIP/PAP-1)、磷酸甘油酸酯激酶、钙网织蛋白、DJ-1和热休克蛋白(HSP)27等因蛋白质组学研究技术的应用而被鉴定,为胰腺癌的早期微创诊断带来希望.     

细胞外HSP70与肿瘤的研究现状

目的：探讨细胞外热休克蛋白70（heatshock protein 70。HSP70）的释放、功能、免疫学机制以及在肿瘤免疫治疗中的应用。方法：应用Medline、PubMed及CNKI期刊全文数据库检索系统．以“细胞外热休克蛋白70的释放、肿瘤免疫、应用”为关键词,检索2002—2013年的相关文献。纳入标准：1）细胞外热休克蛋白的功能;2）细胞外热休克蛋白的释放机制;3）细胞外热休克蛋白与肿瘤免疫。根据纳入标准符合分析的文献28篇。结果：HSP70不仅在细胞内发挥重要的作用,还可以通过其特有机制释放到细胞外。细胞外HSP70有重要的生物学功能．存在于细胞外的HSP70能够发挥抗肿瘤免疫作用。应用细胞外HSP70／HSP70-PCs制成特异性抗肿瘤疫苗,为肿瘤的治疗提供新的思路。结论：细胞外HSP70的肿瘤免疫作用及在肿瘤疫苗方面的应用,将有望成为肿瘤治疗的新方法。     

肿瘤细胞p27kip1蛋白错位分布和低表达的分子机制

p27kip1(p27)蛋白是一种调控细胞周期并抑制细胞分裂的重要因子,p27是细胞周期依赖性激酶抑制因子(CDKI),参与细胞周期的负性调控,在细胞增殖、分化和凋亡等活动中扮演重要角色,p27被认为是人类多种肿瘤独立的预后因子和未来可能的肿瘤治疗靶点。在多种肿瘤细胞内存在p27蛋白低水平表达,p27蛋白的功能异常与多种肿瘤的发生密切相关。除了低丰度表达以外,在多种肿瘤细胞中p27蛋白主要分布在细胞核外,导致p27在肿瘤细胞内错位分布和低丰度表达的分子机制并不清楚。p27蛋白是一种功能广泛的细胞周期调节因子,除了可以和已知几乎所有的细胞周期素(cyclin)和细胞周期激酶(CDK)结合以外,还可以和包括CRM1、Nup50、Jab1和Skp2等在内的细胞核内外多种分子相互作用。推断p27发挥其抑制细胞增殖、促进细胞凋亡等生物学作用是受到以上多种相互作用的蛋白因子调控,这些因子在细胞周期不同的结合顺序和状态是发挥其广泛的生物学效应的分子基础,p27与适当的底物结合后,才能在适当的时间到达适当的细胞内位置并且发挥其生物学活性。因此认为,在肿瘤细胞p27存在和正常细胞不同的相互作用蛋白谱,并且由此决定了p27蛋白错位分布和低表达的可能机制,但是确切调控机制仍需进一步阐明。     

热休克蛋白强化乙型肝炎免疫的基础及展望

本文简要介绍了热休克蛋白的发现，结构，功能，强化诱导肿瘤及感染免疫的分子机制，以及利用这些免疫特性，将来在防治肿瘤及慢性乙型肝炎上，研制热休克蛋白疫苗进行了综述及展望。     

热休克蛋白90与肿瘤

热休克蛋白９０（ＨＳＰ９０）是一种非常重要的应激蛋白，作为分子伴侣参与蛋白质的折叠，运输等过程。在肿瘤细胞中ＨＳＰ９０表达异常，ＨＳＰ９０能与许多癌基因，抑癌基因产物结合，产与肿瘤细胞的细胞周期调控，肿瘤免疫以及肿瘤细胞的发生发展有着密切关系，本文仅就ＨＳＰ９０与肿瘤的关系作一综述。     

HSP27在肝癌中的表达及临床意义

目的:通过观察肝癌组织中热休克蛋白27(HSP27)的表达,探讨HSP27表达与肝癌细胞增殖和转移的关系,并分析其意义.方法:采用免疫组化S-P法检测45例肝癌组织、23例癌旁肝硬化组织、12例正常肝组织标本中HSP27蛋白的表达水平,分析其与肝癌临床病理因素之间关系,结果:HSP27蛋白的阳性表达主要定位在细胞质内,少数也可见胞膜着色.HSP27蛋白在癌旁肝硬化组织及正常肝组织中未见表达,而在恶性肿瘤中的阳性表达率为66.7%,与前两者相比差异有显著性(P<0.05).HSP27的表达与肝癌的临床转移、细胞的分化程度相关,而与患者年龄和肿瘤的大小无明显相关性.结论:HSP27在肝癌组织中有广泛表达,在临床有转移和病理细胞分化低的组织中表达增高,HSP27与肝癌的发生、恶性程度及转移有关,在肝癌的预后判断中具有重要意义.     

Prognostic significance of heat shock protein 27 (HSP27) in patients with oral squamous cell carcinoma

Heat shock proteins (HSPs) have been defined as proteins induced by heat shock and other environmental and pathophysiologic stress. Heat shock protein 27 (HSP27) is one of the small heat shock proteins. HSP27 is implicated in protein-protein interactions such as folding, translocation, and prevention of inappropriate protein aggregation. Many of their functions suggest that they play important roles in cancers. Archival tissues from 40 patients with oral squamous cell carcinoma who received primary surgical resection were examined for HSP27 by immunohistochemistry and correlated with clinical stage, lymph node metastasis, histological grade and survival period. HSP27 expression was positive staining (+) in 20 (50%), weak or negative staining (-) in 20 (50%) of total 40 cases. There was no correlation between HSP27 expression and clinical stage, lymph node metastasis and histological grade. However, when compared with clinicopathological features, the expression of HSP27 correlated inversely with survival period. This study suggests that the expression of HSP27 is frequently promoted in patients with oral squamous cell carcinoma and should be considered an independent prognostic factor of oral squamous cell carcinoma patients.     

Heat shock protein 72 does not modulate ionizing radiation-induced apoptosis in U1810 non-small cell lung carcinoma cells

Heat shock proteins (HSP) have been shown to interfere with apoptosis signaling, suggesting that there might be a role for these proteins as mediators of resistance to ionizing radiation (IR)-induced apoptosis. Protein expression of the stress inducible heat shock proteins, HSP72 and HSP27, was analyzed in a panel of lung carcinoma cell lines displaying various degrees of radiosensitivity. Expression of HSP72 was high in all cell lines investigated while HSP27 was present in all non-small cell lung carcinoma (NSCLC) and 6/9 small cell lung carcinoma (SCLC) cell lines. Heat shock, but not IR, induced or further increased the expression of HSP27 and HSP72. Moreover, elevation of heat shock protein level prior to irradiation did not attenuate IR-induced apoptotic signaling or the induction of apoptosis. Protein level of HSP72 was downregulated in a radioresistant NSCLC cell line by RNA interference. However, this did not sensitize cells to treatment with DNA-damaging agents such as IR, cisplatin or VP16. Thus, the results from this first study on the relationship between stress-inducible HSP expression and IR-induced apoptosis in lung cancer cells do not support a role for HSP 27 and 72 in the radioresistance of NSCLC cells.     

HSP27和GST在大肠腺瘤和大肠癌中表达的临床病理研究

目的探讨热休克蛋白27（HSP27）和谷胱甘肽-S-转移酶（GST）在正常大肠黏膜、大肠腺瘤和大肠癌中的表达及其临床病理意义。方法应用免疫组织化学S-P法检测HSP27和GST在大肠组织中的表达。结果HSP27在正常肠黏膜、大肠腺瘤、无淋巴结转移的大肠癌、有淋巴结转移的大肠癌中表达阳性率分别为30％,33．3％,65％,70％,多组间比较具有显著性差异（x^2=12．723,P=0．013）。两组间比较发现,HSP27表达率在正常组与大肠癌组存在差异,在有淋巴结转移的大肠癌组中的表达具有差异最为显著（x^2=8．688,P=0．003）,而其它组间比较无显著性差异。GST在正常肠黏膜、大肠腺瘤、无淋巴结转移的大肠癌、有淋巴结转移的大肠癌中表达阳性率分别为60％,80．9％,90％,100％,多组间比较具有显著性差异（x^2=16．707,P=0．001）;进一步进行两组间比较发现,GST表达率在有淋巴结转移的大肠癌组中的表达具有差异最为显著（x^2=10．909,P=0．001）,而其它组间比较无显著性差异。GST和HSP27表达无显著相关。结论HSP27和GST在大肠癌中的表达可能在大肠癌发生发展中发挥作用,特别在大肠癌恶性演进中以及预后预测中具有重要意义,可能作为独立的生物标志物。     

Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus

BACKGROUND: Heat shock proteins (HSPs) first were defined as proteins induced by heat shock and other environmental and pathophysiologic stresses and are implicated in protein-protein interactions such as folding, translocation, and prevention of inappropriate protein aggregation. Many of their functions suggest that they play important roles in cancer. METHODS: Immunohistochemical study for HSP 27 and HSP 70 was performed on buffered formalin fixed, paraffin embedded sections of 102 esophageal squamous cell carcinoma specimens using monoclonal anti-HSP 27 antibody and anti-HSP 70 antibody. RESULTS: Normal squamous cells expressed both HSP 27 and HSP 70 with the exception of the basal layer. In cancerous tissue, expression of HSP 27 was evaluated as positive (+) (39 cases; 38%), reduced (+/-) (53 cases; 52%), or negative (-) (10 cases; 10%) and expression of HSP 70 was evaluated as (+) (14 cases; 14%), (+/-) (57 cases; 56%), or (-) (31 cases; 30%). There was a strong correlation between the expression of HSP 27 and HSP 70 (P < 0.0001). When compared with clinicopathologic features, expression of both HSP 27 and HSP 70 correlated negatively with lymph node metastases (P < 0.05), but not with depth of invasion or histologic grade. The reduction of the HSPs was associated significantly with poor postoperative survival (P < 0.0001). In addition, multivariate analysis revealed that HSP 27 (-) was the strongest prognostic factor among the clinicopathologic features. CONCLUSIONS: This study suggests that the expression of HSP 27 and HSP 70 frequently is reduced in patients with esophageal squamous cell carcinoma and therefore should be considered an independent prognostic factor of this disease.     

SUMOylation of HSP27 by small ubiquitin-like modifier 2/3 promotes proliferation and invasion of hepatocellular carcinoma cells

Primary hepatocellular carcinoma (PHC) is a major health problem worldwide and is one of the 10 most commonly diagnosed cancers in China. Heat shock protein 27 (HSP27) were found to be overexpressed in a wide range of malignancies including PHC, however, post-translational modification of HSP27 still needs exploration in PHC. Recently, SUMOylation, an important post-translational modification associating with the development of many kinds of cancers has been intensively studied. In the current study, mRNA and protein level of HSP27 in archived tumor samples representing various pathological characteristics of PHC were examined, and modification of HSP27 by SUMO2/3 was investigated. HSP27 were expressed abundantly in patients' tumor tissues, and found to be associated with pathological progression. Besides, HSP27 was also elevated significantly in liver cancer cell lines Huh7 and HepG2 compared with human hepatocyte cells L02. Furthermore, knockdown of HSP27 was found to be associated with the decreased proliferation and invasion ability in Huh7 and HepG2 cells. Immunofluorescence assay showed that HSP27 and SUMO2/3 were co-localized in the subcellular, and co-immunoprecipitation verified the interaction between HSP27 and SUMO2/3. Overexpression of SUMO2/3 upregulated the HSP27 protein level and promotes Huh7 and HepG2 cell proliferation and invasion, and vice versa when the SUMO2/3 was knockdown. Taken together, increased protein level of HSP27 through SUMO2/3-mediated SUMOylation plays crucial roles in the progression of PHC, and this finding may shed light on developing potential therapeutic targets for PHC.     

Protein Profile of Human Saliva as a Predictive and Prognostic Tool for OSCC in Tamol Chewer’s Population in Assam

Objective:To identify potential proteomic salivary biomarker in tamol chewers and comparing it to healthy and Oral squamous cell carcinoma cases. Methods:A total of fifty unstimulated saliva samples were collected from the healthy volunteers, tamol chewers (without tobacco), and OSCC patients referred to North-East cancer Hospital, Jorabat, Assam, India. The 2-D gel analysis and western blotting were performed to analyze protein profiling. Results:The identified proteins were serum albumin, HSP (Heat shock protein) 27, gamma actin, SCC (Squamous cell carcinoma) 1, and Annexin A4. All the proteins were associated with OSCC development when their values were compared with those of normal healthy subjects. HSP27 was subjected to further validation using western blotting methods. An increase of 18.39% (Serum Albumin), 15.04% (gamma actin), 14.01% (SSC 1), and 20.22% (ANX4) were observed in Tamol chewers when compared with healthy control subjects. Conclusion:Our results revealed that the identified salivary proteins have a positive association with OSCC development. Profiling of these saliva proteomes especially HSP (Heat shock protein) 27 as a potential biomarker for OSCC detection in the high-risk population is recommended. Key Words: OSCC, Oral squamous cell carcinoma, ANXA4, Annexin A4, HSP-Heat shock protein, SCC     

Coinduction of hsp27 phosphorylation and drug-resistance in chinese-hamster cells

Treatments of Chinese hamster fibroblasts with A23187, 2-deoxyglucose, tunicamycin, beta-mercaptoethanol or glucosamine induce an increase in cell resistance to doxorubicin and VM-26 that attains a maximum after 8 h of treatment. We tested the possibility that HSP27, a heat shock protein whose overexpression in cells was shown to confer thermoresistance and chemoresistance, might also be associated with this acquisition of drug resistance. [H-3]leucine incorporation and immunoblot analyses showed that the increased resistance was not accompanied by the synthesis or accumulation of HSP27 or other heat shock proteins. However, drug resistance promoting agents all stimulated protein kinase activities that phosphorylated HSP27 in vitro and stimulated incorporation of P-32 into HSP27 in vivo. HSP27 is thought to exert in unstressed cells functions linked with growth signal pathways. It is suggested that stimulation of HSP27 phosphorylation may modulate a protective function associated with the maintenance of signal transduction homeostasis.     

Protein Profile of Human Saliva as a Predictive and Prognostic Tool for OSCC in Tamol Chewer’s Population in Assam

Objective: To identify potential proteomic salivary biomarker in tamol chewers and comparing it to healthy and Oral squamous cell carcinoma cases. Methods: A total of fifty unstimulated saliva samples were collected from the healthy volunteers, tamol chewers (without tobacco), and OSCC patients referred to North-East cancer Hospital, Jorabat, Assam, India. The 2-D gel analysis and western blotting were performed to analyze protein profiling. Results: The identified proteins were serum albumin, HSP (Heat shock protein) 27, gamma actin, SCC (Squamous cell carcinoma) 1, and Annexin A4. All the proteins were associated with OSCC development when their values were compared with those of normal healthy subjects. HSP27 was subjected to further validation using western blotting methods. An increase of 18.39% (Serum Albumin), 15.04% (gamma actin), 14.01% (SSC 1), and 20.22% (ANX4) were observed in Tamol chewers when compared with healthy control subjects. Conclusion: Our results revealed that the identified salivary proteins have a positive association with OSCC development. Profiling of these saliva proteomes especially HSP (Heat shock protein) 27 as a potential biomarker for OSCC detection in the high-risk population is recommended.     

热休克蛋白 HSP27 抑制食管鳞癌细胞的侵袭转移能力简

目的：探讨HSP27分子的表达水平与食管鳞癌高、低转移潜能细胞系侵袭转移能力的关系。方法：选用EC9706-H、EC9706-L和EC109-H、EC109-L两对食管鳞癌高、低转移潜能细胞系,利用细胞划痕实验检测不同细胞侵袭转移能力的差异;利用Western blot检测HSP27在不同转移潜能细胞中的表达水平;利用慢病毒转染技术上调HSP27低表达细胞中HSP27的表达,采用细胞划痕实验检测其侵袭转移能力的变化。结果：细胞划痕实验证实,EC9706-H细胞和EC109-H细胞的体外侵袭转移能力高于EC9706-L细胞和EC109-L细胞;Western blot实验结果显示,HSP27在EC9706-H细胞和EC109-H细胞中呈低表达,在EC9706-L细胞和EC109-L细胞中呈高表达;通过慢病毒转染技术上调EC9706-H细胞和EC109-H细胞中HSP27的表达,二者的侵袭转移能力明显降低。结论：HSP27与食管鳞癌的侵袭转移能力呈负相关,即HSP27高表达的食管鳞癌细胞其侵袭转移能力受到抑制。     

nm23-H1及热休克蛋白27在非小细胞肺癌中的表达及临床意义

 目的　分析nm23-H1和热休克蛋白27（HSP27）在非小细胞肺癌（NSCLC）发生、发展及转移中的作用。方法　应用免疫组织化学法检测75例NSCLC组织及28例良性肺病变中nm23-H1和HSP27的表达情况,并将检测结果与临床病理特征进行综合分析。结果　nm23-H1和HSP27的表达主要定位于细胞质,nm23-H1和HSP27在NSCLC中表达的阳性率分别为41.3 %（31／75）和80.0 %（60／75）,明显高于良性肺病变7.1 %（2／28）和46.4 %（13／28）（χ2＝10.946,P＝0.001;χ2＝11.131,P＝0.001）。NSCLC中HSP27蛋白的表达与肿瘤分化程度密切相关（χ2＝4.191,P＝0.041）。肺癌组织中nm23-H1、HSP27 的表达水平有相关性（r＝0.284,P＝0.013）。结论　nm23-H1、HSP27与NSCLC的发生、发展有关,二者联合检测对肺癌的诊断和生物学行为判断有一定的意义。