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热休克蛋白gp96 3'UTR作为ceRNA通过miR-642a调控DOHH的表达
盛春海1,2, 孙璐2, 初骁宇2, 李长菲2 , 孟颂东2     
1. 安徽大学生命科学学院,合肥 230601;
2. 中国科学院微生物研究所病原微生物与免疫学重点实验室,北京 100101
摘要: 热休克蛋白gp96在肝脏等多种肿瘤中过量表达,与肿瘤的恶性程度和患者不良预后呈显著相关性,其在肿瘤发生发展中作用机制有待深入探讨.通过生物信息学技术预测、荧光素酶报告基因检测、免疫印迹分析、实时定量PCR、RNA干扰,研究gp96 3'UTR作为ceRNA (competing endogenous RNA)对miR-642a和脱氧羟腐氨酸羟化酶(deoxyhypusine hydroxylase,DOHH)表达的影响.研究结果显示,miR-642a特异性靶向的野生型gp96 3'UTR,而不是miR-642a结合位点突变的gp96 3'UTR,可吸附下调miR-642a并同时上调miR-642a靶基因DOHH的表达,进一步研究发现gp96 3'UTR对DOHH的调控依赖于miR-642a.实验还发现DOHH并不影响gp96的表达.Gp96通过ceRNA上调DOHH的表达,为研究gp96促进肝癌等肿瘤的发生发展提供了新思路.
关键词: 热休克蛋白gp96     miR-642a     脱氧羟腐氨酸羟化酶     ceRNA    
Heat Shock Protein gp96 3'UTR Functions as A ceRNA in Promoting DOHH Expression via miR-642a
SHENG Chun-Hai1,2 , SUN Lu2 , CHU Xiao-Yu2 , LI Chang-Fei2 , MENG Song-Dong2     
1. School of Life Sciences, Anhui University, Hefei 230601, China ;
2. Microbiology and Immunology, Institute of Microbiology, The Chinese Academy of Sciences, Beijing 100101, China
*This work was supported by grants from The National Natural Science Foundation of China (31230026, 81321063, 81471960, 81402840), Natural Science Foundation of Jiangsu Province, China (BK20130495), and Shenzhen Science and Technology Innovation Committee (JSGG20140516112337659, CYZZ20130826112642412)
**Corresponding author: LI Chang-Fei. Tel: 86-10-64807350, E-mail: lichangfei2006@163.com
MENG Song-Dong. Tel: 86-10-64807350, E-mail: mengsd@im.ac.cn
Received: July 27, 2016 Accepted: October 10, 2016
Abstract: Heat shock protein gp96 is overexpressed in many kinds of tumors including hepatic tumors, and its overexpression is significantly correlated with tumor malignant degree and poor prognosis in patients. The mechanisms of heat shock protein gp96 in the development of tumors need to be further investigated. The effects of gp96 3'UTR as a ceRNA (competing endogenous RNA) on miR-642a and DOHH expression was studied through bioinformatics prediction, luciferase reporter assay, Western blotting, real-time PCR, RNA interference. MiR-642a specifically targets gp96 3'UTR. The wild type but not the mutant gp96 3'UTR in miR-642a binding site could sequester and downregulate miR-642a levels, which led to increased expression of the miR-642a target DOHH. Further studies showed that regulation of DOHH expression by gp96 3'UTR was miR-642a dependent. It was also fo und that DOHH does not affect the expression of gp96. Heat shock protein gp96 promotes DOHH expression via its 3'UTR as a ceRNA, providing new insights into the role of gp96 on the development of hepatic tumors and other tumors.
Key words: Gp96     miR-642a     DOHH     ceRNA    

热休克蛋白gp96 (又称GRP94),作为内质网中最主要的蛋白之一,是细胞质热休克蛋白HSP90的同源蛋白质[1],gp96作为分子伴侣参与新生蛋白质的折叠和变性蛋白质的降解[2].我们和他人的研究均发现gp96在肝癌、乳腺癌、骨髓瘤等多种肿瘤高表达,已经查明gp96与Wnt共受体LRP6、胰岛素样生长因子、整合蛋白、HER2、uPAR等相互作用,对于维持这些肿瘤蛋白的稳定性和功能发挥重要调节作用[3-7],然而gp96在调节肿瘤发生、发展的作用机制仍需进一步深入研究.

microRNAs(miRNA)是一类由约22个核苷酸组成的非编码RNAs,可与靶mRNA的3′UTR不完全配对结合,从而导致靶基因的翻译抑制或降解[8-9],参与细胞的生长、凋亡、分化等的调节[10-12].最近的研究发现,长链非编码RNA、假基因编码的RNA以及部分mRNA、甚至病毒mRNA可作为“海绵”吸附、隔离与其相互作用的miRNA,从而抑制miRNA的功能,进而导致miRNA其他靶基因的表达上调[13-17].竞争性内源RNAs(competing endogenous RNA, ceRNAs)首先由Pandolfi等提出,他们发现细胞中的长非编码RNA、假基因RNA和环状RNA与编码蛋白的mRNA包含有共有的miRNA结合序列,通过诱饵或“海绵”吸附的机制可竞争性结合miRNA,因此这些不同类型的RNA之间形成相互调控的网络,可能在生物发育和诸如肿瘤等疾病发生、发展中发挥重要作用[13, 15]

鉴于gp96蛋白、mRNA的丰度在细胞中尤其是在肿瘤细胞中均很高,本研究将探索gp96 mRNA是否作为ceRNA发挥调节功能,研究gp96 3′UTR作为ceRNA对miR-642a和脱氧羟腐氨酸羟化酶(deoxyhypusine hydroxylase,DOHH)表达的影响.结果表明:gp96 3′UTR可通过抑制miR-642a的表达,上调miR-642a靶基因DOHH的表达.

1 材料与方法 1.1 材料

1.1.1 质粒、siRNA和细胞株

通过PCR扩增含有miR-642a结合序列的gp96 3′UTR,特异性引物序列如下:上游引物,5′TTATACTCTCACCATTTGGATC 3′;下游引物5′TGACAAGATTTTACATCAAGAA 3′,将得到的PCR产物克隆到pGL3-control荧光素酶报告载体上,得到的重组载体被命名为gp96-wt.将gp96-wt质粒中miR-642a结合的种子序列通过试剂盒突变后得到的质粒命名为gp96-mut.pcDNA3.1-gp96为本实验室构建,pGL3-control(Promega公司)、pcDNA3.1(+) (Invitrogen公司)和海肾萤光素酶对照报告基因载体pRL-TK由本实验室保存.

gp96的siRNA序列:5′AAGUUGAUGAAC-UGAGAGUACUUCC 3′,由广州市锐博生物科技有限公司合成.

293T购自美国模式菌种收集中心(ATCC),人肝癌细胞系Huh-7购自上海协和细胞库.

1.1.2 试剂与抗体

小鼠抗人gp96抗体和小鼠抗人DOHH抗体购自Santa Cruz Biotechnology;小鼠抗人β-actin抗体和辣根过氧化物酶标记的二抗,购自北京中杉金桥生物技术有限公司.双荧光素酶报告基因检测试剂盒购自Promega公司,转染试剂Lipofectamine 2000和opti-MEM购自Invitrogen公司.RNA提取试剂Trizol购自天根生化科技有限公司.DMEM培养基及胎牛血清购自Gibco公司.SYBR Green Premix试剂、反转录试剂盒,购自TaKaRa公司.ECL超敏发光液,购自北京普利莱基因技术有限公司.miR-642a mimics,miR-642a inhibitor均由广州锐博生物公司合成.

1.2 方法

1.2.1 RNA提取、反转录和荧光定量PCR

按Trizol试剂操作说明提取总RNA,取500 ng RNA作为模板,进行反转录.采用Takara公司的SYBR®Premix Ex TaqTM Ⅱ(Perfect Real Time)检测试剂盒(GAPDH作为内参)进行荧光定量PCR(Real-time PCR)检测mRNA的表达;所用的引物序列为:gp96(forward),5′CAGTTTTGGATC-TTGCTGTGG 3′;gp96(reverse),5′TACAGCAA-CTGTCGCCACC 3′;DOHH(forward),5′TGTCA-TCGCTTGTGTCTTGC 3′;DOHH(reverse),5′G-GAGTCACAGCACAAC 3′;GAPDH(forward),5′GGTGAAGGTCGGTGTGAACG 3′;GAPDH(reverse),5′CTCGCTCCTGGAAGATGGTG 3′.

miR-642a表达水平的检测采用ABI公司的TaqMan miRNA试剂盒进行Real-time PCR检测(U6作为内参).

1.2.2 细胞培养与转染

所有细胞均用含10%胎牛血清的DMEM培养基(100 U/ml青霉素、100 mg/L链霉素)在37℃、5% CO2培养箱中培养.转染前一天消化细胞,按照合适细胞数接种于6孔板或12孔板中,按Lipofectamine 2000说明书进行转染.

1.2.3 双荧光检测

在Huh7细胞中共转染pRL-TK、miR-642a或mimic control(mock)、gp96-wt或gp96-mut质粒48 h后,将细胞裂解后按照说明书进行细胞双荧光素酶检测.通过荧光发光仪分别检测萤火虫荧光素酶的活性和海肾荧光素酶活性,并以海肾荧光素酶活性作为内参分析荧光素酶的活性.

1.2.4 蛋白质免疫印记

细胞转染48 h后,在裂解液(0.05 mol/L Tris, pH 7.6,含0.15 mol/L NaCl,2 mmol/L EDTA,1% Nonidet P-40)中加入蛋白酶抑制剂(德国Roche公司)对细胞进行裂解.用BCA法测蛋白质浓度,每个样品取等量蛋白质用10% SDS-PAGE电泳分离;将蛋白转移到PVDF膜上(美国Millipore公司);用含有5%脱脂奶粉的TBST封闭2 h,加入一抗(1:1 000) 4℃孵育过夜,以TBST洗5次,每次10 min,然后加入辣根过氧化物酶标记的二抗(1:2 000)室温孵育2 h后,同样用TBST洗去二抗,最后用ECL超敏发光液显影检测.

1.2.5 统计学分析

每个试验组有3个复孔,所有的试验都重复2~3次.采用t-test和Pearson’s χ计算各组之间的差异,P < 0.05认为具有差异,P < 0.01认为具有显著差异.结果以x±s表示.

2 结果 2.1 gp96 3′UTR含有miR-642a的靶点

使用Microcosm Targets(http://www.ebi.ac.uk/enright-srv/microcosm/cgi-bin/targets/v5/search.pl)预测gp96 3′UTR上miRNA潜在作用靶点,按分值由高到低依次为:miR-513-3p、miR-642a、miR-152、miR-578、miR-215、miR-192、miR-454、miR-640、miR-99a、miR-613、miR-186、miR-100等.由于Michael等发现在前列腺癌细胞中miR-642a靶向脱氧羟腐氨酸羟化酶(DOHH),下调DOHH从而影响细胞增殖[18].因此本研究进一步验证miR-642a与gp96 3′UTR之间的相互作用.首先使用PGL3-control构建了含有gp96 3′UTR的野生型(gp96-wt)和miR-642a结合位点种子序列突变(gp96-mut)的荧光素酶报告质粒(图 1a),将gp96-wt、gp96-mut质粒和pRL-TK分别与miR-642a、mimic control(mock)在Huh7细胞系中共转染,48 h后用双荧光素酶报告基因检测试剂盒检测荧光活性.结果显示转染miR-642a可明显降低gp96-wt质粒的荧光值,而对gp96-mut没有作用(图 1b).同时Western blot结果显示转染miR-642a能明显下调gp96蛋白质水平(图 1c),以上结果表明miR-642a靶向gp96 3′UTR.

Fig. 1 MiR-642a down-regulates gp96 expression through binding to its 3'UTRc Predicted miR-642a binding sequence located in the gp96 3'UTR at 2612nt to 2613nt. Perfect matches are indicated by a line. Mutations were made in the seed region of the miR-642a binding sites (a). Huh7 cells were co-transfected with a miR-642a mimic or a mimic control (mock) and luciferase reporter containing wild type (gp96-wt) or mutated (gp96-mut) gp96 3' UTR. At 48 h post-transfection, the firefly luciferase and renilla luciferase activities were measured using a dual-luciferase assay kit. **P < 0.01 (b). □: Mock; ■: miR-642a. Huh7 cells were transfected with miR-642 mimic or a mimic control as mock. At 48 h after transfection, gp96 protein levels were measured by Western blotting. Actin was used as a loading control. (c).

2.2 gp96 3′UTR上调DOHH的表达

在Huh-7细胞中过表达野生型gp96 3′UTR显著下调miR-642a的水平,而miR-642a结合位点突变型3′UTR则对miR-642a没有影响(图 2a),说明gp96 3′UTR上与miR-642a结合的位点引起miR-642a的下调.反之,干扰gp96 mRNA的表达则上调miR-642a的水平(图 2b).鉴于前期研究发现DOHH的mRNA是miR-642a的靶分子[18],因此进一步检测gp96 3′UTR对DOHH的影响.正如所预期,与转染空载体和gp96-mut相对比,转染gp96-wt可显著上调DOHH的mRNA(图 2c)和蛋白质水平(图 2d)(P < 0.01),同时利用RNAi敲低gp96的表达引起DOHH mRNA(图 2e)和蛋白质水平(图 2f)的降低.

Fig. 2 Gp96 3'UTR up-regulates DOHH expression At 24 h after Huh7 cells were transfected with gp96-wt, gp96-mut or PGL3 as a control, miR-642a (a) and DOHH mRNA (c) levels was quantified with real-time PCR. The protein levels of DOHH were detected at 48 h by Western blotting. Actin was used as a loading control (d). Huh-7 cells were transfected with gp96 siRNA or the control siRNA as a mock, miR-642a (b) and DOHH mRNA (e) levels was quantified with real-time PCR at 24h. We stern blotting analysis of gp96 and DOHH protein levels at 48 h (f). *P < 0.05, **P < 0.01.

为了进一步排除gp96蛋白质对DOHH表达产生影响的可能性,构建表达gp96的pcDNA3.1的载体pcDNA3.1-gp96,表达载体不含gp96 3′UTR.转染pcDNA3.1-gp96并不明显影响细胞中miR-642a的水平(图 3a),也不影响DOHH的mRNA(图 3b)和蛋白质水平(图 3c).以上结果提示gp96 3′UTR作为ceRNA调节DOHH的表达.

Fig. 3 Overexpression of gp96 protien does not affect miR-642a and DOHH levels 293T cells were transfected with the gp96 expression vector pcDNA3.1-gp96 or pcDNA3.1 as a mock. The miR-642a (a) and DOHH mRNA (b) levels were determined by real-time PCR at 24 h after transfection. At 48 h after transfection, gp96 and DOHH protein levels were assessed by Western blotting. Actin was used as a loading control (c).

2.3 gp96通过miR-642a参与调控DOHH的表达

为进一步探讨gp96 3′UTR是否通过miR-642a调节DOHH的表达,人工合成miR-642a的反义抑制剂(miR-642a inhibitor)如图 4a图 4b所示,与对照组相比,干扰gp96表达能显著下调DOHH的mRNA和蛋白质水平(P < 0.01),但如果同时转染miR-642a抑制剂则gp96失去对DOHH的调节作用,说明gp96调控DOHH的表达依赖于miR-642a.

Fig. 4 Gp96 regulates DOHH expression through miR-642a Huh7 cells were co-transfected with gp96 siRNA or control siRNA and miR-642 inhibitor or an inhibitor control (mock). At 24 h after transfection, DOHH mRNA levels were quantified by real-time PCR (a). □: Mock; ■: gp96 siRNA. At 48 h after transfection, the expression of gp96 and DOHH protein was detected by Western blotting (b). **P < 0.01. 1: Mock; 2: gp96 siRNA; 3: miR-642a inhibitor; 4: gp96 siRNA + miR-642a inhibitor.

2.4 DOHH不影响gp96表达

进一步研究DOHH是否对gp96表达有调控作用.与对照组相比,干扰DOHH基因表达后Huh-7细胞中miR-642a(图 5a),gp96 mRNA(图 5b)和蛋白质(图 5c)水平均没有明显变化,说明DOHH不影响gp96表达.

Fig. 5 DOHH does not affect gp96 expression Huh7 cells were transfected with DOHH siRNA or the control siRNA as mock. At 24 h after transfection, the miR-642a (a) and gp96 (b) mRNA levels were determined by real-time PCR. At 48 h after transfection, gp96 and DOHH protein levels were detected by Western blotting. Actin was used as a loading control (c).

3 讨论

我们及他人的研究均发现,ceRNA的调控依赖于具有相同miRNA结合位点的mRNA的丰度、miRNA的水平以及miRNA与靶mRNA之间的结合能力等[19-20].本研究发现,gp96 3′UTR可调控miR-642a和DOHH的表达,反之DOHH则不能调控gp96的表达,推测这是由于在肝癌细胞中gp96 mRNA的丰度远大于DOHH mRNA的水平,gp96与DOHH mRNA之间的调控机制有待进一步深入探讨.

DOHH又称NHLRC1,是一个参与羟腐氨酸(hypusine)合成的金属酶.它包含8个串联HEAT重复序列,4个重复序列在N端和4个在C端[21].DOHH介导真核细胞翻译起始因子5A(eIF5A)的翻译后修饰,eIF5A翻译后第49位的赖氨酸被修饰为一个特殊氨基酸hypusine,对其发挥功能必需.hypusine残基合成分二步:a.由脱氧羟腐氨酸合成酶(deoxyhypusinesynthase,DHS)催化赖氨酸残基变成脱氧羟腐氨酸;b.脱氧羟腐氨酸残基被DOHH羟基化,完成hypusine[22].由于蛋白质合成异常是导致细胞癌变和细胞异常增殖的标志性特征,因此DOHH以及受其调控的eIF5A与多种肿瘤的发生、发展、转移密切相关[23-25]

本研究通过生物信息预测和靶点验证、实验分析发现热休克蛋白gp96 3′UTR作为ceRNA正向调控DOHH的表达,这种调控作用依赖于miR-642a、不依赖于gp96的蛋白质表达.我们实验室以及其他人的研究均发现乙肝慢性感染显著上调gp96的mRNA和蛋白质表达[26-29],gp96的表达水平与慢性乙肝疾病进展密切相关,gp96在肝肿瘤中过量表达与肿瘤的恶性程度和不良预后呈显著相关性[30].目前对gp96在肿瘤发生发展中的作用机制全部集中在其作为分子伴侣蛋白的功能,并且我们的研究发现gp96 mRNA的3′UTR作为ceRNA可上调肿瘤基因DOHH的表达,这为深入研究gp96如何参与调节肝癌等肿瘤的发生发展提供了一种新思路.需要进一步对包括DOHH在内的可能受gp96 3′UTR调控的基因在肿瘤中的表达水平及信号通路进行深入研究,这将为全面分析gp96促进肿瘤细胞生长的机制以及靶向治疗提供理论依据.

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中国科学院生物物理研究所和中国生物物理学会共同主办
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文章信息

盛春海, 孙璐, 初骁宇, 李长菲, 孟颂东
SHENG Chun-Hai, SUN Lu, CHU Xiao-Yu, LI Chang-Fei, MENG Song-Dong
热休克蛋白gp96 3'UTR作为ceRNA通过miR-642a调控DOHH的表达
Heat Shock Protein gp96 3'UTR Functions as A ceRNA in Promoting DOHH Expression via miR-642a
生物化学与生物物理进展, 2016, 43(10): 990-996
Progress in Biochemistry and Biophysics, 2016, 43(10): 990-996
http://dx.doi.org/10.16476/j.pibb.2016.0086

文章历史

收稿日期: 2016-07-27
接受日期: 2016-10-10

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