摘要
MicroRNAs (miRNAs)是一类非编码蛋白的短序列RNA片段,长度大约为21-23个核苷酸。研究表明miRNAs参与了肿瘤发生、发展和转移等诸多过程,最近研究发现microRNA-520b(miR-520b)与免疫调节有关。CD46, CD55和CD59是一簇膜结合补体调节蛋白(mCRPs),在补体级联反应中可以通过抑制C5转化酶阻止膜攻击复合物(MAC)在肿瘤细胞表面的形成,抑制了补体介导的细胞毒(complement-dependent cytotoxicity, CDC)作用,保护肿瘤细胞免受补体攻击。但是,调节CRP的分子机制尚不清楚,miR-520b是否参与了补体介导的肿瘤免疫逃逸也未见报道。为了阐明乳腺癌细胞中调节mCRPs的分子机制,我们研究了miR-520b或miR-520e在乳腺癌细胞中参与免疫调节的作用,研究应用不同转移能力的乳腺癌细胞系MCF-7和LM-MCF-7(获国家发明专利,ZL.0310107316)探讨了miR-520b与CRP的关系及其分子调控机制,主要研究内容如下：
1. miR-520b和miR-520e靶向CD46影响补体介导的细胞毒作用及其分子机制研究
本实验室前期通过对肝癌细胞与正常肝细胞的microRNA芯片分析发现,microRNA-520b在肝癌细胞中下调。为了进一步研究microRNA-520b及与其高度同源的miR-520e在乳腺癌细胞中的作用及其与补体介导的肿瘤免疫逃逸的关系,我们首先应用实时定量反转录聚合酶链式反应(quantitative RT-PCR)的方法检测分析了miR-520b和miR-520e在正常的乳腺细胞HBL-100以及三株乳腺癌细胞系MCF-7, LM-MCF-7和MDA-MB-231细胞系中的表达水平,实验结果表明,与正常的乳腺细胞HBL-100相比,乳腺癌细胞MCF-7, LM-MCF-7和MDA-MB-231细胞系中miR-520b和miR-520e的基因表达均下调。我们进一步在8例正常乳腺组织和7例乳腺癌组织临床标本中比较了miR-520b的表达水平,发现miR-520b在乳腺癌组织中的表达水平与正常乳腺组织中的表达水平相比显著下调,并发现乳腺癌细胞系抵抗CDC的能力均高于正常乳腺细胞。为了进一步研究miR-520b或miR-520e在乳腺癌细胞中对补体依赖的细胞毒作用的影响,我们外源转染了合成的miR-520b或miR-520e的成熟体(mimics),以及miR-520b或miR-520e的抑制子(anti-mimics), CDC实验表明,在MCF-7或MDA-MB-231乳腺癌细胞系中过表达miR-520b或miR-520e均可增强CDC的作用,而在干扰了miR-520b或miR-520e的乳腺癌细胞中则抑制了其对CDC的敏感性。综上结果表明,miR-520b和miR-520e参与了乳腺癌细胞中补体介导的免疫抑制作用。
为进一步阐明miR-520b和miR-520e在乳腺癌细胞中参与补体介导的免疫抑制的分子机理,我们应用生物信息学软件在TargetScan和DIANA microT 3.0预测microRNA靶基因的数据库中对miR-520b和miR-520e的靶基因进行了预测筛选。结果发现,miR-520b和miR-520e均可以靶向与补体激活级联调节有关的靶基因——膜辅助因子(membrane co-factor, MCP, CD46)。本研究发现在MCF-7乳腺癌细胞中分别过表达miR-520b或miR-520e成熟体可以下调CD46蛋白质表达水平,但不能影响CD46 mRNA转录水平；当分别过表达miR-520b或miR-520e的抑制子时可见CD46蛋白质表达水平上调。这一结果表明CD46是miR-520b和miR-520e两者共同的靶基因。同时也提示miR-520b和miR-520e可能是通过结合CD46 3’非翻译区(3’UTR)抑制其翻译调控CD46蛋白质表达。为了进一步证明这个假设,我们克隆了CD46 3'UTR miR-520b和miR-520e结合区并构建了报告基因载体。报告基因结果表明miR-520b和miR-520e可以直接靶向结合CD46 3'UTR相应的结合区。ELISA结果表明,在乳腺癌细胞中过表达miR-520b或miR-520e可以增加补体成分C3b在肿瘤细胞上的积累,从而激活补体级联反应途径,促进CDC对肿瘤细胞的裂解作用。以上研究阐明乳腺癌细胞中miR-520b和miR-520e均可直接靶向CD46影响补体介导的细胞毒作用。
2.miR-520b靶向HBXIP影响补体介导的细胞毒作用及其分子机制研究
我们前期发现HBXIP在肿瘤细胞中促进增殖、抑制凋亡等方面发挥重要作用。本研究中我们探讨了HBXIP在乳腺癌细胞中对CDC的作用。我们首先检测了HBL-100, MCF-7, LM-MCF-7和MDA-MB-231细胞系中HBXIP的表达水平,发现三株乳腺癌细胞系HBXIP的表达水平均高于HBL-100细胞系,并发现HBXIP的表达水平与膜结合补体调节蛋白(mCRPs)的主要成员CD46, CD55和CD59的表达水平呈正相关。因此,我们设想HBXIP可能与调节CD46, CD55和CD59有关。
报告基因实验结果显示,在过表达HBXIP基因的乳腺癌细胞系中,CD46, CD59报告基因活性升高,而RNA干扰HBXIP基因后其报告基因活性降低。应用Real-time PCR实验检测发现过表达HBXIP可以上调CD46, CD55和CD59的mRNA转录水平,而在干扰的乳腺癌细胞系CD46, CD55和CD59的mRNA水平下调。我们进一步发现在乳腺癌细胞系中瞬时过表达或干扰HBXIP可以以剂量依赖的方式上调或下调mCRPs的蛋白质表达水平。以上结果表明HBXIP在乳腺癌细胞中可以调节CD46, CD55和CD59的表达。
为了进一步阐明HBXIP调节mCRPs的分子机制,我们通过报告基因、Western blot分析、免疫荧光染色方法发现HBXIP在乳腺癌细胞中可以激活NF-κB。双荧光素酶报告基因以及Western blot分析表明,用NF-κB特异性抑制剂PDTC处理MCF-7-HBXIP乳腺癌细胞后可拮抗CD46, CD55和CD59的表达,当RNA干扰NF-κB活性时也可获得相似的结果。上述结果表明HBXIP可以上调CD46, CD55和CD59可以通过NF-κB信号通路。我们还发现HBXIP也可以上调ERK1/2的磷酸化水平,而对丝裂原激活蛋白激酶(MAPK)其他两个成员p38和c-Jun N末端激酶(JNK)的磷酸化水平无影响。发现磷酸化的ERK1/2也可以上调CD46, CD55和CD59的表达水平。ERK1/2上游激酶MEK1的特异性抑制剂PD98059也可有效抑制mCRPs的蛋白质表达水平。进一步通过Western blot、双荧光素酶报告基因实验和免疫荧光染色等实验研究表明,ERK1/2的活化可以促进NF-κB的活性,并使其入核,进而促进mCRPs的表达。上述结果表明,HBXIP可以通过ERK1/2/NF-κB信号转导途径上调CD46,CD55和CD59的表达水平,进而降低乳腺癌细胞对CDC作用的敏感性,发挥乳腺癌细胞的免疫逃逸作用。
为了探讨HBXIP上游调控因子,我们通过TargetScan软件预测发现HBXIP为miR-520b的靶基因。于是,我们克隆并且构建了含有HBXIP 3'UTR的报告基因载体,双荧光素酶报告基因实验以及Western blot分析结果表明miR-520b可以直接结合HBXIP 3'UTR从而抑制HBXIP蛋白质的翻译。表明HBXIP在参与调节CDC作用中可以被miR-520b调控。
综上所述,本研究通过在乳腺癌细胞中对miR-520b或miR-520e的深入研究,发现miR-520b或miR-520e在乳腺癌免疫抑制方面发挥重要的作用,主要阐明了如下分子机制：1)miR-520b或miR-520e通过直接靶向结合补体调节蛋白CD46,影响乳腺癌细胞对补体攻击的效应；2)miR-520b靶蛋白HBXIP可以通过ERK1/2/NF-κB信号转导途径上调CD46, CD55和CD59的表达水平,进而降低乳腺癌细胞对CDC作用的敏感性,发挥乳腺癌细胞的免疫逃逸作用。本研究揭示了乳腺癌免疫抑制调节的一个新的分子机制,为乳腺癌的诊断、治疗提供了更丰富的理论依据。
MicroRNAs (miRNAs) are small approximately 21-23 nucleotide RNA species that are expressed from specialized genes. It has been reported that miRNAs participate cell growth, cell death, apoptosis, and metastasis during the carcinogenesis and tumor progression. Recently, it was reported that miR-520b was involved in immune regulation. CD46, CD55 and CD59 are clusters of membrane-bound complement-regulatory proteins (mCRPs), which are able to inhibit the complement-dependent cytotoxicity (CDC) through inhibiting C5 convertase during the complement activation cascade. Therefore, they play important roles in protecting tumor cells from complement attack. However, the mechanism of regulation for mCRPs remains unclear. It is unclear whether miR-520b is involved in the tumor immunosuppression. In the present study, we investigated the correlation between miR-520b or miR-520e and CRP using parallel breast cancer cell lines, such as MCF-7 and LM-MCF-7 (National patent of invent, China) that have different metastatic capabilities. The investigation contains two parts as follows:
Part one:miR-520b and miR-520e are involved in complement-dependent cytotoxicity in breast cancer cells by directly targeting CD46
According to our previous data in microarray comparing hepatoma cells and normal liver cells, we found that miR-520b was downreguated in hepatoma cells. Furthermore, to investigate the function of miR-520b and miR-520e in immunosuppression during breast cancer progression, we firstly examined the expression levels of miR-520b or miR-520e in normal breast HBL-100 cell line and other three breast cancer cell lines, including MCF-7, LM-MCF-7, and MDA-MB-231, by quantitative real-time PCR.. The results indicated that the expression levels of miR-520b and miR-520e in breast cancer MCF-7, LM-MCF-7, and MDA-MB-231 cells were downregulated relative to HBL-100 cells. Futhermore, we also examined the expression level of miR-520b in normal breast tissue and breast tumor tissue. And we found that the expression level of miR-520b between normal breast tissue and breast tumor tissue was significangtly different. We also found that the resistant capability of the breast cancer cells to CDC was stronger than that of normal breast cell line. To further elucidate the effect of miR-520b and miR-520e on CDC of breast cancer cells, we transfected miR-520b or miR-520e mimics as well as its anti-mimics into MCF-7 or MDA-MB-231 cells. The complement-mediated cytolysis assay revealed that the overexpression of miR-520b or miR-520e mimics was able to enhance the CDC sensitivity in breast cancer cells. Conversely, the suppression of miR-520b or miR-520e in breast cancer cells could decrease the sensitivity of breast cancer cells to CDC. Thus, we conclude that miR-520b and miR-520e are involved in immunosuppressive regulation mediated by complement.
Furthermore, to elucidate the mechanism of immunosuppressive regulation mediated by miR-520b and miR-520e in breast cancer cells, we identified the candidate targets of miR-520b and miR-520e using program online, TargetScan and DIANA microT3.0. We found that both miR-520b and miR-520e could target a complement cascade regulatory target, such as the membrane co-factor (MCP, CD46). Overexpression of miR-520b or miR-520e mimics could decrease the protein expression of CD46 rather than the mRNA level of CD46. Conversely, overexpression of anti-miR-520b or anti-miR-520e could increase the protein expression level of CD46. These data demonstrated that CD46 indeed acted as a target of miR-520b or miR-520e. We also indicated that miR-520b or miR-520e was able to regulate CD46 by directly targeting 3'UTR of CD46 mRNA. To further confirm the finding, we constructed a dual-luciferase reporter gene vector containing the 3'UTR targeting sites of miR-520b or miR-520e mRNA. The luciferase reporter gene assay showed that miR-520b or miR-520e was able to directly target the 3'UTR of CD46 mRNA. And the ELISA assay indicated that overexpression of miR520b or miR-520e could increase the deposition of C3b on breast cancer cells, so that it could promot the CDC effect on breast cancer cells. Thus, we conclude that both miR-520b and miR-520e are involved in CDC by directly targeting CD46.
Part two:Effect of miR-520b targeting HBXIP on complement-dependent cytotoxicity in breast cancer cells
Previous studies revealed that hepatitis B X-interacting protein (HBXIP) was involved in cancer cell growth and inhibiting apoptosis. In this study, we investigated the relationship between HBXIP and CDC in breast cancer cells. We firstly examined the expression levels of HBXIP in HBL-100, MCF-7, LM-MCF-7 and MDA-MB-231 cell lines by RT-PCR and Western blot analysis. We found that the expression levels of HBXIP in the three breast cancer cell lines were higher than that in normal breast cell line. Moreover, Western blot analysis showed that HBXIP expression was positively correlated with the expression levels of CD46, CD55 and CD59. Thus, we supposed that HBXIP might act as a regulator of mCRPs. Then, Dual-luciferase reporter gene assay revealed that the CD46 and CD59 promoter activities were increased in HBXIP stably transfected breast cancer cell line. Contrary, the promoter activities of CD46 and CD59 were decreased by RNAi targeting HBXIP mRNA in breast cancer cells. Furthermore, we showed that HBXIP upregulated the mRNA expression levels of CD46, CD55 and CD59 in breast cancer cells by real-time PCR as well as the protein expression level by Western blot. These data indicate that HBXIP is able to regulate the expression of CD46, CD55, and CD59 in breast cancer cells. We further found that HBXIP could activate NF-κB in breast cancer cells by reporter gene assay, Western blot analysis and immunofluorescence staining. The treatment with NF-κB specific inhibitor PDTC could inhibit the expression of CD46, CD55 and CD59 in breast cancer cells by luciferase reporter gene assay and Western blot analysis. Thus, we conclude that HBXIP is able upregulate the expression of CD46, CD55 and CD59 through NF-κB signaling pathway. Moreover, we found that HBXIP could increase the phosphorylated level of ERK1/2 rather than p38 and c-Jun N-terminal kinase (JNK). The activated ERK1/2 could upregulate the expression levels of CD46, CD55 and CD59. Contrarily, the specific inhibitor of MEK1 (upstream kinase of ERK1/2) PD98059 was able to decrease the expression levels of CD46, CD55 and CD59. Western blot analysis, dual-luciferase reporter gene assay and immunofluorescence staining assay showed that the activation of ERK1/2 could stimulate NF-κB translocation so that promoting the expression levels of CD46, CD55 and CD59. Therefore, we conclude that HBXIP is able to regulate the CDC sensitivity to protect the breast cancer cells from complement attack through upregulating CD46, CD55 and CD59 involving ERK1/2-NF-κB cascade signaling pathways. To investigate the upstream regulator of HBXIP, we constructed a luciferase reporter gene vector containing full-length 3'UTR of HBXIP mRNA according to the predicted bound sites of miR-520b using TargetScan program. Dual-luciferase reporter gene assay and Western blot analysis manifested that miR-520b was able to downregulate the expression of HBXIP at protein level by targeting its 3'UTR, suggesting that miR-520b targeting HBXIP is involved in the regulation of complement-dependent cytotoxicity in breast cancer cells.
In summary, we found that miR-520b and miR-520e were involved in immunosuppression in breast cancer cells. Our finding showed that miR-520b and miR-520e regulated the complement attack in breast cancer cells by directly targeting CD46. Moreover, HBXIP, one of the targets of miR-520b, could upregulate the expression levels of mCRPs to protect breast cancer cells from complement attack involving ERK1/2-NF-κB cascade signaling pathways. Our data provide a novel regulatory mechanism in immunosuppression of breast cancer cells.
引文
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