人激活素受体结合蛋白2的克隆、鉴定及其与乳腺癌相关性的研究
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摘要
激活素(Activin)属于转化生长因子β(TGF-β)超家族成员的多功能生长和分化因子，激活素具有多种生物学功能及广泛的生物学活性，参与全身多种组织、细胞的生长调节，维持其正常功能。尤其是激活素A，对机体的整个生命过程均有重要的作用。激活素的生物学效应与其作用的靶细胞类型有关，具有明显的组织特异性。研究表明，激活素信号参与了乳腺细胞的生长并调节乳腺的发育。而且激活素的受体和它的信号分子存在于人的乳腺癌细胞系。这些结果提示激活素的表达可能与乳腺癌发生、发展具有密切的相关性。
激活素的信号转导途径如下：激活素与其Ⅱ型受体(ActRⅡ)结合后，Ⅱ型受体磷酸化，磷酸化的Ⅱ型受体会进一步使受体Ⅰ磷酸化，磷酸化的受体Ⅰ进一步使细胞内的转录因子Smad2／3磷酸化，磷酸化的Smad2／3会进一步和Smad4结合，并进入细胞核，从而调控下游基因的转录。在激活素的信号转导途径中，激活素受体Ⅱ是直接和激活素结合的受体，其在膜上的表达量将直接影响激活素信号的强度。最近的研究结果表明，小鼠激活素受体相互作用蛋白(ARIPs)可通过调控激活素受体Ⅱ在膜上的表达量来调节激活素的信号，其中小鼠的ARIP2可通过与ActRⅡ结合抑制激活素信号。但目前为止，尚无人ARIP2的相关研究报道。
本研究通过RT-PCR方法从人293细胞中钓取了人ARIP2的cDNA序列。该基因cDNA编码区长546bp，编码一个182个氨基酸的蛋白，与小鼠ARIP2有很高的同源性，在其N末端也有一个PDZ功能区，能特异性与激活素Ⅱ型受体相互作用。
本研究进一步检测了hARIP2对激活素信号的影响。将激活素应答性报告载体CAGA-lux与pcDNA3-FLAG-hARIP2或pcDNA3质粒共转染乳腺癌细胞系MCF-7细胞和MDA-MB-231细胞。结果显示，过表达hARIP2可以抑制激活素应答性基因的转录，并且具有剂量依赖性。而通过RNA干涉方法下调hARIP2的表达，则可增强激活素应答性基因的转录。
为了研究hARIP2对肿瘤细胞增殖的作用，我们分别在乳腺癌细胞系MCF-7细胞和MDA-MB-231细胞中过表达hARIP2或下调hARIP2的表达，之后利用MTT法和平板克隆形成实验检测了hARIP2对MCF-7细胞和MDA-MB-231细胞增殖能力的影响。结果表明，过表达hARIP2能够促进MCF-7细胞和MDA-MB-231细胞的增殖。反之，下调hARIP2基因的表达则抑制MCF-7细胞和MDA-MB-231细胞的增殖。同时，我们也研究了hARIP2对其它肿瘤细胞的作用，发现过表达hARIP2同样能够促进其它肿瘤细胞的增殖，下调hARIP2基因的表达则抑制肿瘤细胞的增殖。
另外，本研究还自行制备了hARIP2多克隆抗体。并用此抗体通过免疫组织化学方法检测了hARIP2在乳腺良性增生组织、乳腺纤维腺瘤、乳腺单纯癌、乳腺浸润性导管癌及乳腺黏液癌组织中的表达情况，同时分析了hARIP2的表达与肿瘤的恶性度、肿瘤大小、肿瘤病理学等级及转移情况的关系。结果表明，hARIP2在乳腺良性增生组织及乳腺纤维腺瘤组织中不表达或低表达，而在乳腺癌组织中则高表达。此结果提示，hARIP2表达水平与乳腺癌的发生具有高度相关性。
本研究为进一步探讨激活素信号的调控机制及其在乳腺癌等疾病的发生、发展中的作用奠定了实验基础。同时，对乳腺癌的诊断及治疗具有重要的指导意义。
Activins are member of the transforming growth factorβ(TGF-β) superfamily of growthand development of differentiation factors and have numerous biological functions and widelybiological actions. Activin regulates the development of cells and tissues and keep thehomeostasis of organisms. Especially activin A, always plays important roles for organismsfrom new born to adult. The biological actions of activin on target cells are tissue-specific,which included regulating the cell proliferation and inhibiting the development of tumor cells.Activin signaling has been associated with mammary cell growth inhibition as well asregulation of mammary glandular development.Studies showed that activin and its receptorsare expressed during postnatal mouse mammary development and glandular formation duringthe lactating phase. Activin receptors and signaling molecules are also present in humanbreast cancer cell lines. These results suggest that the expression of activin A has closerelationship with breast tumorigenesis and progression.
Then signal transduction pathway is as followed: activin binds directly to its typeⅡreceptor, leading to the recruitment, phosphorylation and subsequent activation of the typeⅠreceptor. On activation, the type I receptor binds and then phosphorylates a subset ofcytoplasmic Smad protein-Smad 2/3. The phosphorylated Smad 2/3 can bind to Smad 4.These Smads translocate to the nucleus, where they control the transcription of target genes.In the course of signal transduction, the expression level of typeⅡreceptor in membrane willaffect the intensity of activin signal. The recent investigation indicated that mouse ARIPs canregulate activin signal through control the expression level of typeⅡreceptor on membrane.But to date, there is no report in this aspect.
In this study, we obtained a novel member of ARIPs from 293 cells by RT-PCR. The novelcDNA clone encodes the full length is 546bp. The novel gene encodes a 182 amimo acidprotein. Because of high homology with mouse ARIP2, we named the novel protein as humanactivin receptor interacting protein 2. Like murine ARIP2, hARIP2 has a PDZ domain in itsNH2-terminal region and can interact specifically with ActRIIs.
Our study further tested the effect of hARIP2 on activin-induced signal transductionpathway, the CAGA-lux construct which provides luciferase reporter gene and specificallyresponds to activin was selected. CAGA-lux, pcDNA3-FLAG-hARIP2 or pSilencer-hARIP2were co-transfected into human breast adenocarcinoma MCF-7 cells and MDA-MB-231 cellsin vitro. The results showed that the overexpression of hARIP2 decreased activin-inducedtranscriptional activity. However, inhibiting the expression of hARIP2 augmentedactivin-induced transcriptional activity.
To determine a role of hARIP2 for the proliferation of tumor cells, the control,recombinant plasmid Flag-pcDNA3-hARIP2, control siRNA and pSilencer-hARIP2 weretransfected into human breast adenocarcinoma MCF-7 cells and MDA-MB-231 cellsrespectively. Through MTT assay and plate clonality formation assay, we found that thelevels of cell proliferation increased when hARIP2 was over-expressed compared with control. However, when the cells were transfected with pSilencer-hARIP2, the levels of cellproliferation decreased compared with control siRNA. Meanwhile, similar results wereobtained in other tumor cells. These results indicated that overexpressing hARIP2 promotedbreast tumor cell proliferation.
Moreover, we prepared anti-hARIP2 polyclonal antibody by ourselves. Byimmunohistochemistry method, we determined the distribution of hARIP2 in the tissuesincluding breast benign hyperplasia, fibroadenoma, mucous adenocarcinoma, trachealcarcinoma and simple carcinoma using the antibody, and further investigated the associationof the expression of hARIP2 with malignant progression, tumor size, tumor grade andmetastases by Immunohistochemistry method. The result showed significant correlations inbreast cancer specimens between an increase of hARIP2 abundance and high tumor malignantprogression, high tumor grade, and high tumor metastases. Moreover, hARIP2 was expressedmore frequently and much more intensely in malignant breast tissues such as simplecarcinoma, invasive ductal carcinoma and mucinous adenocarcinoma than in benignhyperplasia or fibroadenoma cases. These results suggesting that the expression level ofhARIP2 has close relationship with breast tumorigenisis, tumor malignant progression, tumorgrade, and tumor metastases.
This study strengthened the bases of activin-mediated breast cancer diseases development,progression and therapies with theoretical and experimental evidence. Further more, this studyhad a significant value for the diagnosis and treatment of breast cancer.
激活素的信号转导途径如下：激活素与其Ⅱ型受体(ActRⅡ)结合后，Ⅱ型受体磷酸化，磷酸化的Ⅱ型受体会进一步使受体Ⅰ磷酸化，磷酸化的受体Ⅰ进一步使细胞内的转录因子Smad2／3磷酸化，磷酸化的Smad2／3会进一步和Smad4结合，并进入细胞核，从而调控下游基因的转录。在激活素的信号转导途径中，激活素受体Ⅱ是直接和激活素结合的受体，其在膜上的表达量将直接影响激活素信号的强度。最近的研究结果表明，小鼠激活素受体相互作用蛋白(ARIPs)可通过调控激活素受体Ⅱ在膜上的表达量来调节激活素的信号，其中小鼠的ARIP2可通过与ActRⅡ结合抑制激活素信号。但目前为止，尚无人ARIP2的相关研究报道。
本研究通过RT-PCR方法从人293细胞中钓取了人ARIP2的cDNA序列。该基因cDNA编码区长546bp，编码一个182个氨基酸的蛋白，与小鼠ARIP2有很高的同源性，在其N末端也有一个PDZ功能区，能特异性与激活素Ⅱ型受体相互作用。
本研究进一步检测了hARIP2对激活素信号的影响。将激活素应答性报告载体CAGA-lux与pcDNA3-FLAG-hARIP2或pcDNA3质粒共转染乳腺癌细胞系MCF-7细胞和MDA-MB-231细胞。结果显示，过表达hARIP2可以抑制激活素应答性基因的转录，并且具有剂量依赖性。而通过RNA干涉方法下调hARIP2的表达，则可增强激活素应答性基因的转录。
为了研究hARIP2对肿瘤细胞增殖的作用，我们分别在乳腺癌细胞系MCF-7细胞和MDA-MB-231细胞中过表达hARIP2或下调hARIP2的表达，之后利用MTT法和平板克隆形成实验检测了hARIP2对MCF-7细胞和MDA-MB-231细胞增殖能力的影响。结果表明，过表达hARIP2能够促进MCF-7细胞和MDA-MB-231细胞的增殖。反之，下调hARIP2基因的表达则抑制MCF-7细胞和MDA-MB-231细胞的增殖。同时，我们也研究了hARIP2对其它肿瘤细胞的作用，发现过表达hARIP2同样能够促进其它肿瘤细胞的增殖，下调hARIP2基因的表达则抑制肿瘤细胞的增殖。
另外，本研究还自行制备了hARIP2多克隆抗体。并用此抗体通过免疫组织化学方法检测了hARIP2在乳腺良性增生组织、乳腺纤维腺瘤、乳腺单纯癌、乳腺浸润性导管癌及乳腺黏液癌组织中的表达情况，同时分析了hARIP2的表达与肿瘤的恶性度、肿瘤大小、肿瘤病理学等级及转移情况的关系。结果表明，hARIP2在乳腺良性增生组织及乳腺纤维腺瘤组织中不表达或低表达，而在乳腺癌组织中则高表达。此结果提示，hARIP2表达水平与乳腺癌的发生具有高度相关性。
本研究为进一步探讨激活素信号的调控机制及其在乳腺癌等疾病的发生、发展中的作用奠定了实验基础。同时，对乳腺癌的诊断及治疗具有重要的指导意义。
Activins are member of the transforming growth factorβ(TGF-β) superfamily of growthand development of differentiation factors and have numerous biological functions and widelybiological actions. Activin regulates the development of cells and tissues and keep thehomeostasis of organisms. Especially activin A, always plays important roles for organismsfrom new born to adult. The biological actions of activin on target cells are tissue-specific,which included regulating the cell proliferation and inhibiting the development of tumor cells.Activin signaling has been associated with mammary cell growth inhibition as well asregulation of mammary glandular development.Studies showed that activin and its receptorsare expressed during postnatal mouse mammary development and glandular formation duringthe lactating phase. Activin receptors and signaling molecules are also present in humanbreast cancer cell lines. These results suggest that the expression of activin A has closerelationship with breast tumorigenesis and progression.
Then signal transduction pathway is as followed: activin binds directly to its typeⅡreceptor, leading to the recruitment, phosphorylation and subsequent activation of the typeⅠreceptor. On activation, the type I receptor binds and then phosphorylates a subset ofcytoplasmic Smad protein-Smad 2/3. The phosphorylated Smad 2/3 can bind to Smad 4.These Smads translocate to the nucleus, where they control the transcription of target genes.In the course of signal transduction, the expression level of typeⅡreceptor in membrane willaffect the intensity of activin signal. The recent investigation indicated that mouse ARIPs canregulate activin signal through control the expression level of typeⅡreceptor on membrane.But to date, there is no report in this aspect.
In this study, we obtained a novel member of ARIPs from 293 cells by RT-PCR. The novelcDNA clone encodes the full length is 546bp. The novel gene encodes a 182 amimo acidprotein. Because of high homology with mouse ARIP2, we named the novel protein as humanactivin receptor interacting protein 2. Like murine ARIP2, hARIP2 has a PDZ domain in itsNH2-terminal region and can interact specifically with ActRIIs.
Our study further tested the effect of hARIP2 on activin-induced signal transductionpathway, the CAGA-lux construct which provides luciferase reporter gene and specificallyresponds to activin was selected. CAGA-lux, pcDNA3-FLAG-hARIP2 or pSilencer-hARIP2were co-transfected into human breast adenocarcinoma MCF-7 cells and MDA-MB-231 cellsin vitro. The results showed that the overexpression of hARIP2 decreased activin-inducedtranscriptional activity. However, inhibiting the expression of hARIP2 augmentedactivin-induced transcriptional activity.
To determine a role of hARIP2 for the proliferation of tumor cells, the control,recombinant plasmid Flag-pcDNA3-hARIP2, control siRNA and pSilencer-hARIP2 weretransfected into human breast adenocarcinoma MCF-7 cells and MDA-MB-231 cellsrespectively. Through MTT assay and plate clonality formation assay, we found that thelevels of cell proliferation increased when hARIP2 was over-expressed compared with control. However, when the cells were transfected with pSilencer-hARIP2, the levels of cellproliferation decreased compared with control siRNA. Meanwhile, similar results wereobtained in other tumor cells. These results indicated that overexpressing hARIP2 promotedbreast tumor cell proliferation.
Moreover, we prepared anti-hARIP2 polyclonal antibody by ourselves. Byimmunohistochemistry method, we determined the distribution of hARIP2 in the tissuesincluding breast benign hyperplasia, fibroadenoma, mucous adenocarcinoma, trachealcarcinoma and simple carcinoma using the antibody, and further investigated the associationof the expression of hARIP2 with malignant progression, tumor size, tumor grade andmetastases by Immunohistochemistry method. The result showed significant correlations inbreast cancer specimens between an increase of hARIP2 abundance and high tumor malignantprogression, high tumor grade, and high tumor metastases. Moreover, hARIP2 was expressedmore frequently and much more intensely in malignant breast tissues such as simplecarcinoma, invasive ductal carcinoma and mucinous adenocarcinoma than in benignhyperplasia or fibroadenoma cases. These results suggesting that the expression level ofhARIP2 has close relationship with breast tumorigenisis, tumor malignant progression, tumorgrade, and tumor metastases.
This study strengthened the bases of activin-mediated breast cancer diseases development,progression and therapies with theoretical and experimental evidence. Further more, this studyhad a significant value for the diagnosis and treatment of breast cancer.
引文
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