Basigin/CD147在人神经胶质瘤侵袭中的作用机制及其反义RNA抑制神经胶质瘤侵袭的实验研究
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摘要
胶质瘤是颅内常见恶性肿瘤,占颅内肿瘤的35.26%～60.96%,平均44.69%,目前尚无根治方法。胶质瘤具有发病率、复发率、死亡率高和治愈率低等“三高一低”的特点。恶性胶质瘤预后极差,中位生存时间少于18个月,2年存活率约为5%。胶质瘤多呈浸润性生长,手术难以全切,需结合放疗、化疗、生物治疗等综合治疗手段以延长病人生存期。随着影像学技术的发展,胶质瘤的诊断、治疗取得了一定进展,但总体疗效并未实现突破。因此,神经胶质瘤是神经外科的难题和医学研究的重要课题之一。
造成神经胶质瘤死亡率高的主要原因是神经胶质瘤的高侵袭性。其侵袭过程中的一个重要因素是细胞外基质的降解,其中,起重要作用的是一类Zn2+依赖的基质金属蛋白酶MMPs(Matrix metalloproteinases)。MMPs能够破坏局部组织结构和基底膜屏障,促进肿瘤生长和转移,并且可促进肿瘤新生血管的形成。CD147作为MMPs的诱导因子,是一个广泛表达的质膜糖蛋白,参与机体多种生理和病理过程。CD147分子表达于许多正常细胞类型,包括成体和胚胎组织。它在炎症的发生发展、病毒的易化介导、细胞之间的黏附及胚胎发育等方面起着一定的作用。研究证实,CD147表达于各种肿瘤组织特别是恶性肿瘤,如乳腺癌、肺癌、肾癌、恶性黑色素瘤、淋巴瘤等,同时其表达较相应正常组织明显要高。
近年来一些研究发现在中枢神经系统,CD147表达于血脑屏障内皮细胞、脉络膜上皮细胞和视网膜色素上皮细胞,并在血脑屏障中起作用。但缺乏CD147分子在神经系统及神经系统肿瘤中表达的系统性研究。以往研究虽然表明CD147功能上与某些恶性肿瘤,如肝癌存在相关性,提示其在致病机制上是一个非常重要的因子,但更明确的作用机制还需要进一步深入探讨。另外,CD147在神经系统肿瘤,尤其是神经胶质瘤侵袭中的作用如何还不明确。
本研究中,我们收集了18例神经胶质瘤样本,并采用63点胶质瘤组织芯片检测Basigin/CD147在人脑组织及神经胶质瘤组织中的表达情况。分别在组织水平及基因水平分析了Basigin/CD147的表达与临床病理学特征的关系;构建Basigin/CD147反义RNA表达载体,建立并筛选低表达CD147的重组人神经胶质瘤细胞株U251/147的克隆;并进一步采用反义RNA技术研究Basigin/CD147在胶质瘤侵袭、血管形成方面的作用及机制。
第一部分:Basigin/CD147在人神经胶质瘤组织中的表达及临床意义。
我们收集了18例神经胶质瘤样本,并采用63点胶质瘤组织芯片检测CD147的表达情况。结果发现,神经胶质瘤组织中Basigin/CD147表达于肿瘤细胞膜和细胞质中,但未见细胞核染色。神经胶质瘤组织中Basigin/CD147蛋白的阳性表达率为74.3%。而正常脑组织中仅血管内皮细胞浆有阳性着色,神经细胞及神经胶质细胞未见表达。表明在正常脑组织中CD147仅表达于血管内皮。此研究结果说明与正常脑组织相比,神经胶质瘤组织中Basigin/CD147存在过度表达。不同级别胶质瘤细胞着色结果分析发现,在胶质瘤细胞胞浆中有CD147着色,并且高级别星型胶质瘤(III、IV级)瘤细胞胞浆CD147着色显著强于低级别星型胶质瘤(I、II级)。说明胶质瘤细胞不仅表达CD147,并且其表达程度与胶质瘤恶性程度成正比。
胶质瘤组织RT-PCR结果显示,Basigin/CD147mRNA的表达在神经胶质瘤组织中阳性率为83.3%,明显高于正常脑组织中的阳性率25%(P<0.05)。在阳性表达病理中,对Basigin/CD147mRNA的RT-PCR产物进行半定量测定(Basigin/β-actin),结果显示Basigin/CD147mRNA在神经胶质瘤组织中的表达量为0.274±0.087,明显高于正常组织0.081±0.043,两者具有显著性差异(P<0.05)。此结果提示Basigin/CD147的表达与神经胶质瘤的发生有关。
第二部分:Basigin/CD147反义RNA表达载体的建立及重组人神经胶质瘤细胞株U251/147的克隆建立及筛选。
我们构建了Basigin/CD147反义RNA质粒,用反义RNA特异封闭肿瘤细胞的mRNA,封闭胶质瘤细胞表面Basigin/CD147的表达,从而抑制其刺激肿瘤细胞分泌MMPs,进而抑制胶质瘤细胞的侵袭。我们选择表达Basigin/CD147的U251细胞系作为反义核酸的封闭靶点,进而研究其被抑制后的生物学变化。实验结果表明,当PCI-147重组质粒转染人神经胶质瘤细胞U251后,转染细胞的流式细胞检测结果证实细胞膜表面荧光强度减弱。Western Blot检测结果也证实Basigin/CD147表达降低。这些变化主要是由于反义RNA与CD147mRNA结合,阻碍了其翻译过程,封闭了Basigin/CD147分子的表达。
第三部分:Basigin/CD147反义核酸对人神经胶质瘤细胞U251侵袭转移能力的影响。
明胶酶谱实验发现,U251/147细胞分泌的MMP-2和MMP-9显著低于U251细胞和U251/neo细胞。说明CD147反义核酸的确影响了U251细胞明胶酶的分泌。U251/147细胞培养上清中VEGF水平显著低于U251细胞和U251/neo细胞,分别降低了37.61%和42.76%,说明CD147有促进胶质瘤细胞VEGF分泌的作用,而CD147反义核酸抑制了U251细胞VEGF的分泌。重组基底膜实验中可以看出,U251/147细胞侵袭人工重组基底膜的数目显著少于U251细胞和U251/neo细胞,U251/147细胞的穿膜数较U251细胞和U251/neo细胞分别降低了65.8%和70.1%,表现出细胞侵袭能力的降低。细胞划伤实验中,U251/147细胞的运动细胞数显著低于U251细胞,说明U251/147细胞的运动能力显著低于U251细胞,CD147反义核酸显著降低了U251细胞的运动能力。
Gliomas are the most common of brain neoplasms and exhibit a high degree of diffuse local invasion of normal nervous tissue. High invasion is the principle reason to the high mortality of Gliomas. Tumor cells often infiltrate beyond any obviously defined tumor margin and contribute to the high incidence of recurrence. In the invasive and metastatic process of malignant tumor, an important step is the degradation of extracellular matrix (ECM).Molecules existing in ECM and receptors or ligands existing on the surfaces of tumor cells play critical roles.
CD147, also named extracelluar matrix metalloproteinase inducer (EMMPRIN). EMMPRIN expressed by cultured tumor cells stimulates fibroblasts to produce very high levels of collagenase activity, which likely facilitates tumor metastasis. Previous studies demonstrated that EMMPRIN concentrated on the surfaces of most tumor cells, promoted invasion of tumor cells by stimulating stromal cells to produce elevated levels of several matrix metalloproteinase (MMPs) which play very important roles in several aspects of tumor progression, including growth, invasion, metastasis, and angiogenesis. Moreover, supporting its key role in the processes of tumorigenesis and metastasis, EMMPRIN was reported as one of the most constantly up-regulated mRNA in metastatic cells. Our interest in gliomas let us to consider the role of CD147 in glioma invasion, metastasis, and angiogenesis.
Here, we investigated expression of Basigin/CD147 in normal brain and gliomas of varying malignancy by using tissue array and tissue obtained from surgical removal. We constructed a vector of antisense RNA of CD147 and investigated its inhibitory effects on invasion and angiogenesis of glioblastoma cells in vitro. We also study the effects of antisense RNA of CD147 to tumor formation in nude mice and the therapy effect to tumor-bearing nude mice.
Part 1: Expression of Basigin/CD147 in normal brain and gliomas.
We investigated expression of Basigin/CD147 in normal brain and gliomas of varying malignancy by immunohistochemistry using tissue array and tissue obtained from surgical removal. Immunolocalization revealed quite different distribution in non-neoplastic brain and glioma: In non-neoplastic portions of the brain, EMMPRIN immunostaining was demonstrated only in vascular endothelial cells, whereas in glioma the tumor cells were stained positively, the positive immunohistochemical staining of gliomas was 74.3%. In astrocytomas, varying percentages of the tumor cells were positive, level of immunohistochemical staining of higher grade astrocytomas(grade III, IV) was higher than that of lower grade astrocytomas(grade I,II). The RT-PCR study indicated that level of Basigin/CD147 mRNA expression was higher in gliomas(0.274±0.087) than in non-neoplastic brain(0.081±0.043). Thus, the Basigin/CD147 mRNA level was up-regulated significantly in gliomas compared with non-neoplastic tissue(P<0.05 by unpaired t-test).
Part 2: Construction of the antisense RNA expression vector of Basigin/CD147. Transfection of the antisense RNA vector to U251 and selection of the positive clone.
Full length cDNA fragment coding for basigin/CD147 was cloned in the antisense orientation into the XbaI and XhoI site of the eukaryotic expression vector PCI-neo. The antisense vector of basigin, named as PCI-147.Empty vector PCI-neo and antisense vector PCI-147 were transfected into human glioblastoma cell line U251 via cation liposome Lipfectinamine2000 (Gibco) according to the manufacturer’s description and the two kinds of transfected cells were named as U251/neo and U251/147 respectively. Stable antisense transfectants were generated and characterized. Basigin/CD147 has been shown to play significant roles in ECM degradation. Transfection of U251 cells with the antisense vector strongly inhibited the expression of CD147 as compared to U251, U251/neo.
Part 3: Study on the inhibitory effects of antisense RNA on proliferation of U251 in vitro.
Gelatin zymography was used to analyze the effect of antisense RNA on MMPs secretion. The results showed that the secretions of MMP-9 and MMP-2 in the antisense transfectants were inhibited compared to parental- and empty vector-transfected cells in Gelatin zymography assay. Since CD147 has implicated in the invasiveness of tumor cells, we evaluated the migration of parental and stable transfectants. In scrape-wound-migration assay, the mobility of stable antisense transfectants was decreased as compared to parental- and empty vector-transfected cells. Matrigel-Boyden chamber method was used to study the inhibitory ability of antisense RNA on tumor cells invasion and mobility through the reconstituted basement membrane. The results showed that the number of stable transfectants infiltrated cells of U251/147 were less than those of U251/neo and intact U251. More over, ELISA was used to detect the VEGF (Vascular endothelial growth factor) production in the supernatant of selected cells. Downregulation of CD147 by antisense transfection in U251 cells resulted in a reduction of VEGF secreted into media by antisense tumor cells compared to parental- and empty vector-transfected cells.
造成神经胶质瘤死亡率高的主要原因是神经胶质瘤的高侵袭性。其侵袭过程中的一个重要因素是细胞外基质的降解,其中,起重要作用的是一类Zn2+依赖的基质金属蛋白酶MMPs(Matrix metalloproteinases)。MMPs能够破坏局部组织结构和基底膜屏障,促进肿瘤生长和转移,并且可促进肿瘤新生血管的形成。CD147作为MMPs的诱导因子,是一个广泛表达的质膜糖蛋白,参与机体多种生理和病理过程。CD147分子表达于许多正常细胞类型,包括成体和胚胎组织。它在炎症的发生发展、病毒的易化介导、细胞之间的黏附及胚胎发育等方面起着一定的作用。研究证实,CD147表达于各种肿瘤组织特别是恶性肿瘤,如乳腺癌、肺癌、肾癌、恶性黑色素瘤、淋巴瘤等,同时其表达较相应正常组织明显要高。
近年来一些研究发现在中枢神经系统,CD147表达于血脑屏障内皮细胞、脉络膜上皮细胞和视网膜色素上皮细胞,并在血脑屏障中起作用。但缺乏CD147分子在神经系统及神经系统肿瘤中表达的系统性研究。以往研究虽然表明CD147功能上与某些恶性肿瘤,如肝癌存在相关性,提示其在致病机制上是一个非常重要的因子,但更明确的作用机制还需要进一步深入探讨。另外,CD147在神经系统肿瘤,尤其是神经胶质瘤侵袭中的作用如何还不明确。
本研究中,我们收集了18例神经胶质瘤样本,并采用63点胶质瘤组织芯片检测Basigin/CD147在人脑组织及神经胶质瘤组织中的表达情况。分别在组织水平及基因水平分析了Basigin/CD147的表达与临床病理学特征的关系;构建Basigin/CD147反义RNA表达载体,建立并筛选低表达CD147的重组人神经胶质瘤细胞株U251/147的克隆;并进一步采用反义RNA技术研究Basigin/CD147在胶质瘤侵袭、血管形成方面的作用及机制。
第一部分:Basigin/CD147在人神经胶质瘤组织中的表达及临床意义。
我们收集了18例神经胶质瘤样本,并采用63点胶质瘤组织芯片检测CD147的表达情况。结果发现,神经胶质瘤组织中Basigin/CD147表达于肿瘤细胞膜和细胞质中,但未见细胞核染色。神经胶质瘤组织中Basigin/CD147蛋白的阳性表达率为74.3%。而正常脑组织中仅血管内皮细胞浆有阳性着色,神经细胞及神经胶质细胞未见表达。表明在正常脑组织中CD147仅表达于血管内皮。此研究结果说明与正常脑组织相比,神经胶质瘤组织中Basigin/CD147存在过度表达。不同级别胶质瘤细胞着色结果分析发现,在胶质瘤细胞胞浆中有CD147着色,并且高级别星型胶质瘤(III、IV级)瘤细胞胞浆CD147着色显著强于低级别星型胶质瘤(I、II级)。说明胶质瘤细胞不仅表达CD147,并且其表达程度与胶质瘤恶性程度成正比。
胶质瘤组织RT-PCR结果显示,Basigin/CD147mRNA的表达在神经胶质瘤组织中阳性率为83.3%,明显高于正常脑组织中的阳性率25%(P<0.05)。在阳性表达病理中,对Basigin/CD147mRNA的RT-PCR产物进行半定量测定(Basigin/β-actin),结果显示Basigin/CD147mRNA在神经胶质瘤组织中的表达量为0.274±0.087,明显高于正常组织0.081±0.043,两者具有显著性差异(P<0.05)。此结果提示Basigin/CD147的表达与神经胶质瘤的发生有关。
第二部分:Basigin/CD147反义RNA表达载体的建立及重组人神经胶质瘤细胞株U251/147的克隆建立及筛选。
我们构建了Basigin/CD147反义RNA质粒,用反义RNA特异封闭肿瘤细胞的mRNA,封闭胶质瘤细胞表面Basigin/CD147的表达,从而抑制其刺激肿瘤细胞分泌MMPs,进而抑制胶质瘤细胞的侵袭。我们选择表达Basigin/CD147的U251细胞系作为反义核酸的封闭靶点,进而研究其被抑制后的生物学变化。实验结果表明,当PCI-147重组质粒转染人神经胶质瘤细胞U251后,转染细胞的流式细胞检测结果证实细胞膜表面荧光强度减弱。Western Blot检测结果也证实Basigin/CD147表达降低。这些变化主要是由于反义RNA与CD147mRNA结合,阻碍了其翻译过程,封闭了Basigin/CD147分子的表达。
第三部分:Basigin/CD147反义核酸对人神经胶质瘤细胞U251侵袭转移能力的影响。
明胶酶谱实验发现,U251/147细胞分泌的MMP-2和MMP-9显著低于U251细胞和U251/neo细胞。说明CD147反义核酸的确影响了U251细胞明胶酶的分泌。U251/147细胞培养上清中VEGF水平显著低于U251细胞和U251/neo细胞,分别降低了37.61%和42.76%,说明CD147有促进胶质瘤细胞VEGF分泌的作用,而CD147反义核酸抑制了U251细胞VEGF的分泌。重组基底膜实验中可以看出,U251/147细胞侵袭人工重组基底膜的数目显著少于U251细胞和U251/neo细胞,U251/147细胞的穿膜数较U251细胞和U251/neo细胞分别降低了65.8%和70.1%,表现出细胞侵袭能力的降低。细胞划伤实验中,U251/147细胞的运动细胞数显著低于U251细胞,说明U251/147细胞的运动能力显著低于U251细胞,CD147反义核酸显著降低了U251细胞的运动能力。
Gliomas are the most common of brain neoplasms and exhibit a high degree of diffuse local invasion of normal nervous tissue. High invasion is the principle reason to the high mortality of Gliomas. Tumor cells often infiltrate beyond any obviously defined tumor margin and contribute to the high incidence of recurrence. In the invasive and metastatic process of malignant tumor, an important step is the degradation of extracellular matrix (ECM).Molecules existing in ECM and receptors or ligands existing on the surfaces of tumor cells play critical roles.
CD147, also named extracelluar matrix metalloproteinase inducer (EMMPRIN). EMMPRIN expressed by cultured tumor cells stimulates fibroblasts to produce very high levels of collagenase activity, which likely facilitates tumor metastasis. Previous studies demonstrated that EMMPRIN concentrated on the surfaces of most tumor cells, promoted invasion of tumor cells by stimulating stromal cells to produce elevated levels of several matrix metalloproteinase (MMPs) which play very important roles in several aspects of tumor progression, including growth, invasion, metastasis, and angiogenesis. Moreover, supporting its key role in the processes of tumorigenesis and metastasis, EMMPRIN was reported as one of the most constantly up-regulated mRNA in metastatic cells. Our interest in gliomas let us to consider the role of CD147 in glioma invasion, metastasis, and angiogenesis.
Here, we investigated expression of Basigin/CD147 in normal brain and gliomas of varying malignancy by using tissue array and tissue obtained from surgical removal. We constructed a vector of antisense RNA of CD147 and investigated its inhibitory effects on invasion and angiogenesis of glioblastoma cells in vitro. We also study the effects of antisense RNA of CD147 to tumor formation in nude mice and the therapy effect to tumor-bearing nude mice.
Part 1: Expression of Basigin/CD147 in normal brain and gliomas.
We investigated expression of Basigin/CD147 in normal brain and gliomas of varying malignancy by immunohistochemistry using tissue array and tissue obtained from surgical removal. Immunolocalization revealed quite different distribution in non-neoplastic brain and glioma: In non-neoplastic portions of the brain, EMMPRIN immunostaining was demonstrated only in vascular endothelial cells, whereas in glioma the tumor cells were stained positively, the positive immunohistochemical staining of gliomas was 74.3%. In astrocytomas, varying percentages of the tumor cells were positive, level of immunohistochemical staining of higher grade astrocytomas(grade III, IV) was higher than that of lower grade astrocytomas(grade I,II). The RT-PCR study indicated that level of Basigin/CD147 mRNA expression was higher in gliomas(0.274±0.087) than in non-neoplastic brain(0.081±0.043). Thus, the Basigin/CD147 mRNA level was up-regulated significantly in gliomas compared with non-neoplastic tissue(P<0.05 by unpaired t-test).
Part 2: Construction of the antisense RNA expression vector of Basigin/CD147. Transfection of the antisense RNA vector to U251 and selection of the positive clone.
Full length cDNA fragment coding for basigin/CD147 was cloned in the antisense orientation into the XbaI and XhoI site of the eukaryotic expression vector PCI-neo. The antisense vector of basigin, named as PCI-147.Empty vector PCI-neo and antisense vector PCI-147 were transfected into human glioblastoma cell line U251 via cation liposome Lipfectinamine2000 (Gibco) according to the manufacturer’s description and the two kinds of transfected cells were named as U251/neo and U251/147 respectively. Stable antisense transfectants were generated and characterized. Basigin/CD147 has been shown to play significant roles in ECM degradation. Transfection of U251 cells with the antisense vector strongly inhibited the expression of CD147 as compared to U251, U251/neo.
Part 3: Study on the inhibitory effects of antisense RNA on proliferation of U251 in vitro.
Gelatin zymography was used to analyze the effect of antisense RNA on MMPs secretion. The results showed that the secretions of MMP-9 and MMP-2 in the antisense transfectants were inhibited compared to parental- and empty vector-transfected cells in Gelatin zymography assay. Since CD147 has implicated in the invasiveness of tumor cells, we evaluated the migration of parental and stable transfectants. In scrape-wound-migration assay, the mobility of stable antisense transfectants was decreased as compared to parental- and empty vector-transfected cells. Matrigel-Boyden chamber method was used to study the inhibitory ability of antisense RNA on tumor cells invasion and mobility through the reconstituted basement membrane. The results showed that the number of stable transfectants infiltrated cells of U251/147 were less than those of U251/neo and intact U251. More over, ELISA was used to detect the VEGF (Vascular endothelial growth factor) production in the supernatant of selected cells. Downregulation of CD147 by antisense transfection in U251 cells resulted in a reduction of VEGF secreted into media by antisense tumor cells compared to parental- and empty vector-transfected cells.
引文
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