应用转基因技术研究Bacp/Nlp在肿瘤发生发展中的作用
摘要
Bacp/Nlp(Brcal associated centrosome protein/Ninein-like protein)是中心体定位的一个新的蛋白。本实验室前期的研究表明,Bacp/Nlp是一个潜在的癌基因,因此,利用转基因技术我们建立了Bacp/Nlp转基因小鼠模型,以探索Bacp/Nlp在肿瘤发生发展中的作用。
在动物实验中,未经任何因素处理的转基因小鼠中有约20%产生自发性肿瘤,包括乳腺癌、睾丸原位癌等,而在对照组中没有发现任何类型肿瘤的形成。另外,我们用化学致癌剂7,12-二甲基苯并蒽(DMBA)和物理致癌因素X-Ray处理Bacp/Nlp转基因小鼠及对照小鼠,发现转基因小鼠对以上致癌因素更为敏感,在DMBA处理组中,Bacp/Nlp转基因小鼠中有约45.8%产生了包括肺腺癌、表皮鳞癌、胃肠道间质瘤在内的多种肿瘤,而对照组小鼠仅有15%的肿瘤产生率;而在X-Ray放射组中,转基因小鼠有60%的小鼠产生淋巴瘤,多于对照组小鼠的肿瘤形成率(42%),而且两组处理中,转基因小鼠肿瘤产生的时间都比对照组早。
为了进一步探讨Bacp/Nlp促进肿瘤发生发展的机制,我们提取了MEF细胞进行了一系列生物学表型的测试,结果显示Bacp/Nlp转基因的MEF细胞比对照组细胞具有更强的体外生长能力和与细胞外基质的粘附能力。在对中心体的观察中发现转基因MEF细胞中有中心体扩增的现象,另外,转基因MEF细胞对凋亡刺激因素比对照的MEF细胞较为不敏感。
因此,以上实验结果表明,Bacp/Nlp能够促进肿瘤的发生发展,而且其中的机制可能是通过促进细胞的生长和抗凋亡能力,以及促进中心体的不稳定性进而导致基因组的不稳定性。
Bacp/Nlp (Brcal associated centrosome protein/Ninein-like protein) is a novel centrosome associated protein. Recently, we found that Bacp/Nlp was a potential oncogene. In order to research into the relationship between Bacp/Nlp and tumorigenesis, we generated Bacp/Nlp transgenic mice by using transgenic technology. After identifying the Bacp/Nlp expressing transgenic mice, we carried out a series of experiments at animal and cell levels to investigate the possible role of Bacp/Nlp in tumorigenesis.
We first carried out animal experimental studies to investigate the role of Bacp/Nlp in governing susceptibility to tumorigenesis under different conditions in vivo, and found that the transgenic mice without any treatment showed a nearly 20% incidence of spontaneous rumors, including breast cancer, carcinoma in situ of testicle, and a suspected ovary cancer. In contrast, none of the wild type mice showed any spontaneous tumors. In addition, we treated the Bacp/Nlp transgenic mice and their corresponding control mice with two types of DNA damage agent, including chemical carcinogen DMBA and physical carcinogen ionizing radiation (IR) to examine their tumorigenesis. In these studies, Bacp/Nlp transgenic mice showed increased tumor susceptibility to DNA damage agents.
In the DMBA group, all mice were injected with a single i.p. dose of DMBA at 10-14days of age. At 42 weeks after DMBA injection, all animals were killed for pathological examination. About 45.8% of Bacp/Nlp transgenic mice were detected to have tumors, including lung adenocarcinoma, gastrointestinal stromal tumor, and squamous cell carcinoma, which were about 3 times as many as the control ones (15%).
In the IR group, all mice were subjected to continued three dose of 3 Gy of X-Ray radiation every 6 days. At 32 weeks after irradiation, all mice were killed for pathological examination. The incidence of tumor of transgenic mice and control mice was 60% and 42%, respectively. The predominant tumor type in this group was lymphoma.
In order to comprehend how Bacp/Nlp promoted tumorigenesis, we isolated MEF (mouse embryo fibroblast) cells from transgenic and the control mice to examine their biological phenotypes in vitro. We observed the transgenic MEF cells grew faster than the control MEF cells, and the former had a higher colony formation rate than the latter. Moreover, the transgenic MEF cells exhibited increased adhesion ability compared with the control MEF cells, but they did not showed obvious differences in in vitro invasion and migration assays. We also found centrosome amplification in transgenic MEF cells. After UV and X-Ray radiation, the apoptotic rate of transgenic MEF cells was less than the control MEF cells, which indicated that expression of Bacp/Nlp enhanced the anti-apoptotic ability of MEF cells.
In summary, our findings indicated that Bacp/Nlp has strong ongenic property and promotes the tumorigenesis. The mechanisms might be through accelerating cell growth, promoting anti-apoptotic ability of cells to all kinds of DNA damage agents, and inducing centrosome abnormality that cause genome instability.
在动物实验中,未经任何因素处理的转基因小鼠中有约20%产生自发性肿瘤,包括乳腺癌、睾丸原位癌等,而在对照组中没有发现任何类型肿瘤的形成。另外,我们用化学致癌剂7,12-二甲基苯并蒽(DMBA)和物理致癌因素X-Ray处理Bacp/Nlp转基因小鼠及对照小鼠,发现转基因小鼠对以上致癌因素更为敏感,在DMBA处理组中,Bacp/Nlp转基因小鼠中有约45.8%产生了包括肺腺癌、表皮鳞癌、胃肠道间质瘤在内的多种肿瘤,而对照组小鼠仅有15%的肿瘤产生率;而在X-Ray放射组中,转基因小鼠有60%的小鼠产生淋巴瘤,多于对照组小鼠的肿瘤形成率(42%),而且两组处理中,转基因小鼠肿瘤产生的时间都比对照组早。
为了进一步探讨Bacp/Nlp促进肿瘤发生发展的机制,我们提取了MEF细胞进行了一系列生物学表型的测试,结果显示Bacp/Nlp转基因的MEF细胞比对照组细胞具有更强的体外生长能力和与细胞外基质的粘附能力。在对中心体的观察中发现转基因MEF细胞中有中心体扩增的现象,另外,转基因MEF细胞对凋亡刺激因素比对照的MEF细胞较为不敏感。
因此,以上实验结果表明,Bacp/Nlp能够促进肿瘤的发生发展,而且其中的机制可能是通过促进细胞的生长和抗凋亡能力,以及促进中心体的不稳定性进而导致基因组的不稳定性。
Bacp/Nlp (Brcal associated centrosome protein/Ninein-like protein) is a novel centrosome associated protein. Recently, we found that Bacp/Nlp was a potential oncogene. In order to research into the relationship between Bacp/Nlp and tumorigenesis, we generated Bacp/Nlp transgenic mice by using transgenic technology. After identifying the Bacp/Nlp expressing transgenic mice, we carried out a series of experiments at animal and cell levels to investigate the possible role of Bacp/Nlp in tumorigenesis.
We first carried out animal experimental studies to investigate the role of Bacp/Nlp in governing susceptibility to tumorigenesis under different conditions in vivo, and found that the transgenic mice without any treatment showed a nearly 20% incidence of spontaneous rumors, including breast cancer, carcinoma in situ of testicle, and a suspected ovary cancer. In contrast, none of the wild type mice showed any spontaneous tumors. In addition, we treated the Bacp/Nlp transgenic mice and their corresponding control mice with two types of DNA damage agent, including chemical carcinogen DMBA and physical carcinogen ionizing radiation (IR) to examine their tumorigenesis. In these studies, Bacp/Nlp transgenic mice showed increased tumor susceptibility to DNA damage agents.
In the DMBA group, all mice were injected with a single i.p. dose of DMBA at 10-14days of age. At 42 weeks after DMBA injection, all animals were killed for pathological examination. About 45.8% of Bacp/Nlp transgenic mice were detected to have tumors, including lung adenocarcinoma, gastrointestinal stromal tumor, and squamous cell carcinoma, which were about 3 times as many as the control ones (15%).
In the IR group, all mice were subjected to continued three dose of 3 Gy of X-Ray radiation every 6 days. At 32 weeks after irradiation, all mice were killed for pathological examination. The incidence of tumor of transgenic mice and control mice was 60% and 42%, respectively. The predominant tumor type in this group was lymphoma.
In order to comprehend how Bacp/Nlp promoted tumorigenesis, we isolated MEF (mouse embryo fibroblast) cells from transgenic and the control mice to examine their biological phenotypes in vitro. We observed the transgenic MEF cells grew faster than the control MEF cells, and the former had a higher colony formation rate than the latter. Moreover, the transgenic MEF cells exhibited increased adhesion ability compared with the control MEF cells, but they did not showed obvious differences in in vitro invasion and migration assays. We also found centrosome amplification in transgenic MEF cells. After UV and X-Ray radiation, the apoptotic rate of transgenic MEF cells was less than the control MEF cells, which indicated that expression of Bacp/Nlp enhanced the anti-apoptotic ability of MEF cells.
In summary, our findings indicated that Bacp/Nlp has strong ongenic property and promotes the tumorigenesis. The mechanisms might be through accelerating cell growth, promoting anti-apoptotic ability of cells to all kinds of DNA damage agents, and inducing centrosome abnormality that cause genome instability.
引文
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