激活PPARγ与视黄醇类受体抑制骨肉瘤生长的作用研究
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摘要
实验目的
骨肉瘤是骨肿瘤中的主重要恶性肿瘤。患者的长期生存依赖于如何预防、治疗这类肿瘤及如何减少其复发率和病灶转移。本课题旨在研究激活PPARγ和视黄醇类核受体抑制人骨肉瘤生长的作用。
实验方法与步骤
本课题采用细胞增殖实验、PCR技术、蛋白免疫印迹技术、重组腺病毒技术、报告质粒技术及常规组织学技术,研究激动PPARγ与类视黄醇类核受体协同抑制人骨肉瘤细胞增殖的作用。实验步骤如下:
1.在基因表达水平和蛋白表达水平检测PPARγ和视黄醇类受体(RAR和RXR)各亚型在人原代骨肉瘤细胞及人骨肉瘤细胞株中的表达。
2.通过体外增殖实验检测曲格列酮(Tro)、全反式维甲酸(ATRA)和9-顺式维甲酸(9CRA)单用,以及Tro与ATRA或与9CRA合用对骨肉瘤增殖的抑制作用。
3.利用AdEasy系统构建视黄醇类受体(RARα和RXRα)重组腺病毒载体,检测外源性过表达核受体或外源性过表达核受体的同时加用核受体激动剂(Tro、ATRA及9CRA)对骨肉瘤细胞生长及凋亡的影响。
4.用核受体重组腺病毒感染骨肉瘤细胞,将感染重组核受体腺病毒的骨肉瘤细胞接种于裸鼠胫骨近端进行异位成瘤实验,通过Xenogen成像系统检测外源性过表达核受体对骨肉瘤生长的影响,采用组织化学技术对肿瘤组织进行增殖、凋亡及分化指标检测。
5.检测Tro、ATRA及9CRA对间充质干细胞及骨肉瘤细胞诱导分化的作用,原代骨肉瘤细胞及骨肉瘤细胞株ALP表达状态及原代骨肉瘤细胞的成瘤性。
实验结果
1.在大多数骨肉瘤细胞中均能检测到PPARγ及RAR、RXR的各型受体表达。
2.成功建立RARα及RXRα重组腺病毒并进行功能测定。
3.Tro、ATAR及9CRA,以及过表达核受体PPARγ、RARα和RXRα的同时加用相应激动剂均能有效抑制骨肉瘤细胞增殖。
4.体内外实验显示,Tro与ATRA或9CRA合用对骨肉瘤细胞生长的有显著协同抑制作用,同时过表达PPARγ2和RARα或PPARγ2和RXRα也具有同样的作用;过表达核受体可抑制骨肉瘤细胞生长及促进骨肉瘤细胞凋亡、分化。
5.Tro、ATRA及9CRA能够诱导间充质干细胞成骨分化,Tro的诱导化作用虽较弱,但与ATRA及9CRA之间存在明显的协同效应。在骨肉瘤细胞中也存在类似的结果。
实验结论
激活PPARγ、RAR及RXR能够抑制肿瘤细胞增殖,并且PPARγ2与RARα与RXRα同时激活能协同性抑制瘤肿生长,这种作用至少与涉及诱导骨肉瘤细胞分化有关。
Aim
Osteosarcoma (OS) is the most common non-hematological malignant tumor of bone in children and adults. Without systemic treatment, few patients with osteosarcoma achieve long term disease free status, even the optimal local treatment is taken. Clinical management of OS faces numerous challenges, including adverse effects associated with chemotherapies, chemoresistance, recurrence, and pulmonary metastasis. In this project, we focused on trying differentiation therapy to OS with activating PPARγ, RARαand RXRα.
Methods and procedure
We used cell proliferation test, PCR, Western blot, recombinant adevovirus, reporter construct and histochemistry technique to elucidate the synergistic anti-proliferation effect on human osteosarcoma when PPARγand retinoids receptors were activated.
1. We checked the mRNA and protein expression for PPARγand different subtype receptors of RAR and RXR in primary human osteosarcoma and osteosarcoma cell lines, in order to make sure these nuclear receptors were available in osteosarcoma cells.
2. We tested the anti-proliferation effects of Tro, ATRA, 9CRA and Tro combinated with ATRA or 9CRA on human osteosarcoma.
3. We constructed the recombinant RARα, RXRαadenovirus with AdEasy system and tested the function of the recombinant adenovirus. We tested the anti-proliferation effects of exogenous overexpress nuclear receptors from the recombinant adenovirus or exogenous overexpress of the nuclear receptors combinated with corresponding nuclear receptor agonists on human osteosarcoma.
4. We infected the osteosarcoma cells with recombinant adenovirus and then injected the cells to proximal tibia for ectopic tumorigencity test in nude mice. Track the tumor with Xenogen system, sacrifice the animals at the end of test, and retrieve the tumor mass for proliferation, apoptosis and differentiation test with histochemistry technique.
5. Test the effects of Tro, ATRA and 9CRA on osteogenic differentiation in Mesenchymal stem cell and osteosarcoma cell lines, the alkaline phosphatase expression in primary osteosarcoma and osteosarcoma cell lines, and the tumorigenicity of primary osteosarcoma.
Results
1. The expressions of PPARγand different type of RAR and RXR were detectalbe in all tested cells.
2. RARαand RXRαrecombinant adenovirus were sucessfully constructed, and the receptors expressed by which could be activated by the corresponding agonists and regulated the target gene expressions.
3. Tro, ATRA and 9CRA, as well as exogenous overexpress PPARγ, RARαand RXRαcombinated with corresponding agonists, could inhibited the proliferation of osteosarcoma.
4. There was a synergistic anti-proliferation effect in combination of Tro with ATRA or 9CRA; similar results were observed if there existed co-overexpressions of PPARγ2 with RARαor RXRαin vivo and in vitro test. Activation of the nuclear receptors induced the apoptosis and differentiation in osteosarcoma cells.
5. Tro,ATRA and 9CRA induced the osteogenic differentiation of Mesenchymal stem cell and there was a apparently synergistic effect in combination Tro with ATRA or 9CRA, although Tro had very little effect on osteogenic differentiation. Similar results were found in osteosarcoma.
Conclusions
Activated PPARγ, RXRαand RARαcan inhibit the growth of osteosarcoma and there exist synergistic anti-proliferation effects on osteosarcoma when co-activations of PPARγ2 with RXRαor RARαoccur. This effect may partly result from the osteogenic differentiation induced by the nuclear receptor agonists.
骨肉瘤是骨肿瘤中的主重要恶性肿瘤。患者的长期生存依赖于如何预防、治疗这类肿瘤及如何减少其复发率和病灶转移。本课题旨在研究激活PPARγ和视黄醇类核受体抑制人骨肉瘤生长的作用。
实验方法与步骤
本课题采用细胞增殖实验、PCR技术、蛋白免疫印迹技术、重组腺病毒技术、报告质粒技术及常规组织学技术,研究激动PPARγ与类视黄醇类核受体协同抑制人骨肉瘤细胞增殖的作用。实验步骤如下:
1.在基因表达水平和蛋白表达水平检测PPARγ和视黄醇类受体(RAR和RXR)各亚型在人原代骨肉瘤细胞及人骨肉瘤细胞株中的表达。
2.通过体外增殖实验检测曲格列酮(Tro)、全反式维甲酸(ATRA)和9-顺式维甲酸(9CRA)单用,以及Tro与ATRA或与9CRA合用对骨肉瘤增殖的抑制作用。
3.利用AdEasy系统构建视黄醇类受体(RARα和RXRα)重组腺病毒载体,检测外源性过表达核受体或外源性过表达核受体的同时加用核受体激动剂(Tro、ATRA及9CRA)对骨肉瘤细胞生长及凋亡的影响。
4.用核受体重组腺病毒感染骨肉瘤细胞,将感染重组核受体腺病毒的骨肉瘤细胞接种于裸鼠胫骨近端进行异位成瘤实验,通过Xenogen成像系统检测外源性过表达核受体对骨肉瘤生长的影响,采用组织化学技术对肿瘤组织进行增殖、凋亡及分化指标检测。
5.检测Tro、ATRA及9CRA对间充质干细胞及骨肉瘤细胞诱导分化的作用,原代骨肉瘤细胞及骨肉瘤细胞株ALP表达状态及原代骨肉瘤细胞的成瘤性。
实验结果
1.在大多数骨肉瘤细胞中均能检测到PPARγ及RAR、RXR的各型受体表达。
2.成功建立RARα及RXRα重组腺病毒并进行功能测定。
3.Tro、ATAR及9CRA,以及过表达核受体PPARγ、RARα和RXRα的同时加用相应激动剂均能有效抑制骨肉瘤细胞增殖。
4.体内外实验显示,Tro与ATRA或9CRA合用对骨肉瘤细胞生长的有显著协同抑制作用,同时过表达PPARγ2和RARα或PPARγ2和RXRα也具有同样的作用;过表达核受体可抑制骨肉瘤细胞生长及促进骨肉瘤细胞凋亡、分化。
5.Tro、ATRA及9CRA能够诱导间充质干细胞成骨分化,Tro的诱导化作用虽较弱,但与ATRA及9CRA之间存在明显的协同效应。在骨肉瘤细胞中也存在类似的结果。
实验结论
激活PPARγ、RAR及RXR能够抑制肿瘤细胞增殖,并且PPARγ2与RARα与RXRα同时激活能协同性抑制瘤肿生长,这种作用至少与涉及诱导骨肉瘤细胞分化有关。
Aim
Osteosarcoma (OS) is the most common non-hematological malignant tumor of bone in children and adults. Without systemic treatment, few patients with osteosarcoma achieve long term disease free status, even the optimal local treatment is taken. Clinical management of OS faces numerous challenges, including adverse effects associated with chemotherapies, chemoresistance, recurrence, and pulmonary metastasis. In this project, we focused on trying differentiation therapy to OS with activating PPARγ, RARαand RXRα.
Methods and procedure
We used cell proliferation test, PCR, Western blot, recombinant adevovirus, reporter construct and histochemistry technique to elucidate the synergistic anti-proliferation effect on human osteosarcoma when PPARγand retinoids receptors were activated.
1. We checked the mRNA and protein expression for PPARγand different subtype receptors of RAR and RXR in primary human osteosarcoma and osteosarcoma cell lines, in order to make sure these nuclear receptors were available in osteosarcoma cells.
2. We tested the anti-proliferation effects of Tro, ATRA, 9CRA and Tro combinated with ATRA or 9CRA on human osteosarcoma.
3. We constructed the recombinant RARα, RXRαadenovirus with AdEasy system and tested the function of the recombinant adenovirus. We tested the anti-proliferation effects of exogenous overexpress nuclear receptors from the recombinant adenovirus or exogenous overexpress of the nuclear receptors combinated with corresponding nuclear receptor agonists on human osteosarcoma.
4. We infected the osteosarcoma cells with recombinant adenovirus and then injected the cells to proximal tibia for ectopic tumorigencity test in nude mice. Track the tumor with Xenogen system, sacrifice the animals at the end of test, and retrieve the tumor mass for proliferation, apoptosis and differentiation test with histochemistry technique.
5. Test the effects of Tro, ATRA and 9CRA on osteogenic differentiation in Mesenchymal stem cell and osteosarcoma cell lines, the alkaline phosphatase expression in primary osteosarcoma and osteosarcoma cell lines, and the tumorigenicity of primary osteosarcoma.
Results
1. The expressions of PPARγand different type of RAR and RXR were detectalbe in all tested cells.
2. RARαand RXRαrecombinant adenovirus were sucessfully constructed, and the receptors expressed by which could be activated by the corresponding agonists and regulated the target gene expressions.
3. Tro, ATRA and 9CRA, as well as exogenous overexpress PPARγ, RARαand RXRαcombinated with corresponding agonists, could inhibited the proliferation of osteosarcoma.
4. There was a synergistic anti-proliferation effect in combination of Tro with ATRA or 9CRA; similar results were observed if there existed co-overexpressions of PPARγ2 with RARαor RXRαin vivo and in vitro test. Activation of the nuclear receptors induced the apoptosis and differentiation in osteosarcoma cells.
5. Tro,ATRA and 9CRA induced the osteogenic differentiation of Mesenchymal stem cell and there was a apparently synergistic effect in combination Tro with ATRA or 9CRA, although Tro had very little effect on osteogenic differentiation. Similar results were found in osteosarcoma.
Conclusions
Activated PPARγ, RXRαand RARαcan inhibit the growth of osteosarcoma and there exist synergistic anti-proliferation effects on osteosarcoma when co-activations of PPARγ2 with RXRαor RARαoccur. This effect may partly result from the osteogenic differentiation induced by the nuclear receptor agonists.
引文
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