乳腺癌转移抑制基因BRMSI功能的研究
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摘要
目的:研究乳腺癌转移抑制基因BRMS1对乳癌细胞生长、增殖、侵袭、转移以及辐射敏感性的影响以及涉及的相关作用机制,为研究乳癌的发生、发展和转移和治疗提供新的研究方向和实验依据。
方法:
1、参照GeneBank中BRMS1的基因序列,通过自行设计并扩增得到BRMS1基因cDNA的引物一对,构建了携带有全长BRMS1 cDNA的真核表达载体(pcDNA3-BRMS1);
2、应用阳离子脂质体Lipofactamin2000介导,进行pcDNA3-BRMS1转染,阳性克隆通过在含G418的培养基中培养筛选得到,并应用RT-PCR和Western Blot法检测阳性克隆中BRMS1的mRNA和蛋白的表达;
3、应用MTT法分析BRMS1基因转染对体外培养的乳癌细胞生长、增殖的影响;
4、应用划痕实验和Boyden小室法,分析BRMS1基因转染对体外培养的乳癌细胞侵袭、转移能力的影响;
5、采用流式细胞术分析BRMS1基因转染对细胞周期进程和细胞凋亡的影响;
6、采用裸鼠原位接种肿瘤模型,观察BRMS1基因在体内对乳癌生长、转移的影响;
7、采用裸鼠尾静脉接种肿瘤转移模型观察BRMS1基因对体内乳癌转移的影响;
8、通过细胞克隆形成实验分析BRMS1基因对乳癌细胞辐射敏感性的影响;
9、采用染色体畸变分析、PCC断片研究BRMS1基因对肿瘤细胞基因组不稳定性的影响;
10、采用Western Blot法检测BRMS1基因对DNA损伤修复相关蛋白表达水平的影响;
11、采用GST-pull down和免疫共沉淀方法检测BRMS1与核受体直接结合;
12、采用荧光素酶报告基因测定方法测定转录活性。
结果:
1、自行构建的BRMS1真核表达载体,经过限制性核酸内切酶BamH I和Xho I酶切后电泳和扩增片断测序,证实载体构建成功;
2、G418筛选得到的稳定阳性克隆,经RT-PCR和Western Blot证实,转染BRMS1基因可以在乳癌细胞中提高BRMS的表达水平,表明高BRMS1表达的细胞株筛选成功;
3、MTT的结果表明BRMS1对乳癌细胞MDA-MB-231、MDA-MB-435的生长无明显影响;
4、划痕实验结果表明BRMS1基因对乳腺癌细胞MDA-MB-231、MDA-MB-435体外迁移能力无明显影响;
5、Boyden小室实验结果表明:BRMS1基因转染细胞的穿越细胞数与未转染组相比显著减少(p<0.05),BRMS1基因转染细胞的穿越细胞数与空载体组相比也显著减少(p<0.05);
6、流式细胞术分析结果表明:BRMS1基因对乳腺癌细胞MDA-MB-231、MDA-MB-435的周期分布及凋亡无明显改变;
7、裸鼠原位接种肿瘤实验结果表明:BRMS1基因对裸鼠的体重及肿瘤的生长速度及肿瘤大小无明显影响;BRMS1基因转染组的原位肿瘤分化程度较高,而恶性程度偏低;
8、肿瘤转移模型观察:未转染对照组裸鼠有5例明显的肺转移,5例出现肝转移;转染空载体组裸鼠也出现5例肺转移,4例肝转移,而BRMS1转基因裸鼠组只有1例出现肝转移。表明体内BRMS1高表达能抑制乳腺癌肿瘤的转移;
9、肿瘤组织血管实验:与未转染组比较,BRMS1转基因组裸鼠的肿瘤血管数目较少,有显著统计差异(P<0.05),表明BRMS1基因能抑制乳腺癌血管生成;
10、克隆形成实验结果: BRMS1转染组与未转染组及空载体组的生存曲线基本一致,表明BRMS1基因不影响肿瘤细胞受照射后的存活率;
11、染色体畸变分析、PCC断片分析结果:不同剂量的X射线照射后,BRMS1转染组的染色体畸变率及PCC断片率低于空载体组与未转染组;
12、Western Blot法检测DNA损伤修复相关蛋白表达,BRMS1基因对辐射修复相关蛋白FEN-1、XRCC1和Ku-70的表达无明显影响;
13、BRMS1可以与雄激素,雌激素等多种核受体蛋白结合,同时作为协同抑制因子抑制AR和ER-α的转录活性。
结论:
1、在体外实验中,BRMS1基因通过降低肿瘤癌细胞的侵袭能力而抑制肿瘤细胞的转移能力;BRMS1基因不影响乳腺癌细胞MDA-MB-231和MDA-MB-435的增殖能力、迁移和转移能力;不影响肿瘤细胞的细胞周期分布与凋亡;
2、BRMS1基因不影响裸鼠原位移植肿瘤的形成及肿瘤细胞本身的生长;BRMS1基因通过抑制移植肿瘤的血管生成及促进体内移植肿瘤的分化,从而降低肿瘤的恶性程度,抑制裸鼠移植肿瘤的远处转移;
3、BRMS1基因对肿瘤细胞受照射后的存活率无明显影响;不影响肿瘤细胞受照前后相关辐射损伤修复蛋白的表达。BRMS1基因通过降低肿瘤细胞的基因组不稳定性而在一定程度上降低了肿瘤细胞的放射敏感性;
4、BRMS1与核受体蛋白结合,调节核受体的转录活性将揭示BRMS1基因的新的重要功能和作用,开辟了一新的研究方向和领域。
Objective To investigate the anti-cancer activities of breast cancer metastasis suppressor1 (BRMS1) in two invasive breast cancer cell lines. Method
1.Based on the BRMS1 gene sequence from the Genebank, a full-length BRMS1 cDNA was amplified by a pair of specifically designed primers and constructed into a pcDNA3 eukaryotic expression vector.
2. Cell lines with high expression of BRMS1 were established by stable transfection of pcDNA3-BRMS1 expression under the help of cationic liposome (Lipofactamin2000) and selection in medium containing G418.
3.The effect of BRMS1 overexpression on cell growth and proliferation were observed using MTT method.
4.Cell migration and invasion were determined by in vitro scratch and modified Boyden chamber assays.
5.Alteration of cell cycle progression and apoptosis induction were studied by flow cytometry.
6.BRMS1 role on the tumor growth and metastasis in vivo were studied in nude mice with orthotopic injection of breast cancer cells.
7.The effects of BRMS1 on lung metastasis was observed via tail intravenous injection of breast cancer cells.
8.Radiosensitivity was analyzed by colony forming assays.
9.Analysis of chromosomal aberrations and PCC fragments were performed to determine the effect of BRMS1 overexpression on genomic instability.
10.Western blot assay was used to measure protein expression.
11.In vitro GST pull-down and in vivo immunoprecipitation-WB assays were employed to determine protein-protein interaction.
12.Luciferase assay was used to determine transcriptional activity
Results
1.Construction of the BRMS1 eukaryotic expression vector was confirmed by sequencing and digestion with restriction endonucleases BamH I and Xho I.
2.Characterization of G418 resistance clone by RT-PCR and Western blot indicates that BRMS1 over-expressing cell lines have been established.
3.Ectopic expression of BRMS1 did not produce any effects on cell growth in both MDA-MB-231 and MDA-MB-435.
4.Ectopic expression of BRMS1 did not alter migration ability of MDA-MB-231 and MDA-MB-435 cells, but significantly reduced cell invasion.
6.BRMS1 overexpression did not cause any effects on cell cycle progression in both MDA-MB-231 and MDA-MB-435.
7.Enhanced expression of BRMS1 did not impact the body weight and tumor growth rate and tumor size. However, tumor with BRMS1 overexpression had well differentiation and low malignant degree compared to control tumors.
8.BRMS1 significantly reduced lung and liver metastases and angiogenesis (formation of new blood vessels).
10.BRMS1 overexpression did not influence sensitivity of breast cancer to radiotherapy, accompanying with no alteration of DNA damage repair proteins.
11.Less chromosomal aberrations and PCC fragments were found in the cells with BRMS1 overexpression.
12.BRMS1 associated with nuclear hormone receptors, including AR, ER(ER-αand ER-β), PR(PRA and PR-B), GR, RXRαand VDR and inhibited AR and ER-αtranscriptional activations.
Conclusion
In in vitro cell models, enhanced expression of BRMS1 by stable transfection of a full-length of BRMS1 cDNA significantly reduces or inhibits potentials of cell invasion, without alteration of cell growth and migration in two highly invasive breast cancer cell lines MDA-MB-231 and MDA-MB-435. Also, no alteration of cell cycle progression and apoptosis induction were observed in the cells with BRMS1 overexpression. In in vivo animal models, tumor formation and growth in nude mouse by orthotopic injection of breast cancer cells with BRMS1 overexpression exhibited no difference from those in the control cells. However, a significant decrease in malignant degree, remote metastasis and angiogenesis was observed in BRMS1 overexpression tumors. Increased expression of BRMS1 did not affect radiosensitivity, but indeed decreased the genomic instability caused by stresses. In summary, BRMS1 plays an important role in breast cancer development and progression as a metastatic and angiogenesis suppressor, and is a potential target to improve therapy of breast cancer. Furthermore, the BRMS1 association with different nuclear hormone receptors as a co-repressor will provide a new avenue to explore other biological functions of BRMS1, besides metastasis and angiogenesis suppression.
方法:
1、参照GeneBank中BRMS1的基因序列,通过自行设计并扩增得到BRMS1基因cDNA的引物一对,构建了携带有全长BRMS1 cDNA的真核表达载体(pcDNA3-BRMS1);
2、应用阳离子脂质体Lipofactamin2000介导,进行pcDNA3-BRMS1转染,阳性克隆通过在含G418的培养基中培养筛选得到,并应用RT-PCR和Western Blot法检测阳性克隆中BRMS1的mRNA和蛋白的表达;
3、应用MTT法分析BRMS1基因转染对体外培养的乳癌细胞生长、增殖的影响;
4、应用划痕实验和Boyden小室法,分析BRMS1基因转染对体外培养的乳癌细胞侵袭、转移能力的影响;
5、采用流式细胞术分析BRMS1基因转染对细胞周期进程和细胞凋亡的影响;
6、采用裸鼠原位接种肿瘤模型,观察BRMS1基因在体内对乳癌生长、转移的影响;
7、采用裸鼠尾静脉接种肿瘤转移模型观察BRMS1基因对体内乳癌转移的影响;
8、通过细胞克隆形成实验分析BRMS1基因对乳癌细胞辐射敏感性的影响;
9、采用染色体畸变分析、PCC断片研究BRMS1基因对肿瘤细胞基因组不稳定性的影响;
10、采用Western Blot法检测BRMS1基因对DNA损伤修复相关蛋白表达水平的影响;
11、采用GST-pull down和免疫共沉淀方法检测BRMS1与核受体直接结合;
12、采用荧光素酶报告基因测定方法测定转录活性。
结果:
1、自行构建的BRMS1真核表达载体,经过限制性核酸内切酶BamH I和Xho I酶切后电泳和扩增片断测序,证实载体构建成功;
2、G418筛选得到的稳定阳性克隆,经RT-PCR和Western Blot证实,转染BRMS1基因可以在乳癌细胞中提高BRMS的表达水平,表明高BRMS1表达的细胞株筛选成功;
3、MTT的结果表明BRMS1对乳癌细胞MDA-MB-231、MDA-MB-435的生长无明显影响;
4、划痕实验结果表明BRMS1基因对乳腺癌细胞MDA-MB-231、MDA-MB-435体外迁移能力无明显影响;
5、Boyden小室实验结果表明:BRMS1基因转染细胞的穿越细胞数与未转染组相比显著减少(p<0.05),BRMS1基因转染细胞的穿越细胞数与空载体组相比也显著减少(p<0.05);
6、流式细胞术分析结果表明:BRMS1基因对乳腺癌细胞MDA-MB-231、MDA-MB-435的周期分布及凋亡无明显改变;
7、裸鼠原位接种肿瘤实验结果表明:BRMS1基因对裸鼠的体重及肿瘤的生长速度及肿瘤大小无明显影响;BRMS1基因转染组的原位肿瘤分化程度较高,而恶性程度偏低;
8、肿瘤转移模型观察:未转染对照组裸鼠有5例明显的肺转移,5例出现肝转移;转染空载体组裸鼠也出现5例肺转移,4例肝转移,而BRMS1转基因裸鼠组只有1例出现肝转移。表明体内BRMS1高表达能抑制乳腺癌肿瘤的转移;
9、肿瘤组织血管实验:与未转染组比较,BRMS1转基因组裸鼠的肿瘤血管数目较少,有显著统计差异(P<0.05),表明BRMS1基因能抑制乳腺癌血管生成;
10、克隆形成实验结果: BRMS1转染组与未转染组及空载体组的生存曲线基本一致,表明BRMS1基因不影响肿瘤细胞受照射后的存活率;
11、染色体畸变分析、PCC断片分析结果:不同剂量的X射线照射后,BRMS1转染组的染色体畸变率及PCC断片率低于空载体组与未转染组;
12、Western Blot法检测DNA损伤修复相关蛋白表达,BRMS1基因对辐射修复相关蛋白FEN-1、XRCC1和Ku-70的表达无明显影响;
13、BRMS1可以与雄激素,雌激素等多种核受体蛋白结合,同时作为协同抑制因子抑制AR和ER-α的转录活性。
结论:
1、在体外实验中,BRMS1基因通过降低肿瘤癌细胞的侵袭能力而抑制肿瘤细胞的转移能力;BRMS1基因不影响乳腺癌细胞MDA-MB-231和MDA-MB-435的增殖能力、迁移和转移能力;不影响肿瘤细胞的细胞周期分布与凋亡;
2、BRMS1基因不影响裸鼠原位移植肿瘤的形成及肿瘤细胞本身的生长;BRMS1基因通过抑制移植肿瘤的血管生成及促进体内移植肿瘤的分化,从而降低肿瘤的恶性程度,抑制裸鼠移植肿瘤的远处转移;
3、BRMS1基因对肿瘤细胞受照射后的存活率无明显影响;不影响肿瘤细胞受照前后相关辐射损伤修复蛋白的表达。BRMS1基因通过降低肿瘤细胞的基因组不稳定性而在一定程度上降低了肿瘤细胞的放射敏感性;
4、BRMS1与核受体蛋白结合,调节核受体的转录活性将揭示BRMS1基因的新的重要功能和作用,开辟了一新的研究方向和领域。
Objective To investigate the anti-cancer activities of breast cancer metastasis suppressor1 (BRMS1) in two invasive breast cancer cell lines. Method
1.Based on the BRMS1 gene sequence from the Genebank, a full-length BRMS1 cDNA was amplified by a pair of specifically designed primers and constructed into a pcDNA3 eukaryotic expression vector.
2. Cell lines with high expression of BRMS1 were established by stable transfection of pcDNA3-BRMS1 expression under the help of cationic liposome (Lipofactamin2000) and selection in medium containing G418.
3.The effect of BRMS1 overexpression on cell growth and proliferation were observed using MTT method.
4.Cell migration and invasion were determined by in vitro scratch and modified Boyden chamber assays.
5.Alteration of cell cycle progression and apoptosis induction were studied by flow cytometry.
6.BRMS1 role on the tumor growth and metastasis in vivo were studied in nude mice with orthotopic injection of breast cancer cells.
7.The effects of BRMS1 on lung metastasis was observed via tail intravenous injection of breast cancer cells.
8.Radiosensitivity was analyzed by colony forming assays.
9.Analysis of chromosomal aberrations and PCC fragments were performed to determine the effect of BRMS1 overexpression on genomic instability.
10.Western blot assay was used to measure protein expression.
11.In vitro GST pull-down and in vivo immunoprecipitation-WB assays were employed to determine protein-protein interaction.
12.Luciferase assay was used to determine transcriptional activity
Results
1.Construction of the BRMS1 eukaryotic expression vector was confirmed by sequencing and digestion with restriction endonucleases BamH I and Xho I.
2.Characterization of G418 resistance clone by RT-PCR and Western blot indicates that BRMS1 over-expressing cell lines have been established.
3.Ectopic expression of BRMS1 did not produce any effects on cell growth in both MDA-MB-231 and MDA-MB-435.
4.Ectopic expression of BRMS1 did not alter migration ability of MDA-MB-231 and MDA-MB-435 cells, but significantly reduced cell invasion.
6.BRMS1 overexpression did not cause any effects on cell cycle progression in both MDA-MB-231 and MDA-MB-435.
7.Enhanced expression of BRMS1 did not impact the body weight and tumor growth rate and tumor size. However, tumor with BRMS1 overexpression had well differentiation and low malignant degree compared to control tumors.
8.BRMS1 significantly reduced lung and liver metastases and angiogenesis (formation of new blood vessels).
10.BRMS1 overexpression did not influence sensitivity of breast cancer to radiotherapy, accompanying with no alteration of DNA damage repair proteins.
11.Less chromosomal aberrations and PCC fragments were found in the cells with BRMS1 overexpression.
12.BRMS1 associated with nuclear hormone receptors, including AR, ER(ER-αand ER-β), PR(PRA and PR-B), GR, RXRαand VDR and inhibited AR and ER-αtranscriptional activations.
Conclusion
In in vitro cell models, enhanced expression of BRMS1 by stable transfection of a full-length of BRMS1 cDNA significantly reduces or inhibits potentials of cell invasion, without alteration of cell growth and migration in two highly invasive breast cancer cell lines MDA-MB-231 and MDA-MB-435. Also, no alteration of cell cycle progression and apoptosis induction were observed in the cells with BRMS1 overexpression. In in vivo animal models, tumor formation and growth in nude mouse by orthotopic injection of breast cancer cells with BRMS1 overexpression exhibited no difference from those in the control cells. However, a significant decrease in malignant degree, remote metastasis and angiogenesis was observed in BRMS1 overexpression tumors. Increased expression of BRMS1 did not affect radiosensitivity, but indeed decreased the genomic instability caused by stresses. In summary, BRMS1 plays an important role in breast cancer development and progression as a metastatic and angiogenesis suppressor, and is a potential target to improve therapy of breast cancer. Furthermore, the BRMS1 association with different nuclear hormone receptors as a co-repressor will provide a new avenue to explore other biological functions of BRMS1, besides metastasis and angiogenesis suppression.
引文
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2. Smith,PW, Liu,Y, Siefert, et al. Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis and correlates with improved patient survival in non-small cell lung cancer.[J].Cancer letters,2009,276(2)8.
3. Samant RS.Debies MT,Shevde LA,et al. Identification and characterization of the murine ortholog(brms1)of breast-cancer metastasis suppressor 1(BRMS1), Int J Cancer,2002,97:15-20.
4. Cicek M ,Samant RS,Kinter M ,et al. Identfication of metastasis associated proteins through protein analysis of metastatic MDA-MB-435 cells[J].Clin Exp Metastasis,2004,21(2):149.
5. Shevde I.A,Samant RS,Goldberg SF,et al. Suppression of human melanoma metastasis by the metastasis suppressor gene,Exp Cell Res,2002,273(2):229.
6. Zhang S,L in QD,DI W , et al. Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene,Int J Gynecol Cancer,2006,16(2):522.
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