携带TIMP-3基因的重组腺病毒增加HPV阳性宫颈癌放疗敏感性的体内外实验研究
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摘要
研究背景与目的细胞对细胞外基质成分(extracellular matrix, ECM)的降解是肿瘤发生和发展过程中最重要的分子事件,基质金属蛋白酶(matrixmetalloproteinases MMPs)是一类最重要的执行ECM降解的水解酶,多种肿瘤组织中都伴有MMPs的高表达.基质金属蛋白酶组织抑制因子(tissue inhibitors of metalloproteinase TIMPs)是一类能特异性抑制MMPs功能的活性因子,对抑制肿瘤浸润和转移有重要功能。TIMP-3是TIMPs家族的新成员,由于它诱导肿瘤细胞凋亡和抑制血管形成的作用,使其在肿瘤治疗中越来越受到重视。
宫颈癌发病率在全球妇女恶性肿瘤中居第二位。本实验室前期的有关体内外实验研究证实Ad-TIMP-3可有效地治疗宫颈癌：Ad-TIMP-3转染可以强烈地诱导宫颈癌细胞的凋亡,并存在显著的旁观者效应；Ad-TIMP-3可引起CaSKi细胞的G2/M期阻滞；Ad-TIMP-3和放疗联合使用可使疗效明显增强,起到效应相加或协同作用；对裸鼠宫颈癌皮下移植瘤用Ad-TIMP-3单独瘤体内注射或与顺铂腹腔内注射联合使用均显示明显抑制肿瘤生长。
基于上述研究结果,本研究着重于TIMP-3增加HPV阳性宫颈癌放疗敏感性方面的探讨。以腺病毒为载体,将TIMP-3基因导入HPV阳性宫颈癌细胞HeLa-Luc和CaSki,分析TIMP-3对宫颈癌细胞的作用以及与放疗联合应用后的效果。
方法应用RT-PCR法及Western Blot法检测HeLa-Luc和CaSki细胞感染Ad-TIMP-3前后TIMP-3 mRNA及蛋白表达水平；MTT法验证Ad-TIMP-3对HeLa-Luc和CaSki细胞增殖的抑制；平板克隆方法检测Ad-TIMP-3与X射线联合应用后对细胞生长的影响；体外侵袭及粘附实验检测Ad-TIMP-3与X射线联合应用后对细胞侵袭、粘附能力的影响；裸鼠体内实验了解Ad-TIMP-3与X射线联合应用后HeLa-Luc细胞体内致瘤性的变化。
结果RT-PCR和Western Blot证实TIMP-3在HeLa-Luc和CaSki两种宫颈癌细胞系中均表达低下,而感染Ad-TIMP-3后TIMP-3表达水平明显升高,Ad-TIMP-3感染HeLa-Luc和CaSki细胞前后TIMP-3的表达有明显差异。MTT结果显示Ad-TIMP-3能够明显抑制HeLa-Luc和CaSki细胞增殖,且具有剂量效应关系。平板克隆方法显示Ad-TIMP-3与x射线联合应用可显著减少平板克隆形成数。体外侵袭及粘附实验显示Ad-TIMP-3与X射线联合应用后显著减弱宫颈癌细胞的侵袭能力及粘附性。裸鼠体内实验显示Ad-TIMP-3与X射线联合组HeLa-Luc细胞的体内致瘤性显著下降。
结论Ad-TIMP-3抑制宫颈癌细胞增殖。与x射线联合应用后,Ad-TIMP-3显著提高宫颈癌细胞放疗敏感性,抑制放疗诱导的肿瘤细胞生长,显著削弱其侵袭及粘附能力,抑制其体内致瘤能力。
The background and objective:Excessive degradation and remodeling of the extracellular matrix (ECM) is one of the hallmarks of cancer progression at nearly every step from the first breakdown of the basal membrane of a primary tumor up to the extended growth of established metastases. Matrix metalloproteinases (MMPs) is the most important proteases in ECM turn over, and many tumors have high levels of MMPs.The activities of MMPs can be inhibited by tissue inhibitors of metalloproteinases (TIMPs), which are the endogenous and specific inhibitors of MMPs. As a new member of the TIMPs family, TIMP-3 has several unique properties that set it apart from other TIMPs, including its ability to induce apoptosis and inhibit angiogenesis in many tumors.
Cervical cancer is the second most common malignancy in women worldwide. The past study by the doctor zhangying in our lab has suggested that Ad-TIMP-3 is an efficient agent for cervical cancer treating. Transfered Ad-TIMP-3 could induce massive apoptosis of cervical cancer cells and it had marked bystand effect. Ad-TIMP-3 remarkably arrested CaSKi cell in G2/M phase prior to apoptotic cell death. Combined Ad-TIMP-3 and radiation could induce stronger cytotoxic effect. In summary, there is additive or synergistic effect when using Ad-TIMP-3 and radiotherapy in combination. In vivo, directed injection of Ad-TIMP-3 into CaSKi tumors subcutaneously implanted into nude mice only, or followed by intraperitoneal administration of cisplatin, both could inhibit tumor growth significantly.
In the base of the study above,our study focuses on the aspect of whether exogenous TIMP-3 sensitizes HPV positive cervical cancer cells to irradiation.
Methods:We measured the expression of TIMP-3 mRNA by RT-PCR and TIMP-3 protein by Western Blot in CaSKi and HeLa-Luc before and after transfered Ad-TIMP-3.An adenovirus expressing TIMP-3 (Ad-TIMP-3), alone or in combination with irradiation, was used to treat HPV positive cervical cancer cells HeLa-Luc and CaSki, we compared the growth inhibition efficacy,invasion and adhesion ability. In vivo, we injected different HeLa-Luc cells treated by Ad-TIMP-3, x-ray, combination of this two or none of these subcutaneously into nude mice, and measured the growth of the tumor.
Results:RT-PCR and Western Blot revealed that the expression of exogenous TIMP-3 was elevated obviously after infection. Ad-TIMP-3 suppressed the growth of HPV positive cervical cancer cells. Combination of Ad-TIMP-3 and irradiation significantly suppressed the cell growth, and decreased the invasion and adhesion ability than separate treatment. In vivo, after being treated by combination of Ad-TIMP-3 and x-ray, the cervical cancer cells growing to tumors was inhibited significantly than other cells in nude mice.
Conclusions:Therefore our findings suggestes that Ad-TIMP-3 is an efficient agent for cervical cancer treating. Ad-TIMP-3 sensitizes HPV positive cervical cancer cells to irradiation.Combination of Ad-TIMP-3 and x-ray is a potential novel approach to the therapy of HPV positive cervical cancer.
宫颈癌发病率在全球妇女恶性肿瘤中居第二位。本实验室前期的有关体内外实验研究证实Ad-TIMP-3可有效地治疗宫颈癌：Ad-TIMP-3转染可以强烈地诱导宫颈癌细胞的凋亡,并存在显著的旁观者效应；Ad-TIMP-3可引起CaSKi细胞的G2/M期阻滞；Ad-TIMP-3和放疗联合使用可使疗效明显增强,起到效应相加或协同作用；对裸鼠宫颈癌皮下移植瘤用Ad-TIMP-3单独瘤体内注射或与顺铂腹腔内注射联合使用均显示明显抑制肿瘤生长。
基于上述研究结果,本研究着重于TIMP-3增加HPV阳性宫颈癌放疗敏感性方面的探讨。以腺病毒为载体,将TIMP-3基因导入HPV阳性宫颈癌细胞HeLa-Luc和CaSki,分析TIMP-3对宫颈癌细胞的作用以及与放疗联合应用后的效果。
方法应用RT-PCR法及Western Blot法检测HeLa-Luc和CaSki细胞感染Ad-TIMP-3前后TIMP-3 mRNA及蛋白表达水平；MTT法验证Ad-TIMP-3对HeLa-Luc和CaSki细胞增殖的抑制；平板克隆方法检测Ad-TIMP-3与X射线联合应用后对细胞生长的影响；体外侵袭及粘附实验检测Ad-TIMP-3与X射线联合应用后对细胞侵袭、粘附能力的影响；裸鼠体内实验了解Ad-TIMP-3与X射线联合应用后HeLa-Luc细胞体内致瘤性的变化。
结果RT-PCR和Western Blot证实TIMP-3在HeLa-Luc和CaSki两种宫颈癌细胞系中均表达低下,而感染Ad-TIMP-3后TIMP-3表达水平明显升高,Ad-TIMP-3感染HeLa-Luc和CaSki细胞前后TIMP-3的表达有明显差异。MTT结果显示Ad-TIMP-3能够明显抑制HeLa-Luc和CaSki细胞增殖,且具有剂量效应关系。平板克隆方法显示Ad-TIMP-3与x射线联合应用可显著减少平板克隆形成数。体外侵袭及粘附实验显示Ad-TIMP-3与X射线联合应用后显著减弱宫颈癌细胞的侵袭能力及粘附性。裸鼠体内实验显示Ad-TIMP-3与X射线联合组HeLa-Luc细胞的体内致瘤性显著下降。
结论Ad-TIMP-3抑制宫颈癌细胞增殖。与x射线联合应用后,Ad-TIMP-3显著提高宫颈癌细胞放疗敏感性,抑制放疗诱导的肿瘤细胞生长,显著削弱其侵袭及粘附能力,抑制其体内致瘤能力。
The background and objective:Excessive degradation and remodeling of the extracellular matrix (ECM) is one of the hallmarks of cancer progression at nearly every step from the first breakdown of the basal membrane of a primary tumor up to the extended growth of established metastases. Matrix metalloproteinases (MMPs) is the most important proteases in ECM turn over, and many tumors have high levels of MMPs.The activities of MMPs can be inhibited by tissue inhibitors of metalloproteinases (TIMPs), which are the endogenous and specific inhibitors of MMPs. As a new member of the TIMPs family, TIMP-3 has several unique properties that set it apart from other TIMPs, including its ability to induce apoptosis and inhibit angiogenesis in many tumors.
Cervical cancer is the second most common malignancy in women worldwide. The past study by the doctor zhangying in our lab has suggested that Ad-TIMP-3 is an efficient agent for cervical cancer treating. Transfered Ad-TIMP-3 could induce massive apoptosis of cervical cancer cells and it had marked bystand effect. Ad-TIMP-3 remarkably arrested CaSKi cell in G2/M phase prior to apoptotic cell death. Combined Ad-TIMP-3 and radiation could induce stronger cytotoxic effect. In summary, there is additive or synergistic effect when using Ad-TIMP-3 and radiotherapy in combination. In vivo, directed injection of Ad-TIMP-3 into CaSKi tumors subcutaneously implanted into nude mice only, or followed by intraperitoneal administration of cisplatin, both could inhibit tumor growth significantly.
In the base of the study above,our study focuses on the aspect of whether exogenous TIMP-3 sensitizes HPV positive cervical cancer cells to irradiation.
Methods:We measured the expression of TIMP-3 mRNA by RT-PCR and TIMP-3 protein by Western Blot in CaSKi and HeLa-Luc before and after transfered Ad-TIMP-3.An adenovirus expressing TIMP-3 (Ad-TIMP-3), alone or in combination with irradiation, was used to treat HPV positive cervical cancer cells HeLa-Luc and CaSki, we compared the growth inhibition efficacy,invasion and adhesion ability. In vivo, we injected different HeLa-Luc cells treated by Ad-TIMP-3, x-ray, combination of this two or none of these subcutaneously into nude mice, and measured the growth of the tumor.
Results:RT-PCR and Western Blot revealed that the expression of exogenous TIMP-3 was elevated obviously after infection. Ad-TIMP-3 suppressed the growth of HPV positive cervical cancer cells. Combination of Ad-TIMP-3 and irradiation significantly suppressed the cell growth, and decreased the invasion and adhesion ability than separate treatment. In vivo, after being treated by combination of Ad-TIMP-3 and x-ray, the cervical cancer cells growing to tumors was inhibited significantly than other cells in nude mice.
Conclusions:Therefore our findings suggestes that Ad-TIMP-3 is an efficient agent for cervical cancer treating. Ad-TIMP-3 sensitizes HPV positive cervical cancer cells to irradiation.Combination of Ad-TIMP-3 and x-ray is a potential novel approach to the therapy of HPV positive cervical cancer.
引文
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