功能性抗体库技术分离鉴定肺癌功能性基因的研究
摘要
肺癌是严重威胁人类生命与健康的恶性肿瘤,发病率、死亡率均位居第一位。目前治疗肺癌的三大手段仍未能显著降低肺癌的死亡率。分子靶向治疗在临床肿瘤治疗中显示出良好的应用前景,也是目前肿瘤研究的热点。实现分子靶向治疗的前提和关键是获得肿瘤特异表达的功能性靶分子、靶基因。为此,本文采用大容量功能性抗体库技术筛选肺癌功能性单抗,再通过功能性抗体分离鉴定肺癌功能性基因。并探讨功能性基因在肺癌发生发展中所起的作用功能及其分子作用机理。从而为肺癌的靶向治疗提供有价值的分子靶标。
第一部分功能性单抗库技术筛选分离、鉴定肺癌功能性抗原基因
采用新鲜肺癌组织分离的有核细胞免疫BALB/c小鼠,融合制备库容为1440个克隆的肺癌功能性单克隆抗体库。免疫细胞化学筛选获得377株稳定分泌抗人肺癌细胞单抗的杂交瘤,通过肺正常组织的免疫组化实验,排除271株与正常肺组织阳性反应的单克隆抗体,获得106株识别肺癌组织中抗原的表达高于正常肺组织表达水平的功能性单抗。肺癌及其正常肺组织的配对组织芯片检测证实67株单抗与肺癌组织呈强阳性反应,而与正常肺组织不反应或弱反应。这些单抗识别的抗原有表达于细胞膜的,也有表达于胞浆和/或胞核的。MTT法测定106株肺癌单抗对肺癌细胞增殖生长的影响,发现抑制肺癌细胞增殖生长的单抗57株,其中,抑制率大于20%的单抗有24株,抑制率在15-20%的单抗22株。RT-CES~(TM)系统实时观察106株单抗对肺癌细胞生长的影响,结果显示49株单抗能够显著抑制肺癌细胞的生长,其中16株单抗抑制率在20%以上,20株单抗抑制率在15-20%,其余单抗抑制率在10-15%。106株单抗的亚类分析证明既有不同的重链类和亚类(IgM,IgA,IgG1,IgG2a及IgG2b),也有不同的轻链型(κ,λ),表明本研究制备的功能性单抗库有很好的多样性。挑选27株功能单抗进行了裸鼠体内移植瘤抑制实验,结果证实23株单抗在裸鼠体内能显著抑制肺癌的生长和瘤重,其中6株单抗体内抑瘤率在70%以上,8株单抗抑瘤率在50-70%,另外6株单抗抑瘤率在30-50%,其余3株抑瘤率在30%以下,这些结果也提示功能性单抗所识别的抗原基因是功能性基因,具有促进肺癌细胞增殖生长功能。选取其中的5株功能性单抗分离鉴定其功能性抗原蛋白,运用免疫亲和层析和MALDI-TOP-PMF质谱技术鉴定获得了3个肺癌功能基因。单抗1E2识别的抗原基因为氨甲酰磷酸合成酶Ⅰ(CPS1),5B8抗体识别的抗原基因为理阿诺碱受体1(RyR1),13H3抗体所识别的抗原基因为凝集素半乳糖苷结合可溶3结合蛋白基因(LGALS3BP或者Mac-2BP)。
第二部分肺癌抗原Mac-2BP基因功能的研究
文献报道Mac-2BP在大部分肿瘤组织高表达,但是关于Mac-2BP在肿瘤发生发展中所起的功能作用却很少有研究报道。因此,以Mac-2BP为研究对象,进行多种功能实验研究,揭示Mac-2BP基因在肺癌发生发展中的功能作用及其在临床疾病研究方面的应用价值。采用基因敲降及免疫共沉淀技术验证质谱鉴定结果,证明肺癌功能单抗13H3识别的抗原基因确实为Mac-2BP。应用细胞免疫荧光和免疫细胞化学实验证实Mac-2BP在多种肺癌细胞有较高水平的表达。免疫组化分析105例肺癌病人癌组织及其配对正常肺组织Mac-2BP基因的表达,发现Mac-2BP在肺癌组织的表达显著高于正常肺组织,同时还发现Mac-2BP的表达水平与肺癌患者的癌组织分化程度具有显著相关性,这些结果提示Mac-2BP可作为一种新的肺癌分子标志物,具有临床诊断及预测病人预后状况价值。应用抗体13H3检测分析Mac-2BP基因体外对肺癌细胞增殖、粘附及侵袭迁移功能的影响,未观察到阳性结果,其原因可能是Mac-2BP在所检肺癌细胞体外培养分泌表达蛋白水平及含量太低所致。应用纯化后抗体再次进行体内抑瘤实验,评估抗体对肺癌生长的影响,13H3单抗能显著抑制肺癌移植瘤生长,且具有剂量依赖关系。结果发现其高、中、低剂量的抑制率分别为60.14%、54.86%和43.84%,进一步证明13H3是功能性肺癌单抗,Mac-2BP基因是肺癌功能性基因,它能促进肺癌的增殖生长。为了从基因水平进一步证明Mac-2BP表达在肺癌细胞生长的促进作用,采用RNAi干扰技术敲降肺癌细胞Mac-2BP基因的表达,检测基因敲降前后肺癌细胞增殖、粘附及迁移侵袭的变化。结果证明Mac-2BP基因敲降后肺癌细胞的增殖能力降低38.5%,肺癌细胞与胞外基质collagenⅠ的粘附降低40%,与matrigel粘附降低50%,与FN粘附水平减少35%以上,肺癌细胞体外迁移和侵袭能力分别下降27%和29%。应用稳转shRNA敲降Mac-2BP基因表达的体外功能实验研究也获得了相似的结果。同时,体内抑瘤实验研究结果也表明Mac-2BP基因敲降后,肺癌细胞在裸鼠体内的增殖生长能力显著降低,其对瘤重的抑制率高达80%。基因敲降的体内外功能实验研究再次证明Mac-2BP是一个具有促进肺癌细胞生长增殖、促进与胞外基质粘附和迁移侵袭功能的功能性基因。为了探讨Mac-2BP促进肺癌生长增殖的作用机制,我们测定了Mac-2BP基因敲降后对肺癌细胞细胞周期变化的影响。研究结果发现该基因敲降后,肺癌细胞发生G1期阻滞,致使增殖减慢,进一步研究发现Mac-2BP基因敲降后,抑癌基因p27诱导上调表达。这表明Mac-2BP基因通过调节P27蛋白水平,影响细胞周期进程,从而促进肺癌细胞在体内外的快速增殖和生长。因此该基因具有作为肺癌靶向治疗的一个新的功能性分子靶标的潜力。
Lung cancer is one of the most common malignancies worldwide with highest incidence and mortality rate.However,the traditional curative methods have only limited effect on reducing the mortality of lung cancer.Presently molecular target therapy shows great promise in clinical treatment of cancer and became one of the hot research fields of cancer. To develop a effective targeting therapy,the initial and key step is to identify the tumor specially expressed molecules.To this end,a novel high-capacity functional monoclonal antibody library screening technique was employed,and then the functional genes was isolated by the functional antibodies.We then studied the functional relevance of these genes in the development of lung cancer and the underlying molecular mechanism.
Part1.Screening and identification of lung cancer related functional genes by functional monoclonal antibody library
BALB/c mice were immunized with cancerous cells isolated from fresh human lung cancer tissue.The spleen cells were fused with SP2/0 cells to establish a lung cancer functional monoclonal antibody library containing 1440 mAbs.By ICC 377 clones were identified which stably secrete mAbs against human lung tumor cells,271 of these clones were abandoned because of immunohistochemical reacting with normal lung epithelium. Then the remaining 106 clones were further assayed by tissue arrays and 67 of these clones showed predominantly tumor tissues reactivity.106 clones were screened by MTT method and 57 clones displayed ability of proliferation suppression to cancer cells,including inhibitory rate of 24 clones over 20%and 22 clones over 15%.RT-CES~(TM) system was also employed to estimate effects on cancer cells growth,the results showed that 49 clones can significantly inhibit cell growth of lung cancer,including inhibitory rate of 24 clones over 20%,20clones clones over 15%,The rest clones showed inhibitory rate by about 10-15%. Subclass of 106 clones identified,including IgM,IgA,IgG1,IgG2a and IgG2b and light/heavy chain includingκ,λ.Those result demonstrated that monoclonal antibodies of this library were diverse.27 mAbs were chosen from the antibody library for further estimating the inhibitory effect on carcinoma xenograft in nude mice.23 clones could significantly inhibit tumor growth and tumor weight.Among them,the inhibitory rates of six clones were above 70%,and eight were about 50-70%,6 of these clones were 30-50%,3 clones were under 30%.The result indicated that the antigens recognized by these mAbs might contribute to growth of lung cancer.5 mAbs were finally produced for antigen identification by immuno-affinity and MALDI-TOP-PMF.At last we acquired 3 functional genes including(CPS1) identified by1E2,RyR1 by 5B8,LGALS3BP by 13H3.
Part2.Studies on the gene functions of Mac2-BP
Several studies have reported that Mac2-BP was overexpressed in carcinoma tissues, however,so far few studies focus on the functional role of Mac2-BP in cancer progression. Therefore,we designed functional studies as follows to reveal the role of Mac2-BP in lung cancer progression as well as its potential application in clinic.We firstly applied RNA interference and immunoprecipitation to confirm the results of mass spectrometry.Then,cell immunofluorescence and cell immunocytochemisry showed that Mac2-BP was high expressed in most lung cancer cell lines.Immunohistochemistry assay on 105 case of lung cancers paired with normal lung tissues revealed that Mac2-BP was significantly overexpressed in cancer tissue,and the overexpression of Mac2-BP was correlated with lung cancer differentiation.13H3 mAb had no effects tumor cell growth,adhesion,migration and invasion in vitro,which might due to Mac2-BP was barely secreted by lung tumor cells in vitro.However,when purified 13H3 mAb was to used to treat lung cancer xenograft in vivo a significant tumor growth inhibition was observed by a dose-dependent manner,with the inhibition rates of 60.14%,54.86%and 43.84%for the high,middle and low dosage of 13H3 respectively.These results showed that 13H3 was a functional mAb and Mac2-BP was a lung cancer associated gene that involved in tumor growth.We then applied RNAi to further revealed the role of Mac-2BP in lung cancer development.Transient RNAi,revealed that downregulating Mac-2BP could suppress cell proliferation,cell adhesion with Matrix of CollagenⅠ,Matrigel or FN,cell migration and invasion by about 38.5%,40%,50%,35%, 27%and 29%respectively.Stable RNAi transfection also certified these result in vitro.We also applied ex vivo to study the role of Mac2-BP on xenograte tumor growth.Mac2-BP knockdown could inhibit 80%xenograft tumor burden.The Mac2-BP knockdown study once again showed that Mac2-BP was a functional gene associated with lung cancer cell proliferation,matrix adhesion,migration and invasion.To further study the mechanism of Mac2-BP on lung cancer cell proliferation,we assayed the cell cycle after RNAi and revealed that Mac2-BP knockdown lead to G1 arrest.Further studies revealed that downregulation of Mac2-BP was correlated with P27 upexpression.These results indicated that Mac2-BP promotes lung cancer cell proliferation in vitro and in vivo through down-regulation P27 to regulate cell cycle.Together,these results demonstrated that Mac2-BP gene was a novel potential functional target for lung cancer therapy.
第一部分功能性单抗库技术筛选分离、鉴定肺癌功能性抗原基因
采用新鲜肺癌组织分离的有核细胞免疫BALB/c小鼠,融合制备库容为1440个克隆的肺癌功能性单克隆抗体库。免疫细胞化学筛选获得377株稳定分泌抗人肺癌细胞单抗的杂交瘤,通过肺正常组织的免疫组化实验,排除271株与正常肺组织阳性反应的单克隆抗体,获得106株识别肺癌组织中抗原的表达高于正常肺组织表达水平的功能性单抗。肺癌及其正常肺组织的配对组织芯片检测证实67株单抗与肺癌组织呈强阳性反应,而与正常肺组织不反应或弱反应。这些单抗识别的抗原有表达于细胞膜的,也有表达于胞浆和/或胞核的。MTT法测定106株肺癌单抗对肺癌细胞增殖生长的影响,发现抑制肺癌细胞增殖生长的单抗57株,其中,抑制率大于20%的单抗有24株,抑制率在15-20%的单抗22株。RT-CES~(TM)系统实时观察106株单抗对肺癌细胞生长的影响,结果显示49株单抗能够显著抑制肺癌细胞的生长,其中16株单抗抑制率在20%以上,20株单抗抑制率在15-20%,其余单抗抑制率在10-15%。106株单抗的亚类分析证明既有不同的重链类和亚类(IgM,IgA,IgG1,IgG2a及IgG2b),也有不同的轻链型(κ,λ),表明本研究制备的功能性单抗库有很好的多样性。挑选27株功能单抗进行了裸鼠体内移植瘤抑制实验,结果证实23株单抗在裸鼠体内能显著抑制肺癌的生长和瘤重,其中6株单抗体内抑瘤率在70%以上,8株单抗抑瘤率在50-70%,另外6株单抗抑瘤率在30-50%,其余3株抑瘤率在30%以下,这些结果也提示功能性单抗所识别的抗原基因是功能性基因,具有促进肺癌细胞增殖生长功能。选取其中的5株功能性单抗分离鉴定其功能性抗原蛋白,运用免疫亲和层析和MALDI-TOP-PMF质谱技术鉴定获得了3个肺癌功能基因。单抗1E2识别的抗原基因为氨甲酰磷酸合成酶Ⅰ(CPS1),5B8抗体识别的抗原基因为理阿诺碱受体1(RyR1),13H3抗体所识别的抗原基因为凝集素半乳糖苷结合可溶3结合蛋白基因(LGALS3BP或者Mac-2BP)。
第二部分肺癌抗原Mac-2BP基因功能的研究
文献报道Mac-2BP在大部分肿瘤组织高表达,但是关于Mac-2BP在肿瘤发生发展中所起的功能作用却很少有研究报道。因此,以Mac-2BP为研究对象,进行多种功能实验研究,揭示Mac-2BP基因在肺癌发生发展中的功能作用及其在临床疾病研究方面的应用价值。采用基因敲降及免疫共沉淀技术验证质谱鉴定结果,证明肺癌功能单抗13H3识别的抗原基因确实为Mac-2BP。应用细胞免疫荧光和免疫细胞化学实验证实Mac-2BP在多种肺癌细胞有较高水平的表达。免疫组化分析105例肺癌病人癌组织及其配对正常肺组织Mac-2BP基因的表达,发现Mac-2BP在肺癌组织的表达显著高于正常肺组织,同时还发现Mac-2BP的表达水平与肺癌患者的癌组织分化程度具有显著相关性,这些结果提示Mac-2BP可作为一种新的肺癌分子标志物,具有临床诊断及预测病人预后状况价值。应用抗体13H3检测分析Mac-2BP基因体外对肺癌细胞增殖、粘附及侵袭迁移功能的影响,未观察到阳性结果,其原因可能是Mac-2BP在所检肺癌细胞体外培养分泌表达蛋白水平及含量太低所致。应用纯化后抗体再次进行体内抑瘤实验,评估抗体对肺癌生长的影响,13H3单抗能显著抑制肺癌移植瘤生长,且具有剂量依赖关系。结果发现其高、中、低剂量的抑制率分别为60.14%、54.86%和43.84%,进一步证明13H3是功能性肺癌单抗,Mac-2BP基因是肺癌功能性基因,它能促进肺癌的增殖生长。为了从基因水平进一步证明Mac-2BP表达在肺癌细胞生长的促进作用,采用RNAi干扰技术敲降肺癌细胞Mac-2BP基因的表达,检测基因敲降前后肺癌细胞增殖、粘附及迁移侵袭的变化。结果证明Mac-2BP基因敲降后肺癌细胞的增殖能力降低38.5%,肺癌细胞与胞外基质collagenⅠ的粘附降低40%,与matrigel粘附降低50%,与FN粘附水平减少35%以上,肺癌细胞体外迁移和侵袭能力分别下降27%和29%。应用稳转shRNA敲降Mac-2BP基因表达的体外功能实验研究也获得了相似的结果。同时,体内抑瘤实验研究结果也表明Mac-2BP基因敲降后,肺癌细胞在裸鼠体内的增殖生长能力显著降低,其对瘤重的抑制率高达80%。基因敲降的体内外功能实验研究再次证明Mac-2BP是一个具有促进肺癌细胞生长增殖、促进与胞外基质粘附和迁移侵袭功能的功能性基因。为了探讨Mac-2BP促进肺癌生长增殖的作用机制,我们测定了Mac-2BP基因敲降后对肺癌细胞细胞周期变化的影响。研究结果发现该基因敲降后,肺癌细胞发生G1期阻滞,致使增殖减慢,进一步研究发现Mac-2BP基因敲降后,抑癌基因p27诱导上调表达。这表明Mac-2BP基因通过调节P27蛋白水平,影响细胞周期进程,从而促进肺癌细胞在体内外的快速增殖和生长。因此该基因具有作为肺癌靶向治疗的一个新的功能性分子靶标的潜力。
Lung cancer is one of the most common malignancies worldwide with highest incidence and mortality rate.However,the traditional curative methods have only limited effect on reducing the mortality of lung cancer.Presently molecular target therapy shows great promise in clinical treatment of cancer and became one of the hot research fields of cancer. To develop a effective targeting therapy,the initial and key step is to identify the tumor specially expressed molecules.To this end,a novel high-capacity functional monoclonal antibody library screening technique was employed,and then the functional genes was isolated by the functional antibodies.We then studied the functional relevance of these genes in the development of lung cancer and the underlying molecular mechanism.
Part1.Screening and identification of lung cancer related functional genes by functional monoclonal antibody library
BALB/c mice were immunized with cancerous cells isolated from fresh human lung cancer tissue.The spleen cells were fused with SP2/0 cells to establish a lung cancer functional monoclonal antibody library containing 1440 mAbs.By ICC 377 clones were identified which stably secrete mAbs against human lung tumor cells,271 of these clones were abandoned because of immunohistochemical reacting with normal lung epithelium. Then the remaining 106 clones were further assayed by tissue arrays and 67 of these clones showed predominantly tumor tissues reactivity.106 clones were screened by MTT method and 57 clones displayed ability of proliferation suppression to cancer cells,including inhibitory rate of 24 clones over 20%and 22 clones over 15%.RT-CES~(TM) system was also employed to estimate effects on cancer cells growth,the results showed that 49 clones can significantly inhibit cell growth of lung cancer,including inhibitory rate of 24 clones over 20%,20clones clones over 15%,The rest clones showed inhibitory rate by about 10-15%. Subclass of 106 clones identified,including IgM,IgA,IgG1,IgG2a and IgG2b and light/heavy chain includingκ,λ.Those result demonstrated that monoclonal antibodies of this library were diverse.27 mAbs were chosen from the antibody library for further estimating the inhibitory effect on carcinoma xenograft in nude mice.23 clones could significantly inhibit tumor growth and tumor weight.Among them,the inhibitory rates of six clones were above 70%,and eight were about 50-70%,6 of these clones were 30-50%,3 clones were under 30%.The result indicated that the antigens recognized by these mAbs might contribute to growth of lung cancer.5 mAbs were finally produced for antigen identification by immuno-affinity and MALDI-TOP-PMF.At last we acquired 3 functional genes including(CPS1) identified by1E2,RyR1 by 5B8,LGALS3BP by 13H3.
Part2.Studies on the gene functions of Mac2-BP
Several studies have reported that Mac2-BP was overexpressed in carcinoma tissues, however,so far few studies focus on the functional role of Mac2-BP in cancer progression. Therefore,we designed functional studies as follows to reveal the role of Mac2-BP in lung cancer progression as well as its potential application in clinic.We firstly applied RNA interference and immunoprecipitation to confirm the results of mass spectrometry.Then,cell immunofluorescence and cell immunocytochemisry showed that Mac2-BP was high expressed in most lung cancer cell lines.Immunohistochemistry assay on 105 case of lung cancers paired with normal lung tissues revealed that Mac2-BP was significantly overexpressed in cancer tissue,and the overexpression of Mac2-BP was correlated with lung cancer differentiation.13H3 mAb had no effects tumor cell growth,adhesion,migration and invasion in vitro,which might due to Mac2-BP was barely secreted by lung tumor cells in vitro.However,when purified 13H3 mAb was to used to treat lung cancer xenograft in vivo a significant tumor growth inhibition was observed by a dose-dependent manner,with the inhibition rates of 60.14%,54.86%and 43.84%for the high,middle and low dosage of 13H3 respectively.These results showed that 13H3 was a functional mAb and Mac2-BP was a lung cancer associated gene that involved in tumor growth.We then applied RNAi to further revealed the role of Mac-2BP in lung cancer development.Transient RNAi,revealed that downregulating Mac-2BP could suppress cell proliferation,cell adhesion with Matrix of CollagenⅠ,Matrigel or FN,cell migration and invasion by about 38.5%,40%,50%,35%, 27%and 29%respectively.Stable RNAi transfection also certified these result in vitro.We also applied ex vivo to study the role of Mac2-BP on xenograte tumor growth.Mac2-BP knockdown could inhibit 80%xenograft tumor burden.The Mac2-BP knockdown study once again showed that Mac2-BP was a functional gene associated with lung cancer cell proliferation,matrix adhesion,migration and invasion.To further study the mechanism of Mac2-BP on lung cancer cell proliferation,we assayed the cell cycle after RNAi and revealed that Mac2-BP knockdown lead to G1 arrest.Further studies revealed that downregulation of Mac2-BP was correlated with P27 upexpression.These results indicated that Mac2-BP promotes lung cancer cell proliferation in vitro and in vivo through down-regulation P27 to regulate cell cycle.Together,these results demonstrated that Mac2-BP gene was a novel potential functional target for lung cancer therapy.
引文
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