腺病毒介导的人白介素24和p16基因体外治疗肺腺癌细胞株A549的实验研究
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摘要
肺癌是人类最常见和最难治愈的恶性肿瘤之一,其发生、发展和转移是一个极其复杂的多基因调控异常的过程。该病确诊时多非早期,故疗效较差。最新统计表明,肺癌死亡率上升幅度居各类肿瘤之首[1]。肺癌在临床上分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC),其中前者约占肺癌发病总数的80%。虽然传统的放疗、化疗可以在一定程度上提高病人的预后情况,但由于存在负作用、转移等各种问题,目前仍缺乏有效的手段进行根治,严重影响着人类的生命健康。因此,关于肺癌的防治研究,尤其是非小细胞肺癌的治疗研究,成为当今最受人们关注的领域之一。
近年来,随着医学分子生物学技术和理论的发展以及对肺癌发病机制认识的不断深入,尤其是DNA重组技术和基因转移技术逐步成熟,研究者们提出了利用基因转移技术向体内导入目的基因,从而对肺癌发病的分子环节进行干预的防治策略,为肺癌的治疗开辟了新途径。
本研究拟以人白介素24(hIL-24)和p16基因作为分子工具,采用重组腺病毒为基因导入载体对非小细胞肺癌中具有代表性的肺腺癌A549细胞株进行体外基因治疗的实验研究,主要探讨外源性hIL-24和p16基因的转入及异位表达对治疗A549肿瘤细胞所发挥的作用及其内在机制,以期为肺癌基因治疗研究的进一步深入奠定必要的实验基础。
研究方法:
1.分离人外周血单个核细胞,提取其RNA作为模板采用RT-PCR方法分别扩增人白介素24(hIL-24)和p16基因cDNA全部编码序列,并将其亚克隆至测序载体pMD18-T上进行测序分析。
2 .将测序正确的IL-24和p16基因片断定向克隆至腺病毒穿梭质粒pAdTrack-CMV上分别构建穿梭质粒pAdTrack-IL24和pAdTrack-p16,然后将阳性重组子分别与腺病毒基因组质粒pAdEasy1在BJ5183工程菌中进行同源重组构建重组腺病毒质粒pAdEasy-IL24和pAdEasy-p16并加以鉴定。
3.采用脂质体DOTAP介导构建正确的重组腺病毒质粒pAdEasy-IL24和
Lung cancer is one of the most common malignancies in the world, and non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers,its incidence and mortality are increasing rapidly year after year.Surgical resection is the only curative treatment for patients with NSCLC. For patients with nonresectable NSCLC, conventional chemotherapy or radiotherapy improves prognosis,but only a little. Therefore, the development of novel strategies for the treatment of NSCLC continues to be necessary.
Advances in our understanding of the molecular biology of tumor cells have led to the development of new treatment strategies, including gene therapy. The molecular basis of cancer is now known to involve activation of dominant oncogenes and inactivation of tumour suppressor genes, these genetic events may represent novel targets for cancer therapy.
Tumor suppressor genes constrain unusual cell proliferation. These genes induce apoptosis and/or cell cycle arrest in malignant cells .There is a growing list of possible tumor suppressors that can potentially be used to control cancer cell growth in the clinic,such as p53, Rb, p21, p16, p27 and so on.Among these genes, p16 and IL-24 are two representative members whose expressions are always lost during tumor progression, and the latter is already inⅡphase clinical trials.More and more subsequent gene transfer studies using plasmid-based or adenoviral vector mediated delivery of IL-24 and p16 confirmed that their protein expression can reduced growth and colony formation in a variety of human cancer models, including breast, lung, colon, prostate carcinomas and so on, but not normal cells. IL-24 can selectively suppressed tumor cell growth via G2/M cell cycle blockade and apoptosis induction;whereas,p16 can suppress cancer by G1/S arrest.Therefore, successful introductin of them into cancerous cells will have therapeutic outcomes.All these are making them promising and popular targets in gene therapy for cancer.
近年来,随着医学分子生物学技术和理论的发展以及对肺癌发病机制认识的不断深入,尤其是DNA重组技术和基因转移技术逐步成熟,研究者们提出了利用基因转移技术向体内导入目的基因,从而对肺癌发病的分子环节进行干预的防治策略,为肺癌的治疗开辟了新途径。
本研究拟以人白介素24(hIL-24)和p16基因作为分子工具,采用重组腺病毒为基因导入载体对非小细胞肺癌中具有代表性的肺腺癌A549细胞株进行体外基因治疗的实验研究,主要探讨外源性hIL-24和p16基因的转入及异位表达对治疗A549肿瘤细胞所发挥的作用及其内在机制,以期为肺癌基因治疗研究的进一步深入奠定必要的实验基础。
研究方法:
1.分离人外周血单个核细胞,提取其RNA作为模板采用RT-PCR方法分别扩增人白介素24(hIL-24)和p16基因cDNA全部编码序列,并将其亚克隆至测序载体pMD18-T上进行测序分析。
2 .将测序正确的IL-24和p16基因片断定向克隆至腺病毒穿梭质粒pAdTrack-CMV上分别构建穿梭质粒pAdTrack-IL24和pAdTrack-p16,然后将阳性重组子分别与腺病毒基因组质粒pAdEasy1在BJ5183工程菌中进行同源重组构建重组腺病毒质粒pAdEasy-IL24和pAdEasy-p16并加以鉴定。
3.采用脂质体DOTAP介导构建正确的重组腺病毒质粒pAdEasy-IL24和
Lung cancer is one of the most common malignancies in the world, and non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers,its incidence and mortality are increasing rapidly year after year.Surgical resection is the only curative treatment for patients with NSCLC. For patients with nonresectable NSCLC, conventional chemotherapy or radiotherapy improves prognosis,but only a little. Therefore, the development of novel strategies for the treatment of NSCLC continues to be necessary.
Advances in our understanding of the molecular biology of tumor cells have led to the development of new treatment strategies, including gene therapy. The molecular basis of cancer is now known to involve activation of dominant oncogenes and inactivation of tumour suppressor genes, these genetic events may represent novel targets for cancer therapy.
Tumor suppressor genes constrain unusual cell proliferation. These genes induce apoptosis and/or cell cycle arrest in malignant cells .There is a growing list of possible tumor suppressors that can potentially be used to control cancer cell growth in the clinic,such as p53, Rb, p21, p16, p27 and so on.Among these genes, p16 and IL-24 are two representative members whose expressions are always lost during tumor progression, and the latter is already inⅡphase clinical trials.More and more subsequent gene transfer studies using plasmid-based or adenoviral vector mediated delivery of IL-24 and p16 confirmed that their protein expression can reduced growth and colony formation in a variety of human cancer models, including breast, lung, colon, prostate carcinomas and so on, but not normal cells. IL-24 can selectively suppressed tumor cell growth via G2/M cell cycle blockade and apoptosis induction;whereas,p16 can suppress cancer by G1/S arrest.Therefore, successful introductin of them into cancerous cells will have therapeutic outcomes.All these are making them promising and popular targets in gene therapy for cancer.
引文
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10. Parker SL, Tong T. Bolden S. and Wingo PA. Cancer statistics, 1997. CA Cancer J. Clin. 1997, 47:5-27.
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15. Huang EY, Madireddi MT, Gopalkrishnan RV, et al. Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducingproperties. Oncogene. 2001, 20(48):7051-7063.
16. Lebedeva IV, Su ZZ, Chang Y, et al. The cancer growth suppressing geng mda-7 induces apoptosis selectively in human melanoma cells. Oncogene. 2002, 21(5):708-718.
17. Su ZZ, Madireddi MT, Lin JJ, et al. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA. 1998, 95(24):14400-14405.
18. Mhashilkar AM, Schrock RD, Hindi M, et al. Melanoma differentiation associated gene-7 (mda-7): a novel anti-tumor gene for cancer gene therapy. Mol Med. 2001, 7(4):271-282.
19. Su ZZ, Lebedeva IV, Gopalkrishnan RV, et al. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci USA. 2001, 98(18):10332-10337.
20. Saeki T, Mhashilkar A, Swanson X, et al. Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene. 2002, 21(29):4558-4566.
21. Pataer A, Vorburger SA, Barber GN, et al. Adenoviral transfer of the melanoma differentiation-associated gene-7 (mda-7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase(PKR). Cancer Res. 2002, 62(8):2239-2243.
22. Kawabe S, Nishikawa T, Munshi A, et al. Adenovirus-mediated mda-7 gene expression radiosensitizes non-small cell lung cancer cells via TP53-independent mechanism. Mol Ther. 2002, 6(5):637-644.
23. Cao XX, Mohuiddin I, Chada S, et al. Adenoviral transfer of mda-7 leads to BAX up-regulation and apoptosis in mesothelioma cells,and is abrogated by over-expression of BCL-XL. Mol Med. 2002, 8(12):869-876.
24. Lebedeva IV, Sarkar D, Su ZZ, et al. Bcl-2 and Bcl-x (L) differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24. Oncogene. 2003, 22(54):8758-8773.
25. Yacoub A, Mitchell C, Lebedeva IV, et al. mda-7 (IL-24) Inhibits growth and enhances radiosenisitivity of glioma cells in vitro via JNK signaling. Cancer Biol Ther. 2003,2(4):347-353.
26. Su ZZ, Lebedeva IV, Sarkar D, et al. Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosenitization in malignant gliomas in a p53-independent manner. Oncogene. 2003, 22(8):1164-1180.
27. Sarkar D, Su ZZ, Lebedeva IV, et al. Mda-7/IL-24 mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Proc Natl Acad Sci. 2002, 99(15):10054-10059.
28. Saeki T, Mhashilkar A, Chada S, et al. Tumor-suppressive effects by adenovirus- mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene therapy. 2000, 7(23):2051-2057.
29. Ramesh R, Ito I, Gopalan B, Saito Y, et al. Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther. 2004, 9(4):510-518.
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