摘要
肿瘤是危害人类健康的杀手之一。肿瘤外科学、肿瘤放射治疗学、肿瘤化学治疗学构成了现代肿瘤治疗学的三大支柱。三种治疗手段各有特点,互为补充。但是很多恶性肿瘤对手术后的放化疗具有抵抗能力。这也是困扰肿瘤治疗的难题之一。目前已发现多种蛋白与肿瘤抗药性有关。HO-1就是近年发现的与肿瘤的抗药性相关的蛋白之一。
HO-1是血红素分解代谢的关键酶,它能催化血红素降解并释放出胆绿素、CO和Fe~(2+),也是一种广泛存在的抗氧化防御酶和内源性抗凋亡蛋白,与临床上多种疾病(如:肿瘤、动脉粥样硬化、高血压等)关系密切。
上世纪80年代以来的研究证实HO-1与多种肿瘤具有相关性,发现HO-1在多种实体肿瘤组织中较正常组织表达上调[1]。但是,HO-1在不同肿瘤中所起的作用不同[2],一方面高表达的HO-1通过抗凋亡作用促进某些肿瘤快速增长,并有利于肿瘤的转移和增殖,如肺癌、结肠癌、前列腺癌、口腔鳞状细胞癌、食管癌等[3],体内外研究还证实HO-1的抑制剂锌原卟啉可增强肺癌、结肠癌、前列腺癌对化疗的敏感性,减慢肿瘤生长速度[4-6] ;另一方面,HO-1表达增高却抑制某些肿瘤细胞的增殖,Hill等的研究发现HO-1表达的上调可抑制乳腺癌细胞增殖[7]。由此可见,需要探讨HO-1在更多的肿瘤中所发挥的作用及其作用机制,为制定新的临床肿瘤治疗方案提供实验依据。
目前国内外研究HO-1与肿瘤关系主要是通过改变HO-1表达水平观察肿瘤细胞的特性变化[1],但HO-1活性变化对肿瘤细胞的影响研究较少,尤其HO-1表达或活性变化对胃癌细胞的影响研究还未见报道;另外,从动物水平上研究HO-1表达水平与肿瘤发生、发展关系的较少,研究者多是利用HO-1的诱导剂或抑制剂(多为卟啉化合物)处理小鼠,观测HO-1表达对肿瘤生长的影响,但这些卟啉化合物本身具有毒性,且作用机制复杂,所得实验数据还不能如实反映机体HO-1水平对肿瘤特性的影响,建立HO-1不同表达水平的转基因小鼠模型可更深入准确研究HO-1表达水平对肿瘤进程的影响。为此我们开展了以下几个方面的工作:
第一部分HO-1活性对胃腺癌细胞BGC823抗药性的影响胃癌是一种常见肿瘤,目前关于HO-1与其相关性研究报道较少,本研究通过构建pcDNA3.1(+)-HHO-1、pcDNA3.1(+)-HHO-1G143H真核重组载体,转染胃腺癌细胞BGC823后,检测HO-1表达、活性变化,并对HO-1活性变化后胃腺癌细胞对化疗药物抗药性进行观察。结果显示转染质粒pcDNA3.1(+)-HHO-1后BGC823细胞HO-1活性显著升高、转染
pcDNA3.1(+)-HHO-1G143H后BGC823细胞HO-1活性降低;转染后胃腺癌细胞BGC823抗顺铂能力发生了改变,pcDNA3.1(+)-HHO-1G143H转染细胞组对药物抵抗力明显高于野生BGC823细胞组,具有统计学意义。结果表明降低胃腺癌细胞HO-1活性会影响顺铂化疗的效果。
第二部分转基因小鼠BDF1HO-1和FVBHO-1模型的建立通过显微注射技术,将纯化后的HO-1片断注入小鼠受精卵原核中,然后将注射后状态良好的受精卵移植到假孕母鼠的输卵管内,得到BDF1转基因小鼠BDF1HO-1和FVB转基因小鼠FVBHO-1转基因小鼠共4个品系。其中,BDF1HO-1包括HO-1高表达系371L、HO-1中表达系820L、HO-1突变系G143HL3个品系;FVBHO-1的显性负性突变体系HO-1G143H。模型建立过程中,发现FVB来源的转基因小鼠FVBHO-1 F0代动物阳性率为3.8%,大大低于一般10~30%的比例,也低于BDF1HO-1中显性负性突变体系的阳性率,因此推测HO-1活性变化对FVB小鼠生殖有影响;并且,发现转基因小鼠BDF1HO-1和FVBHO-1的HO-1在脾脏红髓区表达增高。由于红髓有大量的巨噬细胞、B淋巴细胞和浆细胞,因此推测HO-1在该区域高表达可能会影响动物抗炎能力。
第三部分BDF1转基因小鼠BDF1HO-1对黑色素瘤细胞生长、转移影响的研究应用BDF1HO-1的371L、G143HL和野生鼠3个品系,研究动物机体中HO-1活性变化对黑色素瘤B16F10生长、转移的影响。本实验对肿瘤出现时间、生长速度、动物的致死率、肺部转移灶数量进行统计研究。结果显示,机体中HO-1活性变化对接种的肿瘤细胞在体内生长状况有很大影响。HO-1高表达371L从肿瘤生长速度、动物的致死率和肺部转移灶数量都低于野生鼠。并且,皮下肿瘤HE染色显示,371L动物肿瘤组织中炎细胞较少浸润。可见HO-1活性高的动物可以有效抵抗黑色素瘤B16F10的转移,抑制肿瘤细胞在体内的生长速度,有助于机体的抗炎。
综上所述,本研究通过体外实验改变胃腺癌细胞BGC823 HO-1表达与活性,发现该细胞HO-1活性降低对于顺铂的抵抗能力会提高。同时通过转基因技术,成功建立BDF1转基因小鼠BDF1HO-1和FVB转基因小鼠FVBHO-1。其中,BDF1HO-1得到了3个品系。使用黑色素瘤细胞B16F10在BDF1HO-1小鼠中进行肿瘤生长、转移实验发现,机体中HO-1活性提高,有助于减少肿瘤生长、转移和炎性反应。本实验为研究HO-1活性变化对肿瘤的作用并进一步制定肿瘤诊断及治疗新方案奠定了实验基础。
Tumor is the one of the killers which hazard human health. Oncological surgery, tumor therapeutic radiology and tumor chemical therapy are three sustentaculums of modern tumor therapy which have characteristics respectively and supplement each other. However, many malignant tumors have resistance to postsurgical chemoradiation, which is one of the tough problems that puzzle tumor therapy. Many proteins have been found to correlate with the neoplasm drug resistance and HO-1 is one of them.
HO-1 is the rate-limiting enzyme that catalyzes the conversion of heme to biliverdin, carbon monoxide(CO) and iron. HO-1 is both a kind of anti-oxidant enzyme and an endogenous antiapoptosis protein which correlates with some diseases (such as tumors, atherosclerosis, hypertension, etc.) clinically.
It has been found that HO-1 has correlation with tumors and HO-1 is up-regulated in solid tumors compared with the normal tissue from 1980s. But the functions of HO-1 in different tumors are different. On one hand HO-1 promotes rapid growth of some tumors such as lung cancer, colon cancer, prostate cancer, squamous-celled carcinoma of oral cavity, esophageal cancer, etc. and protects neoplasm metastasis and proliferation through anti-apoptosis effect. The in vitro and in vivo experiments have demonstrated that zinc protoporphyrin ( the inhibitor of HO-1) could enhance the chemotherapy sensitivity of some tumors such as lung cancer, colon cancer, prostate cancer and reduce the growth velocity. On the other hand high expression of HO-1 can inhibit the proliferation of some tumors cells. The study of Hill showed that the up-regulation of HO-1 could inhibit the proliferation of breast cancer cells. It can be seen that it is necessary to investigate the functions and the mechanisms of HO-1 in more tumors.
The studies of the relationship between HO-1 and tumors began with the cells and the expression styles of HO-1 were regulated in different tumors. The relationship between HO-1 and gastric carcinoma is uncertain and it is necessary to investigate the effect of the activity of HO-1 on gastric carcinoma. In addition, the studies about the effect of the activity of HO-1 on the characteristics of tumors are less. The present study only use the inductor of inhibitor of HO-1 to treat mice to observe the effect of the expression of HO-1 on the characteristics of tumors. But the the mechanisms of the drugs are complicated and the function styles are different and the targets are not good. The experimental data cannot reflect the effect of of HO-1 on the characteristics of tumors. Although it is presumed that the expression level of HO-1 correlates to the generation of tumors from the amount of HO-1 promoter (GT)n, it is short of enough data and direct proof. The mice model with the different expression levels of HO-1 is the most effective and direct method of solving the effect of HO-1 expression level on the processes of tumors. Therefore we carried out the following experiments:
The first part The effect of the activity of HO-1 on the drug resistance of gastric adenocarcinoma cells BGC823 Gastric carcinoma is a common cancer and there is a little reports about the correlation with HO-1. We constructed the recombinant plasmids pcDNA3.1(+)-HHO-1 and pcDNA3.1(+)-HHO-1G143H and transfected them to gastric adenocarcinoma cells BGC823. The expression and enzymatic activity of HO-1 were examined and the drug resistance of gastric adenocarcinoma cells with changed HO-1 was observed. The results showed BGC823 cells transfected with pcDNA3.1(+)-HHO-1 had elevated expression of HO-1 mRNA and protein. While the decreased activity of HO-1 was showed in cells transfected with pcDNA3.1(+)-HHO-1G143H. The cell resistance to Cisplatin was changed, and the drug resistance of cells transfected with pcDNA3.1(+)-HHO-1G143H was higher than that of wild BGC823 cells. The results indicated that the decrease of HO-1 activity in gastric adenocarcinoma cells might influence the effect of Cisplatin chemotherapy.
The second part The establishment of transgenic mice models of BDF1HO-1 and FVBHO-1 The fragments of purifed HO-1 were injected to the pronucleus of mice zygotes and the zygotes with good conditions were transplanted into fallopian tubes of the pseudopregnant mice. Five lines of transgenic mice of BDF1HO-1 and FVBHO-1 were obtained. Four lines of BDF1HO-1 mice were 371L with high expression of HO-1, 820L with middle expression of HO-1, G143HL with HO-1 mutant, the wild line and one line of FVBHO-1 was the dominant negative mutation of HO-1G143H. The positive rate of F0 generation of transgenic mice FVBHO-1 was 3.8% which was much lower than the common ratio 10-30% and was also lower than that of BDF1HO-1 dominant negative mutation. So it was presumed that the change of HO-1 activity had effect on the reproduction of FVB mice. HO-1 expression position in the spleen of transgenic mice was changed and the expression of HO-1 was high in the red marrow. Since there are lots of macrophagocytes, B lymphocytes and plasmacytes in the red marrow, it is presumed that high expression of HO-1 in this area might affect the anti-inflammatory capability of the animals.
The third part The study of the effect of transgenic mice BDF1HO-1 on the growth and metastasis of melanoma cells We used three lines of BDF1HO-1 i.e. 371L, G143HL and the wild line to investigate the effect of HO-1 activity in animals on the growth and metastasis of melanoma cells B16F10. Statistic research of tumors emergence time, growth velocity, animals lethality and the amount of pulmonary metastasis was carried out and the results showed that activity of HO-1 in animals had great effect on the growth of animals which was inoculated by tumor cells. The growth velocity of tumors, lethality and the number of metastasis in lungs of 371L with high expression of HO-1 were lower than those in the wild mice. Further the HE stain of the subcutaeous tumors showed that there was less inflammatory cell infiltrate in the animals of 371L. It can be seen that animals with high activity of HO-1 can resist the metastasis of melanoma B16F10 effectively, inhibit the growth velocity of tumors in animals, delay or avoid the formation of tumors mass and inhibit inflammatory.In conclusion, we changed the expression and activity of HO-1 in gastric adenocarcinoma cells BGC823 and found that the decreased activity of HO-1 in the cells might elevate the resistance to Cisplatin. At the same time, the transgenic mice BDF1HO-1 and FVBHO-1 were established successfully through transgenetic technology. Further, four lines of BDF1HO-1 were obtained. The experiments of the growth and metastasis of melanoma cells in three lines of BDF1HO-1 showed that the elevated activity of HO-1 helped to reduce the growth and metastasis of tumors and inhibit inflammatory. This builds up the foundation to the study of the effect of the activity change of HO-1 on tumors.
引文
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[1]. HIRAI K, SASAHIRA T, OHMORI H, et al. Inhibition of heme oxygenase-1 by zine protoporphyrinⅨreduces tumor growth of LL/2 lung cancer in C57BL mice[J]. Int J Cancer. 2007,120(3):500-5.
[2]. HILL M, PEREIRA V, CHAUVEAU C,et al. Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase[J]. FASEB J. 2005 Dec;19(14):1957-68
[3]. MAINES MD, ABRAHAMSSON PA. Expression of heme oxygenase-1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution[J]. Urology,1996, 47(5):727-33
[4]. TSUJI MH, YANAGAWA T, IWASA S, et al. Heme oxygenase-1 expression in oral squamous cell carcinoma as involved in lymph node metastasis[J]. Cancer Lett,1999,138(1-2):53-9.
[5]. KOCANOVA S, BUYTAERT E, MATROULE JY, et al. Induction of heme-oxygenase 1 requires the p38(MAPK) and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy[J]. Apoptosis,2007, 12(4):731-41
[6]. CHEN YH, LIN SJ, LIN MW, et al. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients[J]. Human Genet ,2002,111: 1–8,.
[7]. KIKUCHI A, YAMAYA M, SUZUKI S, et al. Association of susceptibility to the development of lung adenocarcinoma with the heme oxygenase-1 gene promoter polymorphism[J]. Hum Genet,2005 , 116(5):354-60
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