c-myc反义寡核苷酸对增生性瘢痕成纤维细胞增殖及P27表达影响的实验研究
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摘要
研究背景：增生性瘢痕(Hypertrophic scar，HS)是人类皮肤受损、创面愈合后瘢痕持续增生的一种病理现象，它的病理本质是以成纤维细胞(Fibroblast，Fb)为主的细胞成分的过度增殖和以胶原为主的细胞外基质(Extracel lular matrix，ECM)的过度沉积，目前其发病机制还不清楚。瘢痕增生过度挛缩，常常导致各种畸形功能障碍，给患者带来身心痛苦。多年来，瘢痕增生一直无确切的治疗方法。基因治疗是分子生物学的主要应用领域之一，理论上可以从根本上阻止许多疾病的发生与进展，并有望达到治愈的目的，但如何选择靶基因及靶细胞成为其关键。
c-myc是细胞原癌基因，其编码的62KD核蛋白通过与核蛋白Max形成二聚体结合特异的DNA序列(CACTGT)激活许多靶基因的转录，其中很多基因产物与细胞周期调控密切相关。c-myc属于永生性癌基因，在细胞的生长、繁殖、凋亡及分化中具有非常重要的地位。c-myc的过度表达是人类肿瘤细胞最常见的变化之一。近年来国外研究表明c-myc与增生性瘢痕关系密切。国外学者以c-myc反义寡核苷酸(Antisense oligonucleotide，ASODN)转染肿瘤细胞后，分别采用流式细胞术和Western blotting检测的结果均显示，肿瘤细胞c-Myc蛋白水平显著降低。增生性瘢痕形成的早期阶段，通过基因进行干预，是防止瘢痕增生和挛缩的较佳时机。但目前国内外文献尚未见到c-myc ASODN对增生性瘢痕成纤维细胞c-myc mRNA表达影响的报道。国内尚未见到c-myc ASODN处理增生性瘢痕成纤维细胞的类似报道。越来越多的实验证实细胞周期调节蛋白p27对许多肿瘤有抑制作用，因此p27又被称为抑癌基因，是肿瘤抑制性治疗的重要候选者，但其在瘢痕增生过程中的作用尚不清楚。p27蛋白的表达在增生性瘢痕中比正常皮肤组织低，提示p27可能与瘢痕形成有关。研究发现，成纤维细胞高表达c-myc可直接引起p27下调，
Background: Hypertrophic scar (HS), characterized by excessive fibroblast proliferation and local collagen deposition, is a very common pathologic phenomenon of scar hyperplasia after human skin injury and wound healing, and its pathogenesis is still unclear. Hypertrophic scar and scar over-contracture often destroy patient's cosmetics or result in patient's dysfunction of organs. Up to now, there is no effective method to treat scar. With the development in molecular techniques, gene therapy is reported as a hopeful way to treat many diseases. In theory, gene therapy may prevent many kinds of diseases from emerging or developing. The key point for gene therapy is how to select target gene and target cell. Proto-oncogene c-myc encodes a nuclear 62KD phosphorprotein, which acts as a key regulator of cell growth and differentiation. When dimerized with its partner protein Max, c-myc functions as transcription factor, capable of both activating and repressing transcription. C-myc is an eternal oncogene and plays a critical role in regulating cell proliferation, growth, apoptosis and differentiation. Over expression of c-myc is one of the most common alterations in human cancers. Recent years, foreign studies have identified that c-myc oncogene is closely related to hypertrophic scar. Some researchers have found that, by use of flow cytometry and Western Blotting, the level of c-Myc protein in tumor cells significantly reduces after transfection by c-myc ASODN. The early period of hypertrophic scar formation might be a good time for preventing overgrowth and contraction of hypertrophic scar by gene therapy. However, whether c-myc ASODN can cause the reduction of c-myc mRNA expression in fibroblasts is unknown.p27 is a member of the universal cyclin-dependent kinase inhibitor
c-myc是细胞原癌基因，其编码的62KD核蛋白通过与核蛋白Max形成二聚体结合特异的DNA序列(CACTGT)激活许多靶基因的转录，其中很多基因产物与细胞周期调控密切相关。c-myc属于永生性癌基因，在细胞的生长、繁殖、凋亡及分化中具有非常重要的地位。c-myc的过度表达是人类肿瘤细胞最常见的变化之一。近年来国外研究表明c-myc与增生性瘢痕关系密切。国外学者以c-myc反义寡核苷酸(Antisense oligonucleotide，ASODN)转染肿瘤细胞后，分别采用流式细胞术和Western blotting检测的结果均显示，肿瘤细胞c-Myc蛋白水平显著降低。增生性瘢痕形成的早期阶段，通过基因进行干预，是防止瘢痕增生和挛缩的较佳时机。但目前国内外文献尚未见到c-myc ASODN对增生性瘢痕成纤维细胞c-myc mRNA表达影响的报道。国内尚未见到c-myc ASODN处理增生性瘢痕成纤维细胞的类似报道。越来越多的实验证实细胞周期调节蛋白p27对许多肿瘤有抑制作用，因此p27又被称为抑癌基因，是肿瘤抑制性治疗的重要候选者，但其在瘢痕增生过程中的作用尚不清楚。p27蛋白的表达在增生性瘢痕中比正常皮肤组织低，提示p27可能与瘢痕形成有关。研究发现，成纤维细胞高表达c-myc可直接引起p27下调，
Background: Hypertrophic scar (HS), characterized by excessive fibroblast proliferation and local collagen deposition, is a very common pathologic phenomenon of scar hyperplasia after human skin injury and wound healing, and its pathogenesis is still unclear. Hypertrophic scar and scar over-contracture often destroy patient's cosmetics or result in patient's dysfunction of organs. Up to now, there is no effective method to treat scar. With the development in molecular techniques, gene therapy is reported as a hopeful way to treat many diseases. In theory, gene therapy may prevent many kinds of diseases from emerging or developing. The key point for gene therapy is how to select target gene and target cell. Proto-oncogene c-myc encodes a nuclear 62KD phosphorprotein, which acts as a key regulator of cell growth and differentiation. When dimerized with its partner protein Max, c-myc functions as transcription factor, capable of both activating and repressing transcription. C-myc is an eternal oncogene and plays a critical role in regulating cell proliferation, growth, apoptosis and differentiation. Over expression of c-myc is one of the most common alterations in human cancers. Recent years, foreign studies have identified that c-myc oncogene is closely related to hypertrophic scar. Some researchers have found that, by use of flow cytometry and Western Blotting, the level of c-Myc protein in tumor cells significantly reduces after transfection by c-myc ASODN. The early period of hypertrophic scar formation might be a good time for preventing overgrowth and contraction of hypertrophic scar by gene therapy. However, whether c-myc ASODN can cause the reduction of c-myc mRNA expression in fibroblasts is unknown.p27 is a member of the universal cyclin-dependent kinase inhibitor
引文
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