视蛋白基因3（OPN3）对人肺癌A549细胞紫杉醇耐药性作用机制的初步研究
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摘要
肺癌是最常见的恶性肿瘤之一,严重危害人类健康,以非小细胞肺癌多见,而化学治疗是其主要的治疗手段。但随着化疗药物的广泛使用,肿瘤耐药性也不断出现,严重影响了治疗效果。耐药性是由基因决定的,因此,发现和研究肿瘤耐药性相关基因及其作用的分子机制,有助于进行针对性的临床治疗,为研究新的药物作用靶点和治疗方法提供依据,其已成为当前肿瘤防治研究的重点课题。
本室前期研究表明,与淡色库蚊对杀虫剂抗性相关视蛋白基因高度同源的人视蛋白基因3(Opsin3,OPN3)与人肺癌A549细胞紫杉醇耐药性相关,推测其可能作为G蛋白偶联受体(GPCR)成员,参与了肺癌A549细胞对紫杉醇的耐药机制。
本研究采用G蛋白偶联受体信号通路基因芯片,对A549紫杉醇敏感细胞转染OPN3及其空载体对照组、A549_(PTX)紫杉醇耐药细胞干涉OPN3及其空载体对照组共4种细胞系,紫杉醇处理前后2种状态,共8组样品进行高通量筛选,以研究OPN3对其他G蛋白偶联受体及GPCR下游信号通路的影响:采用定量PCR及Western Blot验证目的基因及蛋白质表达差异,研究其对A549细胞紫杉醇耐药影响的可能机制。结果表明,OPN3可以抑制c-Jun表达,从而降低下游基因转录、抑制细胞增殖,增加肿瘤细胞对药物的敏感性。
同时,本研究采用使用annexin V/propidium iodide(PI)双染,流式细胞仪结合荧光显微镜对芯片实验样本细胞进行凋亡检测。结果表明,OPN3相对表达水平与A549细胞在紫杉醇处理下的凋亡水平正相关,提示OPN3可能还上调细胞凋亡信号通路,诱导细胞凋亡,这一结果与前期~3H-TdR增殖试验结果相符。
本研究初步研究了OPN3在肺癌耐药性中的功能,首次发现OPN3对A549细胞紫杉醇耐药性的影响包括抑制c-Jun表达和促进细胞凋亡2方面,为深入研究视蛋白基因在耐药性产生机制中的作用、发现新的肿瘤基因治疗位点奠定了基础。
As one of the most popular fetal diseases all around the world, lung cancer was mainly treated by chemotherapy. Resistance to chemotherapy frequently occurs and represents a major obstacle to successful cancer treatment. Understanding the basis of resistance is a principal goal of molecular oncology. But the mechanisms of drug resistance are polygenetic and incompletely defined. Elucidating the molecular mechanisms of this complex process may lead to the identification of novel molecules that in turn may serve as targets for therapeutic, diagnostic tests or alternatively predictive markers.
In the previous study, we found that 0PN3, the protein component of visual pigment molecules, participated in paclitaxel resistance of the non-small cell lung cancer (NSCLC) cell line (A549).
In the present study, GPCR Signaling PathwayFinder genechips were used to detect the affection of OPN3 to A549 and A549_(PTX) cell lines with it's GPCR activity. The results showed that 0PN3 downregulated the expression of c-Jun, resulted in the depressed transcription of downstream genes, and inhibited cell proliferation and sensitivity of tumor cells to drugs. We analyzed the cell apoptosis by annexin V / propidium iodide (PI) staining detected by flow cytometry and fluorescence microscopy, suggesting that 0PN3 may upregulated the cell apoptosis signal pathway.
The negative regulation of paclitaxel resistance suggested that 0PN3 could be the potential target of tumor therapy. And the data in this work could improve the research of opsins in tumor drug resistance.
本室前期研究表明,与淡色库蚊对杀虫剂抗性相关视蛋白基因高度同源的人视蛋白基因3(Opsin3,OPN3)与人肺癌A549细胞紫杉醇耐药性相关,推测其可能作为G蛋白偶联受体(GPCR)成员,参与了肺癌A549细胞对紫杉醇的耐药机制。
本研究采用G蛋白偶联受体信号通路基因芯片,对A549紫杉醇敏感细胞转染OPN3及其空载体对照组、A549_(PTX)紫杉醇耐药细胞干涉OPN3及其空载体对照组共4种细胞系,紫杉醇处理前后2种状态,共8组样品进行高通量筛选,以研究OPN3对其他G蛋白偶联受体及GPCR下游信号通路的影响:采用定量PCR及Western Blot验证目的基因及蛋白质表达差异,研究其对A549细胞紫杉醇耐药影响的可能机制。结果表明,OPN3可以抑制c-Jun表达,从而降低下游基因转录、抑制细胞增殖,增加肿瘤细胞对药物的敏感性。
同时,本研究采用使用annexin V/propidium iodide(PI)双染,流式细胞仪结合荧光显微镜对芯片实验样本细胞进行凋亡检测。结果表明,OPN3相对表达水平与A549细胞在紫杉醇处理下的凋亡水平正相关,提示OPN3可能还上调细胞凋亡信号通路,诱导细胞凋亡,这一结果与前期~3H-TdR增殖试验结果相符。
本研究初步研究了OPN3在肺癌耐药性中的功能,首次发现OPN3对A549细胞紫杉醇耐药性的影响包括抑制c-Jun表达和促进细胞凋亡2方面,为深入研究视蛋白基因在耐药性产生机制中的作用、发现新的肿瘤基因治疗位点奠定了基础。
As one of the most popular fetal diseases all around the world, lung cancer was mainly treated by chemotherapy. Resistance to chemotherapy frequently occurs and represents a major obstacle to successful cancer treatment. Understanding the basis of resistance is a principal goal of molecular oncology. But the mechanisms of drug resistance are polygenetic and incompletely defined. Elucidating the molecular mechanisms of this complex process may lead to the identification of novel molecules that in turn may serve as targets for therapeutic, diagnostic tests or alternatively predictive markers.
In the previous study, we found that 0PN3, the protein component of visual pigment molecules, participated in paclitaxel resistance of the non-small cell lung cancer (NSCLC) cell line (A549).
In the present study, GPCR Signaling PathwayFinder genechips were used to detect the affection of OPN3 to A549 and A549_(PTX) cell lines with it's GPCR activity. The results showed that 0PN3 downregulated the expression of c-Jun, resulted in the depressed transcription of downstream genes, and inhibited cell proliferation and sensitivity of tumor cells to drugs. We analyzed the cell apoptosis by annexin V / propidium iodide (PI) staining detected by flow cytometry and fluorescence microscopy, suggesting that 0PN3 may upregulated the cell apoptosis signal pathway.
The negative regulation of paclitaxel resistance suggested that 0PN3 could be the potential target of tumor therapy. And the data in this work could improve the research of opsins in tumor drug resistance.
引文
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