CLN3基因在内质网应激引起肿瘤抗药中的功能研究

ERS is the important microenvironment for solid tumor formation. It contributes to tumor progression, and develops. Tumor drug resistance caused by aggravated ERS had become a major obstacle to cancer treatment.Recently researcher focus on special tumor biomarker related with ERS. We previous found that overexpression of CLN3 (juvenile neural ceroid lipofuscinoses disease causative gene) protein can inhibit the endoplasmic reticulum stress (ERS) development induced by Tunicamycin treatment. CLN3 protein can increase cell proliferation and inhibit apoptosis late in the ERS. CLN3 gene is highly expressed in a variety of tumor cells and tissues, suggesting that the gene may be an important cancer gene in tumor development. Drug-resistant biological mechanism of CLN3 protein under the ERS established by anticancer drug in tumor cells will be studied in our study. At the same time, expression correlation of CLN3 gene and endoplasmic reticulum stress chaperone in different regions (hypoxia, the normal oxygen District) of tumor tissue will be determined.The roles of CLN3 gene in tumor development and drug-resistant treatment will be studied in the cultured cells .

内质网应激（endoplasmic reticulum stress，ERS）是实体瘤重要的内环境，与肿瘤细胞的发生、发展具有密切关系。持久适度的ERS会造成肿瘤耐药，成为肿瘤治疗的重大障碍。近年研究者从ERS诱导子或相关的肿瘤特异标记物着手研究，增强了治疗效果。我们前期研究发现，在药物Tunicamycin建立的ERS下，CLN3（Batten Disease的致病基因）高表达可以抑制ERS发展，并与ERS蛋白表达呈相关性。已有报道，CLN3基因在多种肿瘤组织中高表达，提示其可能是重要的癌相关基因。本项目拟开展肿瘤细胞中CLN3蛋白对抗肿瘤药物建立的ERS下的抗药生物机制，确定肿瘤组织不同区域（乏氧、正常氧区）CLN3基因与内质网应激伴侣分子的表达相关性。并以CLN3基因为治疗靶标，在细胞水平上研究其对肿瘤发生发展及其耐药治疗的分子机制研究。

内质网应激（Endoplasmic reticulum strees, ERS）是实体瘤化疗过程中的重要应激反应。与肿瘤细胞的发生、发展具有重要关系。持久适度的ERS成为肿瘤抗化疗药物的重大障碍。CLN3做为胶质瘤相关基因在癌组织中高表达。我们本项研究发现，CLN3基因在ERS条件下对肿瘤细胞增殖起到促进作用，抑制凋亡；CLN3基因表达与内质网应激蛋白的表达具有相关性。提示CLN3在肿瘤细胞内质网应激下发生的增殖、抗药机制发挥重要作用。同时我们对高度抗药的胶质瘤样本与正常脑外伤样本进行miRNA表达差异的比较，筛选到上调2倍以上的表达基因121个，其中上调4倍以上的基因有21个；下调2倍以上的基因有40个，下调4倍的基因有4个。通过靶基因与参与的功能通路的预测，我们将对参与ERS通路的miRNA开展进一步的细胞抗药性的功能验证。