同义突变调控APC蛋白生物学功能及结直肠癌的发生发展

批准号:
32000539
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
潘晨宇
依托单位:
学科分类:
细胞信号转导
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
潘晨宇
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中文摘要
WNT通路持续激活是诱发结直肠癌的重要因素之一。APC作为该通路的抑制因子其突变在肠癌发生发展中起到关键作用。最近研究发现同义突变可调控蛋白质水平或结构等进而调控蛋白质功能,而APC同义突变的功能则被忽略。我们前期在结直肠癌患者癌和癌旁组织中针对APC进行测序,发现APC存在高频同义突变c.2253T>G (p.Ser751Ser)。临床样本以及细胞水平实验证实该突变影响APC蛋白水平;其在促进β-catenin降解以及抑制WNT通路活性方面的功能均低于野生型APC。为研究该突变的生物学功能,我们已构建c.2253T>G突变的结肠癌细胞系,并正在构建该突变的人结直肠类器官以及突变小鼠。我们将从细胞水平、人组织水平以及动物水平进一步揭示c.2253T>G同义突变调控APC蛋白功能的分子机制及其在结直肠癌发生发展中的功能,为深入理解同义突变的调控机制、临床意义以及结直肠癌致病机理提供新的证据。
英文摘要
Colorectal cancer (CRC) is the second most common malignancies worldwide with diverse genetic and clinical features that influence therapeutic outcomes. Adenomatous polyposis coli (APC) is the most frequently mutated, known driver gene in CRC, and has long been considered the ‘gatekeeper’ for the vast majority of CRCs. APC is a tumour-suppressor gene whose protein product functions as an antagonist of the WNT signaling pathway by binding and regulating the β-catenin protein. In widespread reports, a variety of APC nonsense mutations and frameshift mutations have been identified to destroy the function of APC and play pivotal roles in the initiation of the adenoma–carcinoma pathway. In contrast, few studies investigated on synonymous mutations of APC. Mutations in coding regions but not related to amino acid changes are called synonymous mutations and has been generally considered to be functionally neutral. However, in recent years, it has been revealed that synonymous mutations play important roles in cancer and other diseases, and researchers have proposed multiple models to elucidate the underlying mechanisms. For examples, synonymous mutations may alter the stabilization of mRNAs, the efficiency of protein translation or the secondary structures of proteins. .In this study, we performed high-throughput targeted sequencing in sporadic CRCs of Chinese population and identify one important synonymous mutation (c.2253T>G; p.Ser751Ser) of APC with highest frequency. Immunohistochemical experiments showed that APC protein levels were lower in clinical samples with c.2253T>G (p.Ser751Ser) synonymous mutation, compared with APC wild type samples. Besides, cell base-experiments showed that c.2253T>G mutation impaired the function of APC in promotingβ-catenin degradation. Consistently, the activity of WNT signaling was higher in cells with c.2253T>G mutation. Those preliminary results revealed that c.2253T>G (p.Ser751Ser) synonymous mutation of APC alters protein levels and is supposed to play roles in colorectal cancer development. .Next, we will perform in vitro and in vivo study to further investigate the regulation mechanism and explore the function of this synonymous mutation in cell proliferation, apoptosis and migration, as well as in the development of CRC. Our researches will reveal a novel disease-causing mutation in CRC and also contribute to understanding the function and regulation mechanism of synonymous mutation.
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