Proteomics analysis: inhibiting the expression of P62 protein by chloroquine combined with dacarbazine can reduce the malignant progression of uveal melanoma.
Proteomics analysis: inhibiting the expression of P62 protein by chloroquine combined with dacarbazine can reduce the malignant progression of uveal melanoma.
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DOI：
10.1186/s12885-022-09499-z
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发表时间：
2022-04-14
期刊：
影响因子：
3.8
通讯作者：
Wang, Zhimin
中科院分区：
文献类型：
--
作者：
Fei, Xifeng;Xie, Xiangtong;Qin, Ruwei;Wang, Anqi;Meng, Xuan;Sun, Fei;Zhao, Yifan;Jiang, Dongyi;Chen, Hanchun;Huang, Qiang;Ji, Xiaoyan;Wang, Zhimin
关键词：
葡萄膜黑色素瘤（uveal melanoma， UM）早期虽有一定的可控性，但最终因转移而不可避免地导致死亡。目前的困难是没有办法有效地治疗转移。假设这些将由靶分子治疗，但公认的靶分子尚未发现。本研究通过蛋白质组学对靶分子进行了探索。以自发显示肿瘤微环境（TME）的转基因增强绿色荧光蛋白（EGFP）近交裸鼠为模型动物载体。将UM细胞系92.1接种于脑室刺激UM转移生长，移植物再培养，通过单克隆扩增获得UM细胞系92.1- a，并建立92.1与异位92.1- a之间的差异蛋白质组学数据库。最后，采用生物信息学方法对关键调控蛋白进行优化，并进行体内外功能验证和靶向药物筛选。动物模型中显示绿色荧光的细胞和组织被确定为宿主提供的TME特征。检测到的各种生物学表型数据证明92.1- a比92.1更恶性。此外，从5267个可量化的差异蛋白质组学数据库中筛选出的关键蛋白p62 （SQSTM1）是一种多功能自噬连接蛋白，其表达可被氯喹和达卡巴嗪抑制。抑制p62可降低92.1-A的恶性程度。转基因EGFP近交裸鼠作为人UM正位和异位异种移植的载体，明显表现出TME的特征。此外，通过蛋白质组学优化的p62蛋白是92.1细胞恶性增加的关键蛋白，为进一步探索难治性转移性UM的靶分子治疗提供了基础。在线版本包含补充材料，可在10.1186/s12885-022-09499-z获得。
Although uveal melanoma (UM) at the early stage is controllable to some extent, it inevitably ultimately leads to death due to its metastasis. At present, the difficulty is that there is no way to effectively tackle the metastasis. It is hypothesized that these will be treated by target molecules, but the recognized target molecule has not yet been found. In this study, the target molecule was explored through proteomics. Transgenic enhanced green fluorescent protein (EGFP) inbred nude mice, which spontaneously display a tumor microenvironment (TME), were used as model animal carriers. The UM cell line 92.1 was inoculated into the brain ventricle stimulating metastatic growth of UM, and a graft re-cultured Next, the UM cell line 92.1-A was obtained through monoclonal amplification, and a differential proteomics database, between 92.1 and ectopic 92.1-A, was established. Finally, bioinformatics methodologies were adopted to optimize key regulatory proteins, and in vivo and in vitro functional verification and targeted drug screening were performed. Cells and tissues displaying green fluorescence in animal models were determined as TME characteristics provided by hosts. The data of various biological phenotypes detected proved that 92.1-A were more malignant than 92.1. Besides this malignancy, the key protein p62 (SQSTM1), selected from 5267 quantifiable differential proteomics databases, was a multifunctional autophagy linker protein, and its expression could be suppressed by chloroquine and dacarbazine. Inhibition of p62 could reduce the malignancy degree of 92.1-A. As the carriers of human UM orthotopic and ectopic xenotransplantation, transgenic EGFP inbred nude mice clearly display the characteristics of TME. In addition, the p62 protein optimized by the proteomics is the key protein that increases the malignancy of 92.1 cells, which therefore provides a basis for further exploration of target molecule therapy for refractory metastatic UM. The online version contains supplementary material available at 10.1186/s12885-022-09499-z.
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