Mapping the cell-membrane proteome of the SKBR3/HER2+ cell line to the cancer hallmarks.
Mapping the cell-membrane proteome of the SKBR3/HER2+ cell line to the cancer hallmarks.
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DOI：
10.1371/journal.pone.0272384
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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癌症发展的生物学过程的特征早已被认识到，然而，现有的治疗方法无法阻止癌症继续成为全球主要死亡原因之一。这项工作的目的是探索细胞膜蛋白参与触发癌症标志过程的程度，并评估通过组合膜蛋白质组/癌症标志观点来确定肿瘤特异性治疗靶点的能力。通过使用GO注释，创建了与十种癌症标志广泛相关的人类蛋白质数据库。通过高分辨率质谱分析用作模型系统的SKBR 3/HER 2+乳腺癌细胞的细胞膜细胞亚组分，并将通过至少两种独特肽鉴定的高质量蛋白质（FDR<3%）映射到癌症标志数据库。超过1，400种实验检测到的细胞膜或细胞膜相关蛋白，占人类细胞膜蛋白质组的约18%，可以与hallmark数据库相匹配。代表性的膜成分，如受体，CD，粘附和转运蛋白分布在整个基因组中，并存在于每一个标志类别。持续的增殖信号传导/细胞周期，粘附/组织侵入，和免疫破坏的逃避成为膜蛋白代表的普遍标志。蛋白质-蛋白质相互作用网络的构建揭示了标志成员之间的高水平连接性，其中一些受体（EGFR，ERBB 2，FGFR，MTOR，CSF 1 R），抗原（CD 44）和粘附（MUC 1）蛋白涉及大多数标志类别。对包括42个癌基因、24个肿瘤抑制因子、9个癌基因/肿瘤抑制因子和45个批准的药物靶标的138个标志蛋白的说明性子集进行更深入的分析。现有的药物靶点主要涉及信号传导过程。网络中心性分析表明，节点的高度，而不是介数，代表了一个很好的资源，为选择推定的新药物靶点。通过大量参与支持癌症标志过程，我们表明癌细胞膜蛋白的功能多样性和网络化景观为指导新型治疗干预措施的开发提供了独特的机会，包括多药物，免疫肿瘤学和精准医学应用。
The hallmarks of biological processes that underlie the development of cancer have been long recognized, yet, existing therapeutic treatments cannot prevent cancer from continuing to be one of the leading causes of death worldwide. This work was aimed at exploring the extent to which the cell-membrane proteins are implicated in triggering cancer hallmark processes, and assessing the ability to pinpoint tumor-specific therapeutic targets through a combined membrane proteome/cancer hallmark perspective. By using GO annotations, a database of human proteins associated broadly with ten cancer hallmarks was created. Cell-membrane cellular subfractions of SKBR3/HER2+ breast cancer cells, used as a model system, were analyzed by high resolution mass spectrometry, and high-quality proteins (FDR<3%) identified by at least two unique peptides were mapped to the cancer hallmark database. Over 1,400 experimentally detected cell-membrane or cell-membrane associated proteins, representing ~18% of the human cell-membrane proteome, could be matched to the hallmark database. Representative membrane constituents such as receptors, CDs, adhesion and transport proteins were distributed over the entire genome and present in every hallmark category. Sustained proliferative signaling/cell cycle, adhesion/tissue invasion, and evasion of immune destruction emerged as prevalent hallmarks represented by the membrane proteins. Construction of protein-protein interaction networks uncovered a high level of connectivity between the hallmark members, with some receptor (EGFR, ERBB2, FGFR, MTOR, CSF1R), antigen (CD44), and adhesion (MUC1) proteins being implicated in most hallmark categories. An illustrative subset of 138 hallmark proteins that included 42 oncogenes, 24 tumor suppressors, 9 oncogene/tumor suppressor, and 45 approved drug targets was subjected to a more in-depth analysis. The existing drug targets were implicated mainly in signaling processes. Network centrality analysis revealed that nodes with high degree, rather than betweenness, represent a good resource for informing the selection of putative novel drug targets. Through heavy involvement in supporting cancer hallmark processes, we show that the functionally diverse and networked landscape of cancer cell-membrane proteins fosters unique opportunities for guiding the development of novel therapeutic interventions, including multi-agent, immuno-oncology and precision medicine applications.