Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing
Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing
复制标题
DOI：
10.1371/journal.pone.0233380
复制
发表时间：
2020-05-21
期刊：
影响因子：
3.7
通讯作者：
Califano, Joseph A.
中科院分区：
文献类型：
--
作者：
Sakai, Akihiro;Ando, Mizuo;Califano, Joseph A.
选择性mRNA剪接增加蛋白质多样性，并且选择性剪接事件（ASES）驱动多种肿瘤类型中的肿瘤发生。然而，驱动改变的基础广泛失调的ASES是不完全定义。使用头颈部鳞状细胞癌（HNSCC）作为模型，我们假设与剪接体相关的基因的基因组改变可能广泛地诱导跨越广泛的靶基因的ASE，驱动致癌表型。我们鉴定了319个剪接体基因，并使用癌症基因组图谱（TCGA）HNSCC数据，采用发现管道鉴定了HNSCC中改变的13个候选剪接体基因。表型筛选将扩增和过表达的CPSF 1鉴定为靶基因改变，其在细胞系和异种移植系统以及原发性HNSCC中的增殖、集落形成和凋亡测定中得到验证。我们采用敲低和过表达试验，然后鉴定由CPSF1过表达调节的ASES，以鉴定ASES的变化，并使用来自细胞系模型的RNA验证这些ASES的表达。剪接体基因（包括CPSF 1）表达的改变可能通过介导异常ASE表达而导致HNSCC。
Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.