Identification of spliceosome components pivotal to breast cancer survival
Identification of spliceosome components pivotal to breast cancer survival
复制标题
鉴定对乳腺癌生存至关重要的剪接体成分
DOI：
10.1080/15476286.2020.1822636
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发表时间：
2020-09-24
期刊：
影响因子：
4.1
通讯作者：
Liu, Zhaoliang
中科院分区：
文献类型：
--
作者：
An, Jing;Luo, Zhehui;Liu, Zhaoliang
摘要癌细胞通过选择性剪接（AS）获得有利于其生存的剪接异构体。然而，乳腺癌中异常AS的原因知之甚少。在这项研究中，METABRIC（乳腺癌分子分类国际联盟）的数据进行了分析与单变量特征选择。在分析的122个剪接体组分中，U2SURP、PUF60、DDX41、HNRNPAB、EIF4A3和PPIL3与乳腺癌生存率显著相关。选择前4个基因U2SURP、PUF60、DDX41和HNRNPAB用于进一步分析。在METABRIC数据中，它们的表达与癌症分子亚型、肿瘤分期、肿瘤分级、总生存期（OS）和癌症特异性生存期显著相关。这些结果可使用其他队列进行验证。癌症基因组图谱数据揭示了与正常组织相比，PUF60，DDX41和HNRNPAB在肿瘤中的表达升高，并证实了这四种基因在癌症分子亚型中的差异表达，以及U2SURP，PUF60和DDX41表达与肿瘤分期的相关性。荟萃分析数据证实了U2SURP、PUF60和HNRNPAB表达与肿瘤分级的相关性，PUF60、DDX 41和HNRNPAB表达与OS和无远处转移生存期的相关性，以及U2SURP和HNRNPAB表达与无复发生存期的相关性。在实验中，我们证明，抑制这四个基因的表达分别抑制细胞集落的形成，并大大减缓乳腺癌细胞的细胞生长，但不是在永生乳腺上皮细胞。总之，我们已经确定U2SURP，PUF60，DDX41和HNRNPAB是乳腺癌生存的关键剪接体相关基因。
ABSTRACT Cancer cells employ alternative splicing (AS) to acquire splicing isoforms favouring their survival. However, the causes of aberrant AS in breast cancer are poorly understood. In this study, the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) data were analysed with univariate feature selection. Of 122 analysed spliceosome components, U2SURP, PUF60, DDX41, HNRNPAB, EIF4A3, and PPIL3 were significantly associated with breast cancer survival. The top 4 four genes, U2SURP, PUF60, DDX41, and HNRNPAB, were chosen for further analyses. Their expression was significantly associated with cancer molecular subtype, tumour stage, tumour grade, overall survival (OS), and cancer-specific survival in the METABRIC data. These results were verifiable using other cohorts. The Cancer Genome Atlas data unveiled the elevated expression of PUF60, DDX41, and HNRNPAB in tumours compared with the normal tissue and confirmed the differential expression of the four genes among cancer molecular subtypes, as well as the associations of U2SURP, PUF60, and DDX41 expression with tumour stage. A meta-analysis data verified the associations of U2SURP, PUF60, and HNRNPAB expression with tumour grade, the associations of PUF60, DDX41, and HNRNPAB expression with OS and distant metastasis-free survival, and the associations of U2SURP and HNRNPAB expression with relapse-free survival. Experimentally, we demonstrated that inhibiting the expression of the four genes separately suppressed cell colony formation and slowed down cell growth considerably in breast cancer cells, but not in immortal breast epithelial cells. In conclusion, we have identified U2SURP, PUF60, DDX41, and HNRNPAB are spliceosome-related genes pivotal for breast cancer survival.