RBM5 reduces small cell lung cancer growth, increases cisplatin sensitivity and regulates key transformation-associated pathways.
RBM5 reduces small cell lung cancer growth, increases cisplatin sensitivity and regulates key transformation-associated pathways.
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DOI：
10.1016/j.heliyon.2016.e00204
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发表时间：
2016-11
期刊：
影响因子：
4
通讯作者：
Sutherland, Leslie C
中科院分区：
文献类型：
--
作者：
Loiselle, Julie J;Roy, Justin G;Sutherland, Leslie C
小细胞肺癌（SCLC）是最具侵袭性的肺癌类型，几乎95%的患者死于该疾病。尽管RBM5是一种肿瘤抑制基因，在大多数肺癌中下调，但其在SCLC中的作用尚不清楚。使用GLC20 SCLC细胞系，其具有包含RBM5基因座的纯合缺失，我们建立了稳定的RBM5表达亚系，并研究了RBM5再表达的影响。转录组和靶点鉴定研究确定RBM5直接调节SCLC细胞的细胞周期和凋亡，以及显著下调其他重要的转化相关途径，如血管生成和细胞粘附。配对的非肿瘤和肿瘤SCLC患者标本的RNA测序显示肿瘤中RBM5表达降低，并且在大多数相同的途径中表达改变，这些途径在GLC20细胞和亚系中改变。功能研究证实RBM5表达减缓SCLC细胞系生长，并增加对化疗药物顺铂的敏感性。总之，我们的工作证明了RBM5表达对肺细胞非转化状态的重要性，以及其缺失对SCLC发展和进展的影响。
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer, with almost 95% of patients succumbing to the disease. Although RBM5, a tumor suppressor gene, is downregulated in the majority of lung cancers, its role in SCLC is unknown. Using the GLC20 SCLC cell line, which has a homozygous deletion encompassing the RBM5 gene locus, we established stable RBM5 expressing sublines and investigated the effects of RBM5 re-expression. Transcriptome and target identification studies determined that RBM5 directly regulates the cell cycle and apoptosis in SCLC cells, as well as significantly downregulates other important transformation-associated pathways such as angiogenesis and cell adhesion. RNA sequencing of paired non-tumor and tumor SCLC patient specimens showed decreased RBM5 expression in the tumors, and expression alterations in the majority of the same pathways that were altered in the GLC20 cells and sublines. Functional studies confirmed RBM5 expression slows SCLC cell line growth, and increases sensitivity to the chemotherapy drug cisplatin. Overall, our work demonstrates the importance of RBM5 expression to the non-transformed state of lung cells and the consequences of its deletion to SCLC development and progression.