hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing
hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing
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DOI：
10.1172/jci43552
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发表时间：
2010-11-01
影响因子：
15.9
通讯作者：
Chalfant, Charles E.
中科院分区：
文献类型：
--
作者：
Goehe, Rachel Wilson;Shultz, Jacqueline C.;Chalfant, Charles E.
Caspase-9参与了固有的细胞凋亡途径，并被认为发挥了肿瘤抑制因子的作用。目前对caspase-9表达的调控机制知之甚少，但转录后前mRNA处理产生了caspase-9基因的两个剪接变体，即促凋亡的caspase-9a和抗凋亡的caspase-9b。在这里，我们证明了caspase-9剪接变异体的比例在非小细胞肺癌(NSCLC)肿瘤中是失调的。机制分析表明，外显子剪接沉默(ESS)调控NSCLC细胞中caspase-9前mRNA的加工。异源核糖核蛋白L(HnRNP L)与该ESS相互作用，下调hnRNP L的表达可导致caspase-9a/9b比值升高。虽然在非小细胞肺癌细胞中，hnRNP L的表达降低了caspase-9a/9b的比值，但在未转化的细胞中，hnRNP L的表达产生了相反的作用，提示了非小细胞肺癌细胞特有的翻译后修饰。事实上，Ser(52)被认为是调节caspase-9a/9b比率的关键修饰。重要的是，在小鼠异种移植模型中，在非小细胞肺癌细胞中hnRNP L的下调导致肿瘤形成能力的完全丧失，这是由于caspase-9前mRNA处理的变化。因此，这项研究确定了hnRNP L磷酸化并随后降低caspase-9a/9b比率的癌症特异性机制，这是非小细胞肺癌细胞致瘤能力所必需的。
Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser(52) was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells.