Abstract：
Our investigation to explore cellular alterations related to undernutrition in cancer cells revealed that the protein level of heterogenous nuclear ribonucleoprotein A1 (hnRNP A1) is drastically decreased by serum/glucose starvation. Its loss was reversible, serum/glucose starvation-specific and universal throughout cell types and species. The hnRNP A1 mRNA level and hnRNP A1 mRNA/protein stability were not altered under this condition. CCND1 mRNA, which we newly identified as the binding target of hnRNP A1, was decreased by serum/glucose starvation. Under similar conditions, CCND1 protein was reduced in vitro and in vivo, whereas hnRNP A1 mRNA level and CCND1 mRNA level revealed no correlation in most clinical samples. Functional analyses revealed that CCND1 mRNA stability is certainly dependent on hnRNP A1 protein level and that RNA recognition motif-1 (RRM1) in hnRNP A1 plays a central role in maintaining CCND1 mRNA stability and subsequent protein expression. The injection of RRM1-deleted hnRNP A1-expressing cancer cells in the mouse xenograft model did not form any tumours, and that of hnRNP A1-expressing cancer cells retained CCND1 expression at the lesion adjacent to necrosis with a slight increase in tumour volume. Furthermore, RRM1 deletion caused growth suppression with the induction of apoptosis and autophagy, whereas CCND1 restoration completely recovered it. Our results indicate that serum/glucose starvation triggers entire hnRNP A1 protein loss, and its loss may play a role in CCND1 mRNA destabilization and CCND1-mediated cellular event inhibition, i.e. growth promotion, apoptosis induction and autophagosome formation.
摘要：
我们探索与癌细胞营养不良有关的细胞变化的研究表明，血清/葡萄糖饥饿会大大降低异源核核糖核蛋白A1（hnRNPA1）的蛋白质水平。它的损失是可逆的，血清/葡萄糖饥饿特异性，在整个细胞类型和物种中普遍存在。在此条件下，hnRNPA1mRNA水平和hnRNPA1mRNA/蛋白稳定性没有改变。CCND1mRNA,我们新确定为hnRNPA1的结合靶标，通过血清/葡萄糖饥饿降低。在类似条件下,CCND1蛋白在体内和体外均有降低,而hnRNPA1mRNA水平和CCND1mRNA水平在大多数临床样本中没有相关性。功能分析显示，CCND1mRNA的稳定性肯定取决于hnRNPA1蛋白水平，并且hnRNPA1中的RNA识别基序1（RRM1）在维持CCND1mRNA稳定性和随后的蛋白表达中起着核心作用。在小鼠异种移植模型中注射RRM1缺失的hnRNPA1表达癌细胞没有形成任何肿瘤，表达hnRNPA1的癌细胞在坏死附近的病变处保留了CCND1的表达，肿瘤体积略有增加。此外，RRM1缺失引起生长抑制，诱导细胞凋亡和自噬，而CCND1恢复完全恢复。我们的结果表明，血清/葡萄糖饥饿引发整个hnRNPA1蛋白丢失，其丢失可能在CCND1mRNA不稳定和CCND1介导的细胞事件抑制中起作用，即，促进增长,凋亡诱导，和自噬体的形成。
