HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation
HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation
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DOI：
10.1038/s41388-022-02271-4
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发表时间：
2022-03
期刊：
影响因子：
8
通讯作者：
Huajie Song;Jian-qun Wang;Xiaojing Wang;B. Yuan;Dan Li;A. Hu;Yanhua Guo;Shuang Cai;Shikai Jin
中科院分区：
文献类型：
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作者：
Huajie Song;Jian-qun Wang;Xiaojing Wang;B. Yuan;Dan Li;A. Hu;Yanhua Guo;Shuang Cai;Shikai Jin
肿瘤干细胞在肿瘤发生和侵袭性中起着至关重要的作用，而神经母细胞瘤（NB）是一种发病率最高的儿童颅外恶性肿瘤，其调控机制尚不清楚。在此，肝细胞核因子4 α反义RNA 1（HNF 4A-AS 1）编码的51个氨基酸的小肽（sPEP 1）在肿瘤组织和细胞中被鉴定，其促进NB干细胞的自我更新和侵袭性。miRNA-409- 5 p与HNF 4A-AS 1相互作用，通过募集真核翻译起始因子3亚基G促进sPEP 1的翻译，而sPEP 1则抑制去血清诱导的NB干细胞衰老，促进NB干细胞球体形成、生长或转移。从机制上讲，sPEP 1直接与真核翻译延伸因子1 α 1（eEF 1A 1）相互作用，以促进其与SMAD家族成员4（SMAD 4）的结合，从而抑制SMAD 4的反式激活和与肿瘤进展相关的干细胞基因的转录上调。拯救实验表明，sPEP 1通过促进eEF 1A 1和SMAD 4之间的物理相互作用发挥致癌作用。值得注意的是，sPEP 1的敲低在体内显著抑制NB干细胞的自我更新和转移。临床NB组织中高的PEP 1或EF 1A 1水平与患者的生存率低有关。这些发现表明HNF 4A-AS 1编码的sPEP 1通过eEF 1A 1抑制SMAD 4的反式激活促进NB干细胞的自我更新和侵袭性特征。
Cancer stem cells play crucial roles in tumorigenesis and aggressiveness, while regulatory mechanisms in neuroblastoma (NB), a pediatric extracranial malignancy with highest incidence, are still unknown. Herein, a small 51-amino acid peptide (sPEP1) encoded by hepatocyte nuclear factor 4 alpha antisense RNA 1 (HNF4A-AS1) was identified in tumor tissues and cells, which facilitated self-renewal and aggressiveness of NB stem cells. MiRNA-409-5p interacted withHNF4A-AS1to facilitate sPEP1 translation via recruiting eukaryotic translation initiation factor 3 subunit G, while sPEP1 repressed serum deprivation-induced senescence and promoted sphere formation, growth, or metastasis of NB stem cells. Mechanistically, sPEP1 directly interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) to facilitate its binding to SMAD family member 4 (SMAD4), resulting in repression of SMAD4 transactivation and transcriptional upregulation of stem cell genes associated with tumor progression. Rescue experiments revealed that sPEP1 exerted oncogenic roles via facilitating physical interaction between eEF1A1 and SMAD4. Notably, knockdown ofsPEP1significantly repressed the self-renewal and metastasis of NB stem cells in vivo. HighsPEP1oreEF1A1levels in clinical NB tissues were linked to poor patients’ survival. These findings suggest thatHNF4A-AS1-encoded sPEP1 promotes self-renewal and aggressive features of NB stem cells by eEF1A1-repressed SMAD4 transactivation.