DDX3 Activates CBC-eIF3-Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC
DDX3 Activates CBC-eIF3-Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC
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DOI：
10.1158/0008-5472.can-18-0282
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发表时间：
2018-08-15
期刊：
影响因子：
11.2
通讯作者：
Tarn, Woan-Yuh
中科院分区：
文献类型：
--
作者：
Chen, Hung-Hsi;Yu, Hsin-I;Tarn, Woan-Yuh
突变或失调的DDX 3通过其在调节基因表达和细胞信号传导中的多种作用参与癌症的进展和转移。在这里，我们发现DDX 3在头颈部鳞状细胞癌（HNSCC）中的高表达水平与淋巴结转移和预后不良相关，并证明DDX 3对口腔鳞状细胞癌（OSCC）细胞的增殖、侵袭和转移至关重要。微阵列分析显示，DDX 3是一组促转移基因表达所必需的，包括侵袭性OSCC细胞系中的ATF 4调节基因。DDX 3激活了ATF 4及其下游靶标的翻译，所有这些靶标都含有上游开放阅读框（uORF）。DDX 3可能通过跳过抑制性uORF来促进这些靶标的翻译。DDX 3特异性增强了帽结合复合物（CBC）与含uORF的mRNA的结合，并促进了真核起始因子3（eIF 3）的募集。CBC和某些eIF 3亚基有助于转移相关基因的表达。两者合计，我们的研究结果表明，新的DDX 3-CBC-eIF 3翻译复合物在促进metastasis.Significance的作用：发现DDX 3介导的表达致癌uORF-含有基因的翻译控制机制的知识，并提供了潜在的癌症治疗的目标。[图形]。(C)2018年AACR。
Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here, we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes, including ATF4-modulated genes in an aggressive OSCC cell line. DDX3 activated translation of ATF4 and a set of its downstream targets, all of which contain upstream open reading frames (uORF). DDX3 promoted translation of these targets, likely by skipping the inhibitory uORF. DDX3 specifically enhanced the association of the cap-binding complex (CBC) with uORF-containing mRNAs and facilitated recruitment of the eukaryotic initiation factor 3 (eIF3). CBC and certain eIF3 subunits contributed to the expression of metastatic-related gene expression. Taken together, our results indicate a role for the novel DDX3-CBC-eIF3 translational complex in promoting metastasis.Significance: The discovery of DDX3-mediated expression of oncogenic uORF-containing genes expands knowledge on translational control mechanisms and provides potential targets for cancer therapy.[GRAPHICS]. (C) 2018 AACR.