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Aberrant translation regulated by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives head and neck squamous cell carcinoma progression 被引量:13
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作者 Jie Chen Kang Li +12 位作者 Jianwen Chen Xiaochen Wang Rongsong Ling Maosheng Cheng Zhi Chen Fangfang Chen Qianting He Shuai Li Caihua Zhang Yizhou Jiang Qianming Chen Anxun Wang Demeng Chen 《Cancer Communications》 SCIE 2022年第3期223-244,共22页
Background:Cancer cells selectively promote the translation of oncogenic tran-scripts to stimulate cancer progression.Although growing evidence has revealed that tRNA modifications and related genes participate in thi... Background:Cancer cells selectively promote the translation of oncogenic tran-scripts to stimulate cancer progression.Although growing evidence has revealed that tRNA modifications and related genes participate in this process,their roles in head and neck squamous cell carcinoma(HNSCC)remain largely unchar-acterized.Here,we sought to investigate the function and mechanisms of the transfer RNA(tRNA)N7-methylguanosine(m'G)modification in regulating the occurrence and development of HNSCC.Methods:Cell lost of-function and gain-of function assays,xenograft models,conditional knockout and knockin mouse models were used to study the physi-ological functions of tRNA m'G modification in HNSCC tumorigenesis.tRNA modification and expression profiling,mRNA translation profiling and res-cue assays were performed to uncover the underlying molecular mechanisms.Single-cell RNA sequencing(scRNA seq)was conducted to explore the tumor microenvironment changes.Results:The tRNA.m7G methyltransferase complex components Methyltransferase-like 1(METTL1)/WD repeat domain 4(WDR4)were upregulated in HNSCC and associated with a poor prognosis.Functionally,METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models.Mechanistically,ablation of METTL1 reduced the m'G levels of 16 tRNAS,inhibiting the translation of a subset of oncogenic transcripts,including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)signaling pathway.In addition,chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettll in mouse HNSCC.Furthermore,scRNA-seq results revealed that Mettll knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.Conclusions:The tRNA m?G methyltransferase METTLI was found to promote the development and malignancy of HNSCC through regulating global mRNA translation,including the PI3K/AKT/mTOR signaling pathway,and found to alter immune landscape.METTLI could be a promising treatment target for HNSCC patients. 展开更多
关键词 head and neck squamous cell carcinoma m7g modification metastasis METTL1 microenvi-ronment PI3K/AKT/mTOR signaling.scRNA-seq TRNA WDR4
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