RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis.
RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis.
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RBFOX2/GOLIM4剪接轴激活囊泡运输途径促进鼻咽癌发生
DOI：
10.1002/advs.202004852
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Bei JX
中科院分区：
文献类型：
--
作者：
Luo CL;Xu XC;Liu CJ;He S;Chen JR;Feng YC;Liu SQ;Peng W;Zhou YQ;Liu YX;Wei PP;Li B;Mai HQ;Xia XJ;Bei JX
20-30%的鼻咽癌患者发生远处转移或复发，导致生存率较低，其潜在的关键分子事件尚未得到解决。通过对85例鼻咽癌标本进行转录组学分析，发现GOLIM4(-L)外显子7长亚型在鼻咽癌中高表达，且预后不良。一系列证据表明，GOLIM4-L在鼻咽癌细胞中具有促肿瘤作用。进一步研究发现，RBFOX2与第7外显子上的GGAA基序结合并促进其包涵体形成GOLIM4-L。RBFOX2基因敲除抑制鼻咽癌细胞的发生，表现为GOLIM4-L基因敲除，而GOLIM4-L的过表达显著挽救了GOLIM4-L的表达。在鼻咽癌组织中，RBFOX2的高表达与GOLIM4的外显子7包涵体有关，且与预后不良相关。观察到，RBFOX2和GOLIM4可以通过维持高尔基体的组织来影响囊泡介导的转运。结果表明，RAB26与GOLIM4相互作用，并介导其在鼻咽癌细胞中的致瘤潜能。综上所述，这些发现通过强调GOLIM4-L及其剪接调控因子RBFOX2激活涉及RAB26的囊泡介导的转运之间的功能联系，为研究替代剪接如何有助于鼻咽癌的发展提供了见解。用转录组分析鼻咽癌中的选择性剪接事件，发现含有外显子7的GOLIM4的长亚型(GOLIM4-L)的高表达与鼻咽癌的不良生存有关。还揭示了GOLIM4-L与其剪接调控因子RBFOX2之间的功能联系，它通过维持RAB26的高尔基复合体的完整性来激活囊泡介导的转运。
20–30% of patients with nasopharyngeal carcinoma (NPC) develop distant metastasis or recurrence leading to poor survival, of which the underlying key molecular events have yet to be addressed. Here alternative splicing events in 85 NPC samples are profiled using transcriptome analysis and it is revealed that the long isoform of GOLIM4 (‐L) with exon‐7 is highly expressed in NPC and associated with poor prognosis. Lines of evidence demonstrate the pro‐tumorigenic function of GOLIM4‐L in NPC cells. It is further revealed that RBFOX2 binds to a GGAA motif in exon‐7 and promotes its inclusion forming GOLIM4‐L. RBFOX2 knockdown suppresses the tumorigenesis of NPC cells, phenocopying GOLIM4‐L knockdown, which is significantly rescued by GOLIM4‐L overexpression. High expression of RBFOX2 is correlated with the exon‐7 inclusion of GOLIM4 in NPC biopsies and associated with worse prognosis. It is observed that RBFOX2 and GOLIM4 can influence vesicle‐mediated transport through maintaining the organization of Golgi apparatus. Finally, it is revealed that RAB26 interacts with GOLIM4 and mediates its tumorigenic potentials in NPC cells. Taken together, the findings provide insights into how alternative splicing contributes to NPC development, by highlighting a functional link between GOLIM4‐L and its splicing regulator RBFOX2 activating vesicle‐mediated transport involving RAB26. Alternative splicing events are profiled in nasopharyngeal carcinoma (NPC) using transcriptome analysis, and a high expression of the long isoform of GOLIM4 containing exon‐7 (GOLIM4‐L) to be associated with poor survival of NPC is identified. A functional link between GOLIM4‐L and its splicing regulator RBFOX2 is also revealed, which activates vesicle‐mediated transport through maintaining Golgi complex integrity involving RAB26.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Burguete, Alondra Schweizer;Fenn, Timothy D.;Pfeffer, Suzanne R.
通讯作者：
Pfeffer, Suzanne R.
影响因子：
50.3
作者：
Halberg N;Sengelaub CA;Navrazhina K;Molina H;Uryu K;Tavazoie SF
通讯作者：
Tavazoie SF
影响因子：
7.2
作者：
Gannon, Joan;Bergeron, John J. M.;Nilsson, Tommy
通讯作者：
Nilsson, Tommy
影响因子：
8.8
作者：
Chen, Linlin;Luo, Chunling;Feng, Ying
通讯作者：
Feng, Ying