RNA helicase MTR4 drives tumorigenesis of nasopharyngeal carcinoma by regulating the expression of key cell cycle genes.
RNA helicase MTR4 drives tumorigenesis of nasopharyngeal carcinoma by regulating the expression of key cell cycle genes.
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RNA解旋酶MTR4通过调节关键细胞周期基因表达驱动鼻咽癌肿瘤发生
DOI：
10.1093/procel/pwac003
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发表时间：
2023-03-16
期刊：
影响因子：
21.1
通讯作者：
Xu, Yang
中科院分区：
文献类型：
--
作者：
Yu, Lili;Jiang, Lei;Wu, Meng;Dou, Wenlong;Ji, Kaiyuan;Zhou, Jianlong;Kim, Jinchul;Xu, Yang
鼻咽癌（NPC）的发病机制与爱泼斯坦巴尔病毒（EBV）的感染密切相关（Hau等人，2020年）。然而，NPC肿瘤发生的潜在机制仍不清楚，导致缺乏有效治疗NPC的治疗靶点。RNA解旋酶MTR4是将病毒RNA连接到外泌体以进行降解的病毒诱导的辅因子复合物的组分，其在患者的NPC中过表达。MTR4的表达水平与鼻咽癌患者的预后呈负相关。NPC细胞中MTR4的沉默在体外抑制NPC细胞的增殖和集落形成能力，在体内有效抑制NPC细胞系和患者样本形成的NPC的生长，表明MTR4在NPC肿瘤发生中的重要性。MTR4通过促进NPC细胞的细胞周期进程来促进NPC的发展。在这种情况下，MTR4维持其靶mRNA的表达水平，其中一些是重要的细胞周期基因，如CDK2。在MTR4敲低（KD）后NPC中CDK2表达的恢复部分地挽救了NPC的体外增殖和体内肿瘤发生，表明MTR4通过维持关键靶细胞周期基因的表达水平来驱动NPC肿瘤发生。因此，MTR4是一个很有前途的治疗NPC的靶点。我们的研究结果还表明，在功能上将病毒感染与癌症发展联系起来的共同机制，其中EBV利用宿主防御机制促进NPC。RNA衰变是一种抗病毒宿主防御系统，其感测病毒RNA并通过RNA外泌体的病毒RNA降解来抑制病毒复制，RNA外泌体是负责RNA的3 ′核酸外切酶降解的RNA加工/降解复合物（Nayak等人，2017年）。RNA外泌体复合物的核心由辅因子如TRAMP（Trf4/5-Air1/2-MTR4聚腺苷酸化）复合物和Rrp44/Rrp6组成，以靶向RNA进行降解（Houseley等人，2006年）。复合物中的RNA解旋酶MTR4通过识别病毒mRNA和解旋RNA结构以使病毒RNA容易接近外来体，促进病毒RNA衰变而具有抗病毒活性（Houseley等人，2006年; Molben等人，2016年）。为了检测MTR4在NPC肿瘤发生中的潜在参与，我们检测了NPC中MTR4的表达水平。通过对NPC患者样品的芯片的免疫组织化学分析，我们发现MTR4蛋白水平与NPC患者的预后呈负相关（图1A和1B）。此外，从基因表达综合数据库（GEO）检索并构建了27个NPC转录组数据集。当与非肿瘤对照组织相比时，在NPC样品中MTR4的表达水平明显增加（图1A和1B）。1C和S1A）。为了检查MTR4在NPC肿瘤发生中的重要性，使NPC细胞中MTR4的表达沉默（图1A和1B）。S1B和S2）。在多个NPC细胞系中MTR4表达的沉默抑制了它们的增殖和集落形成能力，表明MTR4对于NPC肿瘤发生是重要的（图S2）。为了进一步检查MTR4在体内NPC发展中的致癌功能，将MTR4 KD和对照NPC细胞皮下注射到免疫缺陷小鼠中以形成NPC肿瘤，表明MTR4是NPC肿瘤体内生长所需的（图1A和1B）。为了进一步证实MTR4在NPC肿瘤发生中的重要性，采用CRISPR/CAS 9系统敲除NPC中的MTR4基因。我们未能获得纯合的MTR4敲除细胞，这表明MTR4可能是NPC细胞存活所必需的。
The pathogenesis of nasopharyngeal carcinoma (NPC) is closely associated with the infection of Epstein Barr virus (EBV)(Hau et al., 2020). However, the mechanisms underlying NPC tumorigenesis remain unclear, leading to a lack of therapeutic targets to effectively treat NPC. RNA helicase MTR4, which is a component of the virus-induced cofactor complex linking viral RNA to exosome for degradation, is overexpressed in NPCs of patients. The expression levels of MTR4 are inversely correlated with the prognosis of NPC patients. The silence of MTR4 in NPC cells suppresses the proliferation and colony-forming ability of NPC cells in vitro, and effectively inhibits the growth of NPCs formed by NPC cell lines and patients’ samples in vivo, indicating the importance of MTR4 in NPC tumorigenesis. MTR4 promotes NPC development by promoting the cell cycle progression of NPC cells. In this context, MTR4 maintains the expression levels of its target mRNAs, some of which are important cell cycle genes such as CDK2. The restoration of CDK2 expression in NPCs after MTR4 knockdown (KD) partially rescues the proliferation of NPCs in vitro and tumorigenesis in vivo, indicating that MTR4 drives NPC tumorigenesis by maintaining the expression levels of key target cell cycle genes. Therefore, MTR4 is a promising therapeutic target to treat NPC. Our findings also suggest a common mechanism to functionally link viral infection to cancer development, in which EBV takes advantage of the host defense mechanisms to promote NPC. RNA decay is an anti-viral host defense system that senses viral RNA and suppresses viral replication through viral RNA degradation by the RNA exosome, the RNA processing/degradation complex responsible for 3ʹ exonuclease degradation of RNA (Nayak et al., 2017). The core of RNA exosome complex is composed of cofactors such as TRAMP (Trf4/5-Airl/2-MTR4 polyadenylation) complex and Rrp44/Rrp6 to target RNA for degradation (Houseley et al., 2006). RNA helicase MTR4 in the complex has anti-viral activities by recognizing viral mRNAs and unwinding RNA structures to make easy access of viral RNAs to exosome, promoting viral RNA decay (Houseley et al., 2006; Molleston et al., 2016). To examine the potential involvement of MTR4 in the tumorigenesis of NPCs, we examined the expression levels of MTR4 in NPCs. By immunohistochemistry analysis of chips of NPC patient samples, we found that the MTR4 protein levels were inversely correlated with the prognosis of the NPC patients (Fig. 1A and 1B). In addition, 27 NPC transcriptome datasets were retrieved and constructed from the Gene Expression Omnibus (GEO) database. The expression levels of MTR4 were apparently increased in NPC samples when compared to non-tumor control tissues (Figs. 1C and S1A). To examine the importance of MTR4 in NPC tumorigenesis, the expression of MTR4 in NPC cells was silenced (Figs. S1B and S2). The silence of MTR4 expression in multiple NPC lines suppressed their proliferation and colony-forming ability, suggesting that MTR4 is important for NPC tumorigenesis (Fig. S2). To further examine the oncogenic functions of MTR4 in NPC development in vivo, MTR4 KD and control NPC cells were subcutaneously injected into immunodeficient mice to form NPC tumors, indicating that MTR4 is required for NPC tumor growth in vivo (Figs. 1D, 1E and S1C).To further confirm the importance of MTR4 in NPC tumorigenesis, CRISPR/CAS 9 system was employed to knockout the MTR4 gene in NPCs. We failed to obtain homozygous MTR4 knockout cells, suggesting that MTR4 might be required for the survival of NPC cells …
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影响因子：
30.8
作者：
Zapatka M;Borozan I;Brewer DS;Iskar M;Grundhoff A;Alawi M;Desai N;Sültmann H;Moch H;PCAWG Pathogens;Cooper CS;Eils R;Ferretti V;Lichter P;PCAWG Consortium
通讯作者：
PCAWG Consortium
影响因子：
10.5
作者：
Molleston JM;Sabin LR;Moy RH;Menghani SV;Rausch K;Gordesky-Gold B;Hopkins KC;Zhou R;Jensen TH;Wilusz JE;Cherry S
通讯作者：
Cherry S
DOI：
10.3390/v9010003
发表时间：
2017-01-06
期刊：
Viruses
影响因子：
--
作者：
Nayak TK;Mamidi P;Kumar A;Singh LP;Sahoo SS;Chattopadhyay S;Chattopadhyay S
通讯作者：
Chattopadhyay S
MTR4通过选择性剪接促进癌症代谢转换来驱动肝脏肿瘤发生
影响因子：
16.6
作者：
Yu, Lili;Kim, Jinchul;Xu, Yang
通讯作者：
Xu, Yang