N(6)-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma.
N(6)-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma.
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DOI：
10.1186/s12943-022-01549-1
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发表时间：
2022-05-10
期刊：
影响因子：
37.3
通讯作者：
Li, Gonghui
中科院分区：
文献类型：
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作者：
Chen, Yuanlei;Lu, Zeyi;Qi, Chao;Yu, Chenhao;Li, Yang;Huan, Wang;Wang, Ruyue;Luo, Wenqin;Shen, Danyang;Ding, Lifeng;Ren, Liangliang;Xie, Haiyun;Xue, Dingwei;Wang, Mingchao;Ni, Kangxin;Xia, Liqun;Qian, Jun;Li, Gonghui
舒尼替尼耐药可分为原发性和继发性耐药。虽然越来越多的研究表明，一些潜在的因素有助于舒尼替尼耐药，肾细胞癌的确切机制仍不清楚。使用RNA测序和m6 A测序来筛选与舒尼替尼耐药性相关的功能基因。进行体外和体内实验，并获得患者样本和临床信息用于临床分析。我们鉴定了肿瘤坏死因子受体相关因子TRAF 1，其在舒尼替尼耐药细胞、耐药细胞衍生的异种移植物（CDX-R）模型和舒尼替尼耐药的临床患者中显著增加。沉默TRAF 1增加了舒尼替尼诱导的细胞凋亡和抗血管生成作用。从机制上讲，舒尼替尼耐药细胞中TRAF 1水平的上调源自TRAF 1 RNA稳定性的增加，这是由N6-甲基腺苷（m6 A）水平以胃L14依赖性方式增加引起的。此外，在体内腺相关病毒9（AAV 9）介导的TRAF 1转导抑制舒尼替尼诱导的细胞凋亡和抗血管生成作用的CDX模型，而敲低TRAF 1有效地重新敏感的舒尼替尼耐药的CDX舒尼替尼治疗。TRAF 1的过表达通过以CDL 14依赖性方式调节细胞凋亡和血管生成途径来促进舒尼替尼耐药性。靶向TRAF 1及其通路可能是舒尼替尼治疗患者的一种新的药物干预。在线版本包含补充材料，可通过10.1186/s12943-022-01549-1获得。
Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients. The online version contains supplementary material available at 10.1186/s12943-022-01549-1.
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DOI：
10.1186/s13046-021-02072-9
发表时间：
2021-08-25
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
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作者：
Miranda-Gonçalves V;Lobo J;Guimarães-Teixeira C;Barros-Silva D;Guimarães R;Cantante M;Braga I;Maurício J;Oing C;Honecker F;Nettersheim D;Looijenga LHJ;Henrique R;Jerónimo C
通讯作者：
Jerónimo C
影响因子：
15.3
作者：
Bhatt, Jaimin R.;Finelli, Antonio
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Finelli, Antonio
影响因子：
50.3
作者：
Li Z;Weng H;Su R;Weng X;Zuo Z;Li C;Huang H;Nachtergaele S;Dong L;Hu C;Qin X;Tang L;Wang Y;Hong GM;Huang H;Wang X;Chen P;Gurbuxani S;Arnovitz S;Li Y;Li S;Strong J;Neilly MB;Larson RA;Jiang X;Zhang P;Jin J;He C;Chen J
通讯作者：
Chen J
影响因子：
5.7
作者：
Makhov P;Joshi S;Ghatalia P;Kutikov A;Uzzo RG;Kolenko VM
通讯作者：
Kolenko VM
影响因子：
64.8
作者：
通讯作者：
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