MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer.
MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer.
复制标题
DOI：
10.1186/s12943-021-01418-3
复制
发表时间：
2021-09-14
期刊：
影响因子：
37.3
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Li H;Lin PH;Gupta P;Li X;Zhao SL;Zhou X;Li Z;Wei S;Xu L;Han R;Lu J;Tan T;Yang DH;Chen ZS;Pawlik TM;Merritt RE;Ma J
癌细胞通过过度形成应激颗粒(SGS)而对化疗干预产生抵抗力，SGS受致癌蛋白G3BP2调节。选择性调控G3BP2/SG信号通路是治疗非小细胞肺癌(NSCLC)的潜在手段。免疫共沉淀法鉴定MG53与G3BP2的相互作用。用免疫组织化学和活细胞成像技术观察亚细胞的表达或共定位。我们用shRNA下调MG53或G3BP2的表达，以检测细胞迁移和集落形成。免疫印迹法检测MG53和G3BP2在人非小细胞肺癌组织中的表达水平。采用ATO诱导的氧化应激模型，观察重组人MG53对SG形成的影响。在MG53基因敲除或MG53过表达的野生型和转基因小鼠上进行了小鼠非小细胞肺癌移植实验。采用小鼠人非小细胞肺癌移植模型，观察MG53过表达对肿瘤形成的影响。我们发现MG53是TRIM蛋白家族(TRIM72)的成员，它调节G3BP2的活性来控制肺癌的进展。MG53基因缺失导致MG53-/-小鼠肺癌的进行性发展。血液中MG53持续升高的转基因小鼠在小鼠NSCLC细胞同种移植后肿瘤生长减少。生化分析揭示了G3BP2通过MG53的TRIM结构域与MG53之间的物理作用。MG53基因敲除促进了NSCLC细胞的增殖和迁移，而G3BP2表达下调则降低了NSCLC细胞的致瘤性。重组人MG53(RhMG53)蛋白可进入NSCLC细胞，诱导G3BP2核翻译，阻断三氧化二砷诱导的SG形成。G3BP2基因被敲除后，rh MG53对NSCLC细胞的抗增殖作用消失。RhMG53可增强NSCLC细胞对顺铂诱导的细胞死亡的敏感性。在异种移植模型中，通过减少SG的形成，在NSCLC细胞中量身定制地诱导MG53表达抑制肺癌生长。总体而言，这些发现支持MG53通过靶向NSCLC中的G3BP2/SG活性而发挥肿瘤抑制作用的观点。网上版载有补充材料，可在10.1186/s12943-021-01418-3查阅。
Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis. We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53-/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model. Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs. The online version contains supplementary material available at 10.1186/s12943-021-01418-3.
登录
查看更多内容
影响因子：
5.8
作者：
Fournier MJ;Gareau C;Mazroui R
通讯作者：
Mazroui R
影响因子：
48
作者：
Chow, Ryan D.;Wang, Guangchuan;Chen, Sidi
通讯作者：
Chen, Sidi
影响因子：
--
作者：
De G;Ko JK;Tan T;Zhu H;Li H;Ma J
通讯作者：
Ma J
影响因子：
17.1
作者：
Duann P;Li H;Lin P;Tan T;Wang Z;Chen K;Zhou X;Gumpper K;Zhu H;Ludwig T;Mohler PJ;Rovin B;Abraham WT;Zeng C;Ma J
通讯作者：
Ma J
影响因子：
13.8
作者：
Kedersha, Nancy;Ivanov, Pavel;Anderson, Paul
通讯作者：
Anderson, Paul