EWI2 promotes endolysosome-mediated turnover of growth factor receptors and integrins to suppress lung cancer.
EWI2 promotes endolysosome-mediated turnover of growth factor receptors and integrins to suppress lung cancer.
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EWI2促进了内溶性介导的生长因子受体和整合素的周转率，以抑制肺癌。
DOI：
10.1016/j.canlet.2022.215641
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发表时间：
2022-06-28
期刊：
影响因子：
9.7
通讯作者：
Zhang, Xin A.
中科院分区：
文献类型：
--
作者：
Wang, Jie;Wren, Jonathan D.;Ding, Yingjun;Chen, Junxiong;Mittal, Nikhil;Xu, Chao;Li, Xing;Zeng, Cengxi;Wang, Meng;Shi, Jing;Zhang, Yanhui H.;Han, Sangyoon J.;Zhang, Xin A.
EWI2作为四跨蛋白的合作伙伴，可抑制胶质母细胞瘤、黑色素瘤和前列腺癌；但其在肺癌中的作用尚未被调查。生物信息学分析显示，EWI2基因在肺腺癌中表达上调，EWI2 mRNA的高表达可能预示较差的总生存期。然而，实验分析表明，EWI2蛋白在肺腺癌和肺鳞状细胞癌组织中实际上是持续下调的。EWI2在人肺腺癌细胞中的强制表达降低了各种整合素和生长因子受体的总细胞和细胞表面水平，从而启动了由外而内的运动和有丝分裂信号传导。这些减少导致1)细胞基质粘附、细胞运动和体外细胞转化的减少，以及2)体内肿瘤生长、负担和转移的减少，这是由于这些膜受体的溶酶体运输和蛋白水解降解的增加。EWI2通过促进TFEB的核保留来促进溶酶体的形成，TFEB是驱动溶酶体生成的主要转录因子。综上所述，EWI2作为一种肺癌抑制因子，通过抑制肿瘤生长和肿瘤转移，全面减弱肺癌细胞；EWI2作为内溶酶体调节因子，促进溶酶体活性，增强溶酶体对生长因子受体和整合素的降解，进而降低其水平和功能；EWI2具有细胞表面可及性、对生长因子受体和整合素的双重抑制以及广谱抗癌活性，因此有望成为一种有前景的治疗候选药物。更重要的是，我们的观察还提供了一种新的治疗策略来绕过对EGFR抑制剂的耐药性。
As a partner of tetraspanins, EWI2 suppresses glioblastoma, melanoma, and prostate cancer; but its role in lung cancer has not been investigated. Bioinformatics analysis reveals that EWI2 gene expression is up regulated in lung adenocarcinoma and higher expression of EWI2 mRNA may predict poorer overall survival. However, experimental analysis shows that EWI2 protein is actually downregulated constantly in the tissues of lung adenocarcinoma and lung squamous cell carcinoma. Forced expression of EWI2 in human lung adenocarcinoma cells reduces total cellular and cell surface levels of various integrins and growth factor receptors, which initiates the outside-in motogenic and mitogenic signaling. These reductions result in the decreases in 1) cell-matrix adhesion, cell movement, and cell transformation in vitro and 2) tumor growth, burden, and metastasis in vivo, and result from the increases in lysosomal trafficking and proteolytic degradation of theses membrane receptors. EWI2 elevates lysosome formation by promoting nuclear retention of TFEB, the master transcription factor driving lysosomogenesis. In conclusion, EWI2 as a lung cancer suppressor attenuates lung cancer cells in a comprehensive fashion by inhibiting both tumor growth and tumor metastasis; EWI2 as an endolysosome regulator promotes lysosome activity to enhance lysosomal degradation of growth factor receptors and integrins and then reduce their levels and functions; and EWI2 can become a promising therapeutic candidate given its accessibility at the cell surface, dual inhibition on growth factor receptors and integrins, and broad-spectrum anti-cancer activity. More importantly, our observations also provide a novel therapeutic strategy to bypass the resistance to EGFR inhibitors.
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影响因子：
4.6
作者：
Somchai, Parinyachat;Phongkitkarun, Kriengkrai;Sampattavanich, Somponnat
通讯作者：
Sampattavanich, Somponnat
影响因子：
6.6
作者：
Fu C;Zhang Q;Wang A;Yang S;Jiang Y;Bai L;Wei Q
通讯作者：
Wei Q
DOI：
10.3109/15419069809004478
发表时间：
1998-01-01
期刊：
CELL ADHESION AND COMMUNICATION
影响因子：
--
作者：
Friedl, P;Bröcker, EB;Zänker, KS
通讯作者：
Zänker, KS
影响因子：
3.3
作者：
Prall, Friedrich;Huehns, Maja
通讯作者：
Huehns, Maja
波形蛋白是肺腺癌在集体侵袭过程中通过异型肿瘤细胞-癌症相关成纤维细胞相互作用进行转移所必需的。
DOI：
10.1158/1078-0432.ccr-17-1776
发表时间：
2018-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Richardson AM;Havel LS;Koyen AE;Konen JM;Shupe J;Wiles WG 4th;Martin WD;Grossniklaus HE;Sica G;Gilbert-Ross M;Marcus AI
通讯作者：
Marcus AI