The E3 ubiquitin ligase, FBXW5, promotes the migration and invasion of gastric cancer through the dysregulation of the Hippo pathway.
The E3 ubiquitin ligase, FBXW5, promotes the migration and invasion of gastric cancer through the dysregulation of the Hippo pathway.
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E3泛素连接酶FBXW5通过Hippo通路失调促进胃癌的迁移和侵袭
DOI：
10.1038/s41420-022-00868-y
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发表时间：
2022-02-24
影响因子：
7
通讯作者：
Deng J
中科院分区：
文献类型：
--
作者：
Yao Y;Liu Z;Huang S;Huang C;Cao Y;Li L;Guo H;Liu F;Huang S;Liao Q;He X;Chen J;Li J;Xiang X;Xiong J;Deng J
F-box和WD重复结构域5(FBXW5)与WD40重复，可与大肿瘤抑制因子1/2(LATS1/2)激动域的PPxY序列结合，导致泛素化。泛素化和随后的LATS1/2的降解破坏了河马途径，恶化了胃癌(GC)。然而，FBXW5在GC中的作用及其分子机制尚不清楚。为探讨FBXW5的临床意义，采用免疫组织化学方法显示FBXW5的表达与淋巴结转移(P <； 0.001)和临床分期(训练队列：P = 0.018；验证队列：P = 0.001)呈正相关。此外，高表达FBXW5的患者预后较差(训练队列：对数等级p = 0.020；验证队列：对数等级p = 0.025)。细胞实验显示FBXW5对GC细胞的增殖、侵袭、转移和化疗耐药有促进作用。阻断LATS1-YAP1导致FBXW5介导的河马通路和部分功能的丧失。此外，免疫共沉淀和体内泛素化实验表明FBXW5与LATS1之间存在相互作用，促进了LATS1的泛素化和降解。根据小鼠异种移植实验，沉默FBXW5可减弱皮下移植瘤的生长。综上所述，FBXW5通过促进LATS1泛素化和降解来失活Hippo信号通路，从而促进GC细胞的侵袭、转移和耐药。
F-box and WD repeat domain-containing 5 (FBXW5), with WD40 repeats, can bind to the PPxY sequence of the large tumor suppressor kinases 1/2 (LATS1/2) kinase domain, resulting in ubiquitination. Ubiquitination and the subsequent degradation of LATS1/2 abrogate the Hippo pathway and worsen gastric cancer (GC). However, the effects and molecular mechanisms of FBXW5 in GC remain unexplored. To elucidate the clinical significance of FBXW5, immunohistochemistry was conducted to reveal the positive correlation between FBXW5 expression and lymph node metastasis (p < 0.001) and TNM stage (training cohort: p = 0.018; validation cohort: p = 0.001). Further, patients with high FBXW5 expression were found to have poor prognosis (training cohort: log-rank p = 0.020; validation cohort: log-rank p = 0.025). Cell experiments revealed the promoting effects of FBXW5 on the proliferation, invasion, metastasis, and chemoresistance of GC cells. Blocking LATS1-YAP1 leads to the loss of FBXW5-mediated regulation of the Hippo pathway and partial functions. Further, co-immunoprecipitation and in vivo ubiquitination assays revealed the interaction between FBXW5 and LATS1, which promoted the ubiquitination and degradation of LATS1. Based on mouse xenograft assays, FBXW5 silencing attenuated the growth of subcutaneous tumor xenografts. Altogether, FBXW5 was found to inactivate the Hippo signaling pathway by enhancing LATS1 ubiquitination and degradation, which promoted the invasion, metastasis, and drug resistance of GC cells.
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Hippo 通路在器官大小控制、组织稳态和癌症中的作用
影响因子：
64.5
作者：
Yu FX;Zhao B;Guan KL
通讯作者：
Guan KL
DOI：
10.1016/j.bbrc.2009.02.052
发表时间：
2009-04-10
影响因子：
3.1
作者：
Minoda, Yasumasa;Sakurai, Hiroaki;Takaesu, Giichi
通讯作者：
Takaesu, Giichi
影响因子：
20.3
作者：
Chen, Qing;Xie, Weilin;Orlowski, Robert Z.
通讯作者：
Orlowski, Robert Z.
影响因子：
5.2
作者：
Yeo, Mei Shi;Subhash, Vinod Vijay;Yong, Wei Peng
通讯作者：
Yong, Wei Peng
影响因子：
8
作者：
Barbash, O.;Lee, E. K.;Diehl, J. A.
通讯作者：
Diehl, J. A.