MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage
Author:
Chen Kelie, Yuan Xiaoyu, Wang Shengchao, Zheng Fang, Fu Zhiqin, Shen Zhangjin, Cheng Xiaodong, Wang Yuwei, Tang Song, Ni Heng, Wang Fang, Lu GuangORCID, Wu YihuaORCID, Xia Dajing, Lu WeiguoORCID
Abstract
AbstractPeritoneal metastasis is a key feature of advanced ovarian cancer, but the critical protein required for ovarian cancer metastasis and progression is yet to be defined. Thus, an unbiased high throughput and in-depth study is warranted to unmask the mechanism. Transcriptomic sequencing of paired primary ovarian tumors and metastases unveiled that MAP4K4, a serine/threonine kinase belongs to the Ste20 family of kinases, was highly expressed in metastatic sites. Increased MAP4K4 expression in metastasis was further validated in other independent patients, with higher MAP4K4 expression associated with poorer survival, higher level of CA125 and more advanced FIGO stage. Down regulation of MAP4K4 inhibited cancer cell adhesion, migration, and invasion. Notably, MAP4K4 was found to stabilize N-cadherin. Further results showed that MAP4K4 mediated phosphorylation of ADAM10 at Ser436 results in suppression of N-cadherin cleavage by ADAM10, leading to N-cadherin stabilization. Pharmacologic inhibition of MAP4K4 abrogated peritoneal metastases. Overall, our data reveal MAP4K4 as a significant promoter in ovarian cancer metastasis. Targeting MAP4K4 may be a potential therapeutic approach for ovarian cancer patients.
Funder
Natural Science Foundation of Zhejiang Province the Key Research and Development Program of Zhejiang Province, China the Fundamental Research Funds for the Central Universities
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Molecular Biology
Reference77 articles.
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. 2018;68:394–424. 2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA: Cancer J Clin. 2022;72:7–33. 3. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA: Cancer J Clin. 2018;68:284–96. 4. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet (Lond, Engl). 2019;393:1240–53. 5. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|