2. Academic Validation
  3. MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage

MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage

  • Oncogene. 2023 Mar 15. doi: 10.1038/s41388-023-02650-5.
Kelie Chen # 1 2,  Xiaoyu Yuan # 2,  Shengchao Wang # 1,  Fang Zheng # 1 2,  Zhiqin Fu 3,  Zhangjin Shen 1,  Xiaodong Cheng 1,  Yuwei Wang 2,  Song Tang 1 2,  Heng Ni 2,  Fang Wang 2,  Guang Lu 4,  Yihua Wu 5 6,  Dajing Xia 7 8 9,  Weiguo Lu 10 11
Affiliations

Affiliations

  • 1 Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
  • 2 Department of Toxicology of School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
  • 3 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang Province, China.
  • 4 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
  • 5 Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. [email protected].
  • 6 Department of Toxicology of School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. [email protected].
  • 7 Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. [email protected].
  • 8 Department of Toxicology of School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. [email protected].
  • 9 Cancer Center, Zhejiang University, Hangzhou, Zhejiang Province, China. [email protected].
  • 10 Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. [email protected].
  • 11 Cancer Center, Zhejiang University, Hangzhou, Zhejiang Province, China. [email protected].
  • # Contributed equally.
PMID: 36922678 DOI: 10.1038/s41388-023-02650-5
Abstract

Peritoneal 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.

Figures
Products
Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100343
    99.40%, MAP4K4 Inhibitor
Other Products