2. Academic Validation
  3. Enhanced CHOLESTEROL biosynthesis promotes breast cancer metastasis via modulating CCDC25 expression and neutrophil extracellular traps formation

Enhanced CHOLESTEROL biosynthesis promotes breast cancer metastasis via modulating CCDC25 expression and neutrophil extracellular traps formation

  • Sci Rep. 2022 Oct 17;12(1):17350. doi: 10.1038/s41598-022-22410-x.
Qiqi Tang # 1 2,  Beibei Liang # 1 3,  Lisha Zhang # 1 2,  Xuhui Li 3,  Hengyu Li 4,  Wei Jing 4,  Yingjie Jiang 4,  Felix Zhou 5,  Jian Zhang 6 7,  Yanchun Meng 6 7,  Xinhua Yang 1 2,  Hao Yang 1 3,  Gang Huang 1 3,  Jian Zhao 8 9 10
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Science, 279Th Zhouzhu Road, Shanghai, 201318, China.
  • 2 Shanghai University of Traditional Medicine, Shanghai, 201203, China.
  • 3 Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
  • 4 Changhai Hospital, Navy Military Medical University, Shanghai, 200438, China.
  • 5 Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
  • 6 Phase I Clinical Trial Center, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
  • 7 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 8 Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Science, 279Th Zhouzhu Road, Shanghai, 201318, China. j-zhao@vip.126.com.
  • 9 Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China. j-zhao@vip.126.com.
  • 10 Shanghai University of Traditional Medicine, Shanghai, 201203, China. j-zhao@vip.126.com.
  • # Contributed equally.
PMID: 36253427 DOI: 10.1038/s41598-022-22410-x
Abstract

Neutrophil extracellular traps (NETs) has been demonstrated to regulate the metastasis of breast Cancer. In this study, we showed that de novo Cholesterol biosynthesis induced by ASPP2 depletion in mouse breast Cancer cell 4T1 and human breast Cancer cell MDA-MB-231 promoted NETs formation in vitro, as well as in lung metastases in mice intravenously injected with ASPP2-deficient 4T1 cells. Simvastatin and berberine (BBR), Cholesterol synthesis inhibitors, efficiently blocked ASPP2-depletion induced NETs formation. Cholesterol biosynthesis greatly enhanced Coiled-coil domain containing protein 25 (CCDC25) expression on Cancer cells as well as in lung metastases. CCDC25 expression was co-localized with caveolin-1, a lipid raft molecule, and was damped by inhibitor of lipid rafts formation. Our data suggest that Cholesterol biosynthesis promotes CCDC25 expression in a lipid raft-dependent manner. Clinically, the expression of CCDC25 was positively correlated with the expression of 3-hydroxy-3-methylglutaryl-CoAreductase (HMRCG), and citrullinated histone H3 (H3cit), in tissues from breast Cancer patients. High expression of CCDC25 and HMGCR was related with worse prognosis in breast Cancer patients. In conclusion, our study explores a novel mechanism for de novo Cholesterol biosynthesis in the regulation of CCDC25 expression, NETs formation and breast Cancer metastasis. Targeting Cholesterol biosynthesis may be promising therapeutic strategies to treat breast Cancer metastasis.

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