1. Academic Validation
  2. CypA/TAF15/STAT5A/miR-514a-3p feedback loop drives ovarian cancer metastasis

CypA/TAF15/STAT5A/miR-514a-3p feedback loop drives ovarian cancer metastasis

  • Oncogene. 2024 Nov;43(49):3570-3585. doi: 10.1038/s41388-024-03188-w.
Ying Li # 1 2 3 Huiwen Yang # 1 2 An Li # 1 2 Buze Chen 4 5 Yue Wang 2 Ziwei Song 2 3 Haozhou Tan 6 Hui Li 7 Qian Feng 2 3 Yuan Zhou 1 2 Shibao Li 8 9 10 Lingyu Zeng 11 12 Ting Lan 13 14 15 16
Affiliations

Affiliations

  • 1 Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
  • 2 School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
  • 3 Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
  • 4 Department of Gynecology, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
  • 5 Huaihai Academy of Chinese Medicine, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
  • 6 School of Anesthesiology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
  • 7 School of Life Sciences, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
  • 8 Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. sdjnshlb@xzhmu.edu.cn.
  • 9 School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. sdjnshlb@xzhmu.edu.cn.
  • 10 Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. sdjnshlb@xzhmu.edu.cn.
  • 11 Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. zengly2000@163.com.
  • 12 School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. zengly2000@163.com.
  • 13 Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. tinglan@xzhmu.edu.cn.
  • 14 School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. tinglan@xzhmu.edu.cn.
  • 15 Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. tinglan@xzhmu.edu.cn.
  • 16 Huaihai Academy of Chinese Medicine, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China. tinglan@xzhmu.edu.cn.
  • # Contributed equally.
Abstract

Cyclophilin A (CypA) is a peptidyl-prolyl isomerase that participates in multiple Cancer events, but the molecular mechanisms of abnormal expression and regulation of CypA in ovarian Cancer (OC) have never been considered. This study identifies CypA as a key driver of epithelial-mesenchymal transition (EMT) in ovarian Cancer and explores the mechanisms that underly this process. We show that CypA is upregulated in tissues and serum of ovarian Cancer patients and that CypA overexpression correlates with poor prognosis. CypA facilitates tumor growth and metastasis in vivo in subcutaneous tumor xenograft and abdominal metastatic models, and in vitro studies suggest a mechanism, showing that CypA accelerates ovarian Cancer cell epithelial-mesenchymal transition by activating a PI3K/Akt signaling pathway. Mechanistic studies showed that STAT5A binds pri-miR-514a-3p and inhibits its activity, whereas miR-514a-3p directly binds to the 3'-UTR of CypA to suppress its expression, resulting in STAT5A promoting the expression of CypA, forming the STAT5A/miR-514a-3p/CypA axis. Furthermore, immunoprecipitates and mass spectrometry analysis identifies a CypA interaction with TAF15 that stabilizes TAF15 by suppressing its Proteasome degradation and promotes its entry into the nucleus. While STAT5A is positively regulated by TAF15. Our findings identify a novel feedback loop for CypA that drives EMT and ovarian tumor growth and metastasis via a TAF15/STAT5A/miR-514a-3p pathway in ovarian Cancer and facilitates the release of CypA into the extracellular, which provides a promising therapeutic target for OC treatment and a diagnostic biomarker.

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