2. Academic Validation
  3. FBXO22 mediates the NGF/TRKA signaling pathway in bone metastases in prostate cancer

FBXO22 mediates the NGF/TRKA signaling pathway in bone metastases in prostate cancer

  • Am J Pathol. 2023 Jun 8;S0002-9440(23)00204-3. doi: 10.1016/j.ajpath.2023.05.012.
Yuehua Zhang 1,  Wen Li 1,  Shenghu Guo 1,  Zheng Wu 1,  Lei Zhang 1,  Ya Liu 1,  Xing Li 1,  Xiaojin Guo 1,  Jing Cao 1,  Chunwang Yang 1,  Zhiyu Wang 2
Affiliations

Affiliations

  • 1 Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, P. R. China.
  • 2 Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, P. R. China. Electronic address: [email protected].
PMID: 37301536 DOI: 10.1016/j.ajpath.2023.05.012
Abstract

Prostate Cancer (PC) is a malignancy with high morbidity and mortality. Bone metastasis is the main driver of short survival time and difficulties in the treatment and prevention of PC. This study aims to explore the biological function of E3 ubiquitin ligase F-box only protein 22 (FBXO22) in PC metastasis and its specific regulation mechanism. It was revealed by transcriptome sequencing that FBXO22 was overexpressed in PC tissues (versus adjacent tissues) and bone tissues (versus biopsied bone tissues without bone metastases). Fbxo22 downregulation reduced bone metastases and macrophage M2 polarization in mice. FBXO22 was downregulated in macrophages, and polarization was observed by flow cytometry. Macrophages were co-cultured with PC cells and osteoblasts to assess PC cell and osteoblast activity. FBXO22 knockdown restored osteoblast capacity. FBXO22 ubiquitinated and degraded Krueppel-like factor 4 (KLF4) which regulated the NGF/TrkA pathway by repressing NGF transcription. Silencing of KLF4 mitigated the metastasis-suppressing properties of FBXO22 knockdown, while NGF reversed the metastasis-suppressing properties of KLF4 in vitro and in vivo. Cumulatively, these data indicated that FBXO22 promoted PC cell activity and osteogenic lesions by stimulating macrophage M2 polarization. It also degraded KLF4 in macrophages and promoted NGF transcription, thereby activating the NGF/TrkA pathway.

Keywords

Bone metastases; FBXO22; Macrophages; NGF/TRKA pathway; Prostate cancer.

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