1. Academic Validation
  2. FGFR2 upregulates PAI-1 via JAK2/STAT3 signaling to induce M2 polarization of macrophages in colorectal cancer

FGFR2 upregulates PAI-1 via JAK2/STAT3 signaling to induce M2 polarization of macrophages in colorectal cancer

  • Biochim Biophys Acta Mol Basis Dis. 2023 Feb 11;166665. doi: 10.1016/j.bbadis.2023.166665.
Yiming Li 1 Yongkang Shi 2 Xiuyuan Zhang 1 Piao Li 1 Li Ma 1 Pengbo Hu 1 Liang Xu 1 Yuhong Dai 1 Shu Xia 1 Hong Qiu 3
Affiliations

Affiliations

  • 1 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
  • 2 Department of Biliary and Pancreatic Surgery/Cancer Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
  • 3 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address: qiuhong@hust.edu.cn.
Abstract

Fibroblast Growth Factor receptor 2 (FGFR2) is frequently activated by overexpression or mutation, and an abnormal Fibroblast Growth Factor (FGF)/FGFR signaling pathway is associated with the occurrence, development, and poor prognosis of colorectal Cancer (CRC). Our preliminary analysis found that plasminogen activator inhibitor-1 (PAI-1) expression may be related to FGF/FGFR signaling, however, their role in the tumor immune microenvironment remains unclear. In this study, we observed markedly higher PAI-1 expression in CRC patients with poor survival rates. PAI-1 is regulated by FGF/FGFR2 in colon Cancer cells and is involved in M2 macrophage polarization. Mechanistically, inhibiting the JAK2/STAT3 signaling pathway could cause PAI-1 downregulation. Furthermore, the activation of phosphorylated STAT3 upregulated PAI-1. In vivo, FGFR2 overexpression in tumor-bearing mouse models suggested that a PAI-1 Inhibitor could rescue FGFR2/PAI-1 axis-induced M2 macrophage polarization, which leads to effective immune activity and tumor suppression. Moreover, the combination of a PAI-1 Inhibitor and anti-PD-1 therapy exhibited superior antitumor activity in mice. These findings offer novel insights into the molecular mechanisms underlying tumor deterioration and provide potential therapeutic targets for CRC treatment.

Keywords

Colorectal cancer; FGFR2; JAK2/STAT3; Macrophage polarization; PAI-1.

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