2. Academic Validation
  3. Bcl-xL mediates interferon-beta secretion by protease-activated receptor 2 deficiency through the mitochondrial permeability transition pore in colorectal cancer metastasis

Bcl-xL mediates interferon-beta secretion by protease-activated receptor 2 deficiency through the mitochondrial permeability transition pore in colorectal cancer metastasis

  • Cancer Lett. 2023 Nov 14:216483. doi: 10.1016/j.canlet.2023.216483.
Jianhui Ma 1,  Yu Liu 1,  Junhu Yuan 1,  Yiming Ma 1,  Xinhua Zhao 1,  Kun Chen 2,  Xiaoli Zhang 3,  Fanyu Zhang 1,  Hongying Wang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
  • 2 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
  • 3 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Department of Injury and Repair, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China.
  • 4 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. Electronic address: hongyingwang@cicams.ac.cn.
PMID: 37972702 DOI: 10.1016/j.canlet.2023.216483
Abstract

Cellular plasticity and immune escape are synergistic drivers of tumor colonization in metastatic organs. Activation of Protease-activated Receptor 2 (PAR2) signaling promotes metastasis of colorectal carcinoma (CRC). The role of PAR2 in regulating the immune microenvironment and Cancer progression remains unclear. We demonstrated that the regulation of liver metastasis by PAR2 requires a competent immune system. PAR2 knockdown enhanced liver infiltration of activated CD8+ T cells prior to metastatic foci formation in an interferon receptor-dependent manner. PAR2 depletion increased interferon (IFN)-β production via the cGAS-STING and RIG1 pathways. PAR2 inhibition increased mitochondrial permeability and cytosolic accumulation of mitochondrial DNA, which was reversed by Bcl-xL expression. Strikingly, shRNA against PAR2 with an immune checkpoint blocker (ICB) acted synergistically to suppress liver metastasis. Analysis of single-cell sequence data and 24 paired samples confirmed the regulatory effect of PAR2 on the metastatic immune environment in human CRC. Therefore, PAR2 signaling is involved in stabilizing the mitochondrial membrane and regulating the immune microenvironment through IFN-β during liver metastasis in CRC. The synergistic effect of the PAR2 Inhibitor and ICB provides a potential therapeutic strategy for metastatic CRC treatment.

Keywords

Colorectal cancer; Interferon; Metastasis; Mitochondria; Permeability transition pore.

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