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

被引：3

作者：

Ma, Jianhui ^{[1
]}

Liu, Yu ^{[1
]}

Yuan, Junhu ^{[1
]}

Ma, Yiming ^{[1
]}

Zhao, Xinhua ^{[1
]}

Chen, Kun ^{[1
,2
]}

Zhang, Xiaoli ^{[1
,3
]}

Zhang, Fanyu ^{[1
]}

Wang, Hongying ^{[1
,4
]}

机构：

[1] Chinese Acad Med Sci, Natl Canc Ctr, Natl Clin Res Ctr Canc, State Key Lab Mol Oncol,Canc Hosp,Peking Union Med, Beijing, Peoples R China

[2] Chinese Acad Med Sci, Canc Hosp, Peking Union Med Coll, Natl Canc Ctr,Dept Immunol,Natl Clin Res Ctr Canc, Beijing, Peoples R China

[3] Capital Med Univ, Beijing Neurosurg Inst, Dept Injury & Repair, Beijing 100070, Peoples R China

[4] 17 Panjiayuan Nanli, Beijing 100021, Peoples R China

来源：

CANCER LETTERS | 2024年 / 580卷

关键词：

Colorectal cancer; Metastasis; Mitochondria; Permeability transition pore; Interferon; TUMOR-CELLS; INFLAMMATION; AGONIST; BLOCKADE; PD-1;

D O I：

10.1016/j.canlet.2023.216483

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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)-beta production via the cGAS-STING and RIG-1 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-beta during liver metastasis in CRC. The synergistic effect of the PAR2 inhibitor and ICB provides a potential therapeutic strategy for metastatic CRC treatment.

引用

页数：14

共 5 条

[1] Protease-activated receptor 2 stabilizes Bcl-xL and regulates EGFR-targeted therapy response in colorectal cancer
Li, Weiwei
Ma, Yiming
He, Longmei
Li, Hongwei
Chu, Yi
Jiang, Zheng
Zhao, Xinhua
Nie, Yongzhan
Wang, Xishan
Wang, Hongying
CANCER LETTERS, 2021, 517 : 14 - 23
[2] Deficiency of protease-activated receptor 2 signaling sensitizes EGFR-TKI-induced apoptosis in colorectal cancer
Li, Weiwei
Ma, Yiming
He, Longmei
Wang, Hongying
CANCER RESEARCH, 2017, 77
[3] Protease activated receptor 2 signaling promotes self-renewal and metastasis in colorectal cancer through β-catenin and periostin
Ma, Yiming
He, Longmei
Zhao, Xinhua
Li, Weiwei
Lv, Xue
Zhang, Xiaoli
Peng, Jian
Yang, Lan
Xu, Quan
Wang, Hongying
CANCER LETTERS, 2021, 521 : 130 - 141
[4] Protease activated receptor 2 mediates tryptase-induced cell migration through MYO10 in colorectal cancer
Zhang, Xiaoli
Fang, Qing
Ma, Yiming
Zou, Shuangmei
Liu, Qian
Wang, Hongying
AMERICAN JOURNAL OF CANCER RESEARCH, 2019, 9 (09): : 1995 - +
[5] Overexpression of hRFI enhances chemoresistance against 5-FU through the inhibition of mitochondrial apoptotic pathway with the up-regulation of Bcl-2 and Bcl-XL in colorectal cancer cells
Sasaki, Shin
Watanabe, Toshiaki
Konishi, Tsuyoshi
Kitayama, Joji
Nagawa, Hirokazu
CANCER RESEARCH, 2006, 66 (08)

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