Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis
Journal
Oncogene
Journal Volume
41
Journal Issue
20
Pages
2833
Date Issued
2022
Author(s)
Lin, Hsin-Ying
Lo, Tzu-Yu
Wu, Shang-Ru
Lan, Shao-Wei
Huang, Chen-An
Lin, Yi-Chin
Lin, Hsin-Hsien
Tu, Hsin-Fang
Lee, Cheng-Fan
Hsiao, Pei-Wen
Chang, Kai-Hsiung
Abstract
Dysregulation of pericellular proteolysis is strongly implicated in cancer metastasis through alteration of cell invasion and the microenvironment. Matriptase-2 (MT-2) is a membrane-anchored serine protease which can suppress prostate cancer (PCa) cell invasion. In this study, we showed that MT-2 was down-regulated in PCa and could suppress PCa cell motility, tumor growth, and metastasis. Using microarray and biochemical analysis, we found that MT-2 shifted TGF-β action towards its tumor suppressor function by repressing epithelial-to-mesenchymal transition (EMT) and promoting Smad2 phosphorylation and nuclear accumulation to upregulate two TGF-β1 downstream effectors (p21 and PAI-1), culminating in hindrance of PCa cell motility and malignant growth. Mechanistically, MT-2 could dramatically up-regulate the expression of nuclear receptor NR4A3 via iron metabolism in PCa cells. MT-2-induced NR4A3 further coactivated Smad2 to activate p21 and PAI-1 expression. In addition, NR4A3 functioned as a suppressor of PCa and mediated MT-2 signaling to inhibit PCa tumorigenesis and metastasis. These results together indicate that NR4A3 sustains MT-2 signaling to suppress PCa cell invasion, tumor growth, and metastasis, and serves as a contextual factor for the TGF-β/Smad2 signaling pathway in favor of tumor suppression via promoting p21 and PAI-1 expression.
Subjects
SERINE-PROTEASE MATRIPTASE-2; UROKINASE PLASMINOGEN-ACTIVATOR; ORPHAN NUCLEAR RECEPTORS; BREAST-CANCER; IN-VITRO; IRON; TMPRSS6; SMAD2; EXPRESSION; PROGNOSIS
SDGs
Publisher
SPRINGERNATURE
Type
journal article