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FASEB Journal

FASEB Journal

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CAFs-derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling

Published:15 April 2020 DOI: 10.1096/fj.201902659R PMID: 32293074
Zheng Zhou, Di Cui, Meng-Hao Sun, Jing-Lang Huang, Zheng Deng, Bang-Min Han, Xiao-Wen Sun, Shu-Jie Xia, Feng Sun, Fei Shi

Abstract

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment and contribute to tumor cell proliferation and metastasis. Microfibrillar-associated protein 5 (MFAP5), a component of elastic microfibers and an oncogenic protein in several types of tumors, is secreted by CAFs. However, the role of MFAP5 in the bladder cancer remains unclear. Here, we report that MFAP5 is upregulated in bladder cancer and is associated with poor patient survival. Downregulation of MFAP5 in CAFs led to an impairment in proliferation and invasion of bladder cancer cells. Luciferase reporter assays and electrophoretic mobility shift assays (EMSA) showed QKI directly downregulates MFAP5 in CAFs. In addition, CAFs-derived MFAP5 led to an activation of the NOTCH2/HEY1 signaling pathway through direct interaction with the NOTCH2 receptor, thereby stimulating the N2ICD release. RNA-sequencing revealed that MFAP5-mediated PI3K-AKT signaling activated the DLL4/NOTCH2 pathway axis in bladder cancer. Moreover, downregulation of NOTCH2 by short hairpin RNA or the inactivating anti-body NRR2Mab was able to reverse the adverse effects of MFAP5 stimulation in vitro and in vivo. Together, these results demonstrate CAFs-derived MFAP5 promotes the bladder cancer proliferation and metastasis and provides new insight for targeting CAFs as novel diagnostic and therapeutic strategy.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
PF-04691502 1013101-36-4 C22H27N5O4 174 suppliers $19.00-$3728.10
PF-04691502 1013101-36-4 C22H27N5O4 174 suppliers $19.00-$3728.10
PF-04691502 1013101-36-4 C22H27N5O4 174 suppliers $19.00-$3728.10
PF-04691502 1013101-36-4 C22H27N5O4 174 suppliers $19.00-$3728.10

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