The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer.

Oncogene
Zongsheng HeJohn W M Creemers

Abstract

Mutations in KRAS and/or BRAF that activate the ERK kinase are frequently found in colorectal cancer (CRC) and drive resistance to targeted therapies. Therefore, the identification of therapeutic targets that affect multiple signaling pathways simultaneously is crucial for improving the treatment of patients with KRAS or BRAF mutations. The proprotein convertase furin activates several oncogenic protein precursors involved in the ERK-MAPK pathway by endoproteolytic cleavage. Here we show that genetic inactivation of furin suppresses tumorigenic growth, proliferation, and migration in KRAS or BRAF mutant CRC cell lines but not in wild-type KRAS and BRAF cells. In a mouse xenograft model, these KRAS or BRAF mutant cells lacking furin displayed reduced growth and angiogenesis, and increased apoptosis. Mechanistically, furin inactivation prevents the processing of various protein pecursors including proIGF1R, proIR, proc-MET, proTGF-β1 and NOTCH1 leading to potent and durable ERK-MAPK pathway suppression in KRAS or BRAF mutant cells. Furthermore, we identified genes involved in activating the ERK-MAPK pathway, such as PTGS2, which are downregulated in the KRAS or BRAF mutant cells after furin inactivation but upregulated in wild-ty...Continue Reading

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Citations

Nov 30, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Daniela GerovskaIker Badiola
Apr 16, 2021·Pathology, Research and Practice·Abhishek MohantySudhir Rawal
May 11, 2021·Frontiers in Molecular Biosciences·Bolun Zhou, Shugeng Gao
Jun 3, 2021·Biomedicines·Maria Grazia Cerrito, Emanuela Grassilli
Jun 7, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Benjamin LietGeraldine Siegfried
Jul 3, 2021·International Journal of Molecular Sciences·Ilaria CoppolaJohn W M Creemers
Jun 6, 2021·Clinics and Research in Hepatology and Gastroenterology·Youxin ZhouYuting Kuang
Jul 17, 2021·Biostatistics·Jordan G Bryan, Peter D Hoff

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Datasets Mentioned

BETA
GSE130969

Methods Mentioned

BETA
RNA-seq
xenografts
FCS
protein assays
PCR
HT-Seq

Software Mentioned

Bioconductor package
Image J
metascape
Image Quant
DESeq
TopHat
NIS
R
Elements AR

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