RRC ID 77042
Author Hiraide S, Takahashi M, Yoshida Y, Yamada H, Komine K, Ishioka C.
Title Tumor suppressor miR-193a-3p enhances efficacy of BRAF/MEK inhibitors in BRAF-mutated colorectal cancer.
Journal Cancer Sci
Abstract Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and epidermal growth factor receptor (EGFR) inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of BRAF inhibitor dabrafenib (DAB) and MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Reverse-phase protein array analysis revealed that proteins with altered phosphorylation induced by miR-193a-3p were involved in several oncogenic pathways including MAPK-related pathways. Furthermore, overexpression of miR-193a-3p in BRAF-mutated cells enhanced the efficacy of DAB and TRA through inhibiting reactivation of MAPK signaling and inducing inhibition of Mcl1. Inhibition of Mcl1 by siRNA or by Mcl1 inhibitor increased the antiproliferative effect of combination therapy with DAB, TRA, and anti-EGFR antibody cetuximab. Collectively, our study demonstrated the possibility that miR-193a-3p acts as a tumor suppressor through regulating multiple proteins involved in oncogenesis and affects cellular sensitivity to MAPK-related pathway inhibitors such as BRAF inhibitors, MEK inhibitors, and/or anti-EGFR antibodies. Addition of miR-193a-3p and/or modulation of proteins involved in the miR-193a-3p-mediated pathway, such as Mcl1, to EGFR/BRAF/MEK inhibition may be a potential therapeutic strategy against BRAF-mutated CRC.
Volume 112(9)
Pages 3856-3870
Published 2021-9-1
DOI 10.1111/cas.15075
PMID 34288281
PMC PMC8409311
MeSH Antineoplastic Agents / pharmacology* Apoptosis / genetics Cell Line, Tumor Cell Proliferation / genetics Cetuximab / pharmacology Colorectal Neoplasms / genetics Colorectal Neoplasms / metabolism* Colorectal Neoplasms / pathology Drug Therapy, Combination / methods ErbB Receptors / antagonists & inhibitors Genes, Tumor Suppressor* Humans Imidazoles / pharmacology* MicroRNAs / genetics* MicroRNAs / metabolism* Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors* Mitogen-Activated Protein Kinase Kinases / metabolism Mutation* Oximes / pharmacology* Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins B-raf / antagonists & inhibitors* Proto-Oncogene Proteins B-raf / genetics* Pyridones / pharmacology* Pyrimidinones / pharmacology* RNA, Small Interfering / genetics Signal Transduction / drug effects Signal Transduction / genetics Transfection
IF 4.966
Human and Animal Cells COLO-320(RCB1193) LoVo(RCB1639)