Concomitant Overexpression of Mir-182-5P and Mir-182-3P Raises the Possibility of Il-17–Producing Treg Formation in Breast Cancer by Targeting Cd3d, Itk, Foxo1, and Nfats: A Meta-Analysis and Experimental Study Publisher Pubmed



Soheilifar MH¹ ; Vaseghi H² ; Seif F³ ; Ariana M⁴ ; Ghorbanifar S¹ ; Habibi N¹ ; Papari Barjasteh F¹ ; Pornour M¹
Source: Cancer Science Published:2021

Abstract

T cells are polarized toward regulatory T cells (Tregs) in tumor microenvironment by the shuttling of microRNAs that target T cell–activating signaling pathways. We evaluated the expression of the miR-182 cluster (miR-96, 182, and 183) in peripheral blood mononuclear cells (PBMCs) of patients with breast cancer (BC), and T cell polarization by the expression of FOXO1, NFATs, ITK, TCR/CD3 complex, and IL-2/IL-2RA. Twenty-six microRNAs overexpressed in tumor tissues and sera of these patients were extracted by a meta-analysis. Then, the expression of the miR-182 cluster was investigated in PBMCs and sera of these patients and correlated with their targets in PBMCs. Finally, miR-182 was cloned into Jurkat cells to evaluate its effects on T cell polarization. FOXO1, CD3d, ITK, NFATc3, NFATc4, and IL-2RA were targeted by miR-182, due to which their expression decreased in PBMCs of patients. Although IL-6, IL-17, and TGF-β increased after miR-182 transduction, IL-2 dramatically decreased. We revealed CD4+FOXP3+ T cell differentiation in the miR-182–transduced group. Although miR-182 has inhibitory effects on T cells by the inhibition of FOXO1, TCR/CD3 complex, NFATs, and IL-2/IL-2RA signaling pathways, it increases FOXP3, TGF-β, and IL-17 expression to possibly drive T cell deviation toward the transitional state of IL-17–producing Tregs and Treg formation in the end. © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.