Open Access

ARTICLE

Uncoupling tumor necrosis factor-α and interleukin-10 at tumor immune microenvironment of breast cancer through miR-17-5p/MALAT-1/H19 circuit

by RAGHDA A. SOLIMAN¹, RANA A. YOUNESS^1,2,*, TAMER M. MANIE³, EMAD KHALLAF⁴, MOHAMED EL-SHAZLY¹, MONA ABDELMOHSEN⁵, HEBA HANDOUSSA¹, MOHAMED Z. GAD^6,*

1 Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt
2 School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, 11578, Egypt
3 Breast Surgery Department, National Cancer Institute, Cairo University, Cairo, Egypt
4 General Surgery Department, Faculty of Medicine, Cairo University, Cairo, Egypt
5 Department of Phytochemistry, National Research Centre, Giza, 12622, Egypt
6 Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt

* Corresponding Authors: RANA A. YOUNESS. Email: ; MOHAMED Z. GAD. Email:

(This article belongs to the Special Issue: Noncoding RNAs & Associated Human Diseases)

BIOCELL 2022, 46(3), 769-783. https://doi.org/10.32604/biocell.2022.016636

Received 14 April 2021; Accepted 01 June 2021; Issue published 18 November 2021

Abstract

Triple Negative Breast Cancer (TNBC) immunotherapy has recently shown promising approach. However, some TNBC patients presented with resistance. One of the reasons was attributed to the excessive release of cytokines at the tumor microenvironment (TME) such as Tumor necrosis factor alpha (TNF-α) and Interleukin-10 (IL-10). Fine regulation of these cytokines’ levels via non-coding RNAs (ncRNAs) might alleviate the immune quiescent nature of TME at TNBC tumors. However, the extrapolation of ncRNAs as therapeutic tools is highly challenging. Therefore, disentanglement the nature for the isolation of natural compounds that could modulate the ncRNAs and their respective targets is an applicable translational therapeutic approach. Hence, this study aimed to targeting the chief immune suppressive cytokines at the TME (TNF-α and IL-10) via ncRNAs and to examine the effects of Rosemary aerial parts extract on the expression levels of these ncRNAs in TNBC. Results revealed miR-17-5p as a dual regulator of TNF-α and IL-10. Moreover, an intricate interaction has been shown between miR-17-5p and the oncogenic lncRNAs: MALAT1 and H19. Knocking down of MALAT1 and/or H19 caused an induction in miR-17-5p and reduction in TNF-α and IL-10 expression levels. miR-17-5p was found to be down-regulated, while TNF-α, IL-10, MALAT1 and H19 were up-regulated in BC patients. Forced expression of miR-17-5p in MDA-MB-231 cells reduced TNF-α, IL-10, MALAT1 and H19 expression levels, as well as several BC hallmarks. In a translational approach, ursolic acid (UA) isolated from rosemary induced the expression of miR-17-5p, MALAT1 and decreased H19 expression levels. In conclusion, this study suggests miR-17-5p as a tumor suppressor and an immune-activator miRNA in BC through tuning up the immunological targets TNF-α, IL-10 at the TME and the oncological mediators MALAT1 and H19 lncRNAs.

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