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MALAT-1/p53/miR-155/miR-146a ceRNA circuit tuned by methoxylated quercitin glycoside alters immunogenic and oncogenic profiles of breast cancer

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Abstract

Triple-Negative Breast Cancer (TNBC) is one of the most aggressive and hot BC subtypes. Our research group has recently shed the light on the utility of natural compounds as effective immunotherapeutic agents. The aim of this study is to investigate the role of a methoxylated quercetin glycoside (MQG) isolated from Cleome droserifolia in harnessing TNBC progression and tuning the tumor microenvironment and natural killer cells cytotoxicity. Results showed that MQG showed the highest potency (IC50 = 12 µM) in repressing cellular proliferation, colony-forming ability, migration, and invasion capacities. Mechanistically, MQG was found to modulate a circuit of competing endogenous RNAs where it was found to reduce the oncogenic MALAT-1 lncRNA and induce TP53 and its downstream miRNAs; miR-155 and miR-146a. Accordingly, this leads to alteration in several downstream signaling pathways such as nitric oxide synthesizing machinery, natural killer cells' cytotoxicity through inducing the expression of its activating ligands such as MICA/B, ULBP2, CD155, and ICAM-1 and trimming of the immune-suppressive cytokines such as TNF-α and IL-10. In conclusion, this study shows that MQG act as a compelling anti-cancer agent repressing TNBC hallmarks, activating immune cell recognition, and alleviating the immune-suppressive tumor microenvironment experienced by TNBC patients.

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Data availability

Data are available from the corresponding author based on a reasonable request.

Abbreviations

BC:

Breast cancer

CD155:

Cluster of differentiation 155

IL-10:

Interleukin-10

ICAM-1:

Intracellular adhesion molecule-1

MICA:

MHC class I-related chain A

MICB:

MHC class I-related chain B

miRNA/miR:

MicroRNA

NK cells:

Natural Killer cells

TNBC:

Triple negative breast cancer

TNF-α:

Tumor necrosis factor-alpha

ULBP2:

UL-16 binding protein

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Funding

This study was not supported by any funding agency.

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Authors and Affiliations

  1. Molecular Genetics Research Team (MGRT), Biotechnology Program, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt

    Mustafa Abdel-Latif & Ahmed Riad

  2. Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt

    Mustafa Abdel-Latif, Ahmed Riad, Raghda A. Soliman, Aisha M. Elkhouly, Heba Nafae & Rana A. Youness

  3. Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt

    Aisha M. Elkhouly, Heba Nafae & Mohamed Z. Gad

  4. Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia

    Amira Abdel Motaal

  5. Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Amira Abdel Motaal

  6. Department of Biology and Biochemistry, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, 11578, Egypt

    Rana A. Youness

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  1. Mustafa Abdel-Latif
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Contributions

MA-L and RAY contributed to most of the practical work and wrote the manuscript. AR, RS, AE-K, HN contributed to the practical work. MZG, AM co-supervised the work. RAY conceived the original idea, designed the experimental setup, supervised the work. All authors discussed the results and contributed to the final manuscript.

Corresponding author

Correspondence to Rana A. Youness.

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Abdel-Latif, M., Riad, A., Soliman, R.A. et al. MALAT-1/p53/miR-155/miR-146a ceRNA circuit tuned by methoxylated quercitin glycoside alters immunogenic and oncogenic profiles of breast cancer. Mol Cell Biochem 477, 1281–1293 (2022). https://doi.org/10.1007/s11010-022-04378-4

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  • DOI: https://doi.org/10.1007/s11010-022-04378-4

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