MicroRNA-520/373 Family Functions As a Tumor Suppressor in Estrogen Receptor Negative Breast Cancer by Targeting NF-κB and TGF-β Signaling Pathways
Overview
Oncology
Authors
Affiliations
MicroRNAs (miRNAs) as modulators of gene expression have been described to display both tumor-promoting and tumor-suppressive functions. Although their role has been studied in different tumor types, little is known about how they regulate nuclear factor κB (NF-κB) signaling in breast cancer. Here, we performed an unbiased whole genome miRNA (miRome) screen to identify novel modulators of NF-κB pathway in breast cancer. The screen identified 13 miRNA families whose members induced consistent effects on NF-κB activity. Among those, the miR-520/373 family inhibited NF-κB signaling through direct targeting of RELA and thus strongly reduced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8. With a combination of in vitro and in vivo approaches, we propose a metastasis-suppressive role of miR-520/373 family. miR-520c and miR-373 abrogated both in vitro cell invasion and in vivo intravasation of highly invasive MDA-MB-231 cells. However, knockdown of RELA did not affect their metastatic ability. mRNA profiling of MDA-MB-231 cells on overexpression of miR-520/373 members revealed a strong downregulation of transforming growth factor-β (TGF-β) signaling. Mechanistically, the metastasis-suppressive role of miR-520/373 can be attributed to direct suppression of TGFBR2, as the silencing of TGFBR2 phenocopied the effects of miR-520/373 overexpression on suppression of Smad-dependent expression of the metastasis-promoting genes parathyroid hormone-related protein, plasminogen activator inhibitor-1 and angiopoietin-like 4 as well as tumor cell invasion, in vitro and in vivo. A negative correlation between miR-520c and TGFBR2 expression was observed in estrogen receptor negative (ER(-)) breast cancer patients but not in the ER positive (ER(+)) subtype. Remarkably, decreased expression of miR-520c correlated with lymph node metastasis specifically in ER(-) tumors. Taken together, our findings reveal that miR-520/373 family has a tumor-suppressive role in ER(-) breast cancer by acting as a link between the NF-κB and TGF-β pathways and may thus contribute to the interplay of tumor progression, metastasis and inflammation.
Pan-cancer analysis of the potential of PEA3 subfamily genes as tumor markers.
Guan L, Zeng R, Chen Y, He G, Yao W, Liu Z Sci Rep. 2024; 14(1):31518.
PMID: 39732961 PMC: 11682092. DOI: 10.1038/s41598-024-82973-9.
Khan M, Wong G, Zhuang C, Najjar M, Lo H Front Oncol. 2024; 14:1436942.
PMID: 39175471 PMC: 11338853. DOI: 10.3389/fonc.2024.1436942.
Khan M, Sharma V, Serajuddin M, Kirabo A Noncoding RNA Res. 2024; 9(3):954-963.
PMID: 38699204 PMC: 11063115. DOI: 10.1016/j.ncrna.2024.04.004.
Pinpointing Functionally Relevant miRNAs in Classical Hodgkin Lymphoma Pathogenesis.
Pan Y, Cengiz R, Kluiver J, Diepstra A, van den Berg A Cancers (Basel). 2024; 16(6).
PMID: 38539461 PMC: 10968648. DOI: 10.3390/cancers16061126.
Kimna C, Lieleg O Biophys Rev (Melville). 2024; 1(1):011305.
PMID: 38505628 PMC: 10903406. DOI: 10.1063/5.0033378.