MiR-4638-3p regulates transforming growth factor-β1-induced activating transcription factor-3 and cell proliferation, invasion, and apoptosis in human breast cancer cells

R. L. Akshaya, M. Rohini, Z. He, N. C. Partridge, N. Selvamurugan

Research output: Contribution to journalArticlepeer-review

Abstract

TGF-β1 (transforming growth factor-beta1), a secreted polypeptide cytokine, stimulates ATF-3 (activating transcription factor-3) expression in a sustained and prolonged manner in human breast cancer cells (MDA-MB231), but not in normal human mammary epithelial cells (MCF-10A). Cyclin A (cell proliferation gene), Runx2 (metastasis gene), and MMP-13 (matrix metalloproteinase-13; invasive gene) were identified as ATF-3 target genes in these cells. Because ATF-3 has very few druggable sites, its direct targeting is difficult. Recent evidence has indicated that microRNAs (miRNAs) are key players in the post-transcriptional modulation of gene expression under several conditions. Bioinformatic analysis suggested a list of putative miRNAs that target ATF-3. Therefore, we hypothesized that TGF-β1 downregulates the miRNAs that target ATF-3, resulting in the activation of genes that participate in breast cancer progression and skeletal metastasis. Our findings indicate that TGF-β1 downregulated the expression of miR-4638-3p in MDA-MB231 cells. At the molecular level, forced expression of miR-4638-3p reduced the expression of ATF-3 and its downstream targets, Runx2 and MMP-13, in these cells. At the cellular level, overexpression of miR-4638-3p reduced proliferation, invasion, and migration, and induced G0/G1 cell cycle arrest and apoptosis in MDA-MB231 cells. Overall, this study highlights the possibility of utilizing miR-4638-3p as a therapeutic molecule to curb skeletal metastasis of breast cancer cells.

Original languageEnglish (US)
Pages (from-to)1974-1982
Number of pages9
JournalInternational Journal of Biological Macromolecules
Volume222
DOIs
StatePublished - Dec 1 2022

Keywords

  • ATF-3
  • Bone metastases
  • Breast cancer
  • TGF-β1
  • miRNAs

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

Fingerprint

Dive into the research topics of 'MiR-4638-3p regulates transforming growth factor-β1-induced activating transcription factor-3 and cell proliferation, invasion, and apoptosis in human breast cancer cells'. Together they form a unique fingerprint.

Cite this