TY - JOUR
T1 - MiR-4638-3p regulates transforming growth factor-β1-induced activating transcription factor-3 and cell proliferation, invasion, and apoptosis in human breast cancer cells
AU - Akshaya, R. L.
AU - Rohini, M.
AU - He, Z.
AU - Partridge, N. C.
AU - Selvamurugan, N.
N1 - Funding Information:
This work was supported by the Indian Council of Medical Research, India [No. 5/13/05/2019/NCD-III to N.S.], and the Department of Science & Technology [DST/INSPIRE Fellowship/2019/IF190170 to R. L. A.].
Funding Information:
This work was supported by the Indian Council of Medical Research , India [No. 5/13/05/2019/NCD-III to N.S.], and the Department of Science & Technology [ DST /INSPIRE Fellowship/2019/ IF190170 to R. L. A.].
Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
KW - ATF-3
KW - Bone metastases
KW - Breast cancer
KW - TGF-β1
KW - miRNAs
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U2 - 10.1016/j.ijbiomac.2022.09.286
DO - 10.1016/j.ijbiomac.2022.09.286
M3 - Article
C2 - 36208811
AN - SCOPUS:85139420548
SN - 0141-8130
VL - 222
SP - 1974
EP - 1982
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -