Mechanisms of miR-3189-3p-mediated inhibition of c-MYC translation in triple negative breast cancer

Authors

Cecilia Vittori, Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, 1700 Tulane Ave, New Orleans, LA, USA.
Duane Jeansonne, Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, 1700 Tulane Ave, New Orleans, LA, USA.
Hassan Yousefi, Department of Biochemistry, Louisiana State University Health Sciences Center, 533 Bolivar St., New Orleans, LA, USA.
Celeste Faia, Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, 1700 Tulane Ave, New Orleans, LA, USA.
Zhen Lin, Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center and Tulane Cancer Center, 1700 Tulane Ave, New Orleans, LA, USA.
Krzysztof Reiss, Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, 1700 Tulane Ave, New Orleans, LA, USA.
Francesca Peruzzi, Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, 1700 Tulane Ave, New Orleans, LA, USA. fperuz@lsuhsc.edu.

Document Type

Article

Publication Date

5-31-2022

Abstract

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the lack of estrogen receptor, progesterone receptor, and HER2. Our lab previously characterized miR-3189-3p as a microRNA with potent anti-cancer activity against glioblastoma. Here, we hypothesized a similar activity in TNBC cells. As miR-3189-3p is predicted to target a variety of RNA binding proteins, we further hypothesized an inhibitory effect of this miRNA on protein synthesis. METHODS: MDA-MB-231 and MDA-MB-468 cells were used to investigate the effect of miR-3189-3p on cell proliferation, migration, and invasion. TGCA database was used to analyze the expression of miR-3189-3p, c-MYC, 4EPB1, and eIF4E in breast cancer. Western blotting and RT-qPCR assays were used to assess the expression of selected proteins and RNAs after transfections. RESULTS: Although c-MYC is not a predicted gene target for miR-3189-3p, we discovered that c-MYC protein is downregulated in miRNA-treated TNBC cells. We found that the downregulation of c-MYC by miR-3189-3p occurs in both normal growth conditions and in the absence of serum. The mechanism involved the direct inhibition of eIF4EBP1 by miR-3189-3p. Additionally, we found that miR-3189-3p could negatively affect cap-independent translation mediated by internal ribosome entry sites (IRES) or by m6A. Finally, miR-3189-3p sensitized TNBC cells to doxorubicin. CONCLUSION: Overall, results indicated that miR-3189-3p exerts its anti-tumor activity through targeting translational regulatory proteins leading to an impairment in c-MYC translation, and possibly other oncogenic factors, suggesting that miR-3189-3p, alone or in combination, could be a valuable therapeutic approach against a malignancy with few treatment options.

Publication Source (Journal or Book title)

Cancer cell international

First Page

204

Recommended Citation

Vittori, C., Jeansonne, D., Yousefi, H., Faia, C., Lin, Z., Reiss, K., & Peruzzi, F. (2022). Mechanisms of miR-3189-3p-mediated inhibition of c-MYC translation in triple negative breast cancer. Cancer cell international, 22 (1), 204. https://doi.org/10.1186/s12935-022-02620-z