miR-623 Targets Metalloproteinase-1 and Attenuates Extravasation of Brain Metastatic Triple-Negative Breast Cancer Cells

Dua Hammash; Mona Mahfood; Ghalia Khoder; Munazza Ahmed; Abdelaziz Tlili; Rifat Hamoudi; Rania Harati

doi:10.2147/BCTT.S372083

miR-623 Targets Metalloproteinase-1 and Attenuates Extravasation of Brain Metastatic Triple-Negative Breast Cancer Cells

Breast Cancer (Dove Med Press). 2022 Aug 1:14:187-198. doi: 10.2147/BCTT.S372083. eCollection 2022.

Authors

Dua Hammash^{1

2}, Mona Mahfood³, Ghalia Khoder⁴, Munazza Ahmed^{1

2}, Abdelaziz Tlili³, Rifat Hamoudi^{2

5

6}, Rania Harati^{1

2}

Affiliations

¹ Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
² Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
³ Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates.
⁴ Department of Pharmaceutics and Pharmaceutical Technologies, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
⁵ Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
⁶ Division of Surgery and Interventional Science, University College London, London, UK.

Abstract

Background: Most breast cancer-related deaths result from metastasis. Understanding the molecular basis of metastasis is needed for the development of effective targeted and preventive strategies. Matrix metalloproteinase-1 (MMP1) plays an important role in brain metastasis (BM) of triple-negative breast cancer (TNBC) by promoting extravasation of cancer cells across the brain endothelium (BE). MMP1 expression is controlled by endogenous microRNAs. Preliminary bioinformatics analysis has revealed that miR-623, known to target the 3'UTR of MMP1, is significantly downregulated in brain metastatic tumors compared to primary BC tumors. However, the involvement of miR-623 in MMP1 upregulation in breast cancer brain metastatic cells (BCBMC) remains unexplored. Here, we investigated the role of miR-623 in MMP1 regulation and its impact on the extravasation of TNBC cells through the BE in vitro.

Materials and methods: A loss-and-gain of function method was employed to address the effect of miR-623 modulation on MMP1 expression. MMP1 regulation by miR-623 was investigated by real-time PCR, western blot, luciferase and transwell migration assays using an in vitro human BE model.

Results: Our results confirmed that brain metastatic TNBC cells express lower levels of miR-623 compared with cells having low propensity to spread toward the brain. miR-623 binds to the 3'-untranslated region of MMP1 transcript and downregulates its expression. Restoring miR-623 expression significantly decreased MMP1 expression, preserved the endothelial barrier integrity, and attenuated transmigration of BCBMC through the BE.

Conclusion: Our study elucidates, for the first time, the crucial role of miR-623 as MMP1 direct regulator in BCBMC and sheds light on miR-623 as a novel therapeutic target that can be exploited to predict and prevent brain metastasis in TNBC. Importantly, the presents study helps in unraveling a brain metastasis-specific microRNA signature in TNBC that can be used as a guide to personalized metastasis prediction and preventive approach with better therapeutic outcome.

Keywords: brain endothelial junctions; brain endothelium; brain metastasis; matrix metalloproteinase-1; metastasis prediction; microRNA-623; personalized preventive therapy; precision medicine; primary and secondary care; targeted prevention; triple-negative breast cancer.

Grants and funding

This research was funded by the Terry Fox Foundation’s International Run Program, grant number I1032 and the University of Sharjah Competitive Grant, grant number 210111350.