HIF-1α/Malat1/miR-141 Axis Activates Autophagy to Increase Proliferation, Migration, and Invasion in Triple-negative Breast Cancer

Abstract

Background: The mechanism of metastasis-associated lung adenocarcinoma transcript 1 (Malat1) in triple-negative breast cancer (TNBC) is still unclear.

Objective: This study aimed to investigate the role of miR-141-3p and Malat1 in autophagy in TNBC under hypoxia.

Methods: The expression levels of Malat1 and miR-141-3p were detected via quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression levels of hypoxia-inducible factor 1α (HIF-1α), HIF-2α, MMP9, p62 and LC3 were determined via western blotting. A Cell Counting Kit-8 assay was used to detect cell viability, while a Transwell assay to detect cell proliferation and invasion. A luciferase assay was used to confirm the relationship between Malat1 and miR-141-3p.

Results: A significant increase was observed in the expression level of Malat1 and the autophagic activity in TNBC tissues and cells. The expression level of Malat1 was higher in a hypoxic environment, which can significantly promote the proliferation, migration, and invasion of TNBC cells by activating autophagy. HIF-1α, but not HIF-2α, was identified to induce the upregulation of Malat1 in TNBC cells. The dual-luciferase assay results identified a miR-141-binding site in Malat1. Malat1 knockdown and miR-141-3p overexpression were demonstrated to significantly inhibit autophagy, thereby inhibiting cell proliferation, invasion, and migration. Moreover, hypoxia can inhibit the effect of miR-141-3p on TNBC cells.

Conclusion: miR-141-3p could suppress autophagy and inhibit proliferation, migration, and invasion by targeting Malat1 in TNBC cells under hypoxia. The existence of the HIF-1α/Malat1/miR-141 axis plays a vital role in the development of TNBC and may be a target for the diagnosis and treatment of TNBC.

Keywords: HIF-1α; Malat1; TNBC; autophagy; invasion; miR-141; migration; proliferation.