miR-140-5p Attenuates Hypoxia-Induced Breast Cancer Progression by Targeting Nrf2/HO-1 Axis in a Keap1-Independent Mechanism.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Disease Progression*; Breast Neoplasms/*genetics ; Breast Neoplasms/*pathology ; Heme Oxygenase-1/*metabolism ; Kelch-Like ECH-Associated Protein 1/*metabolism ; MicroRNAs/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Tumor Hypoxia/*genetics; Animals ; Apoptosis/genetics ; Base Sequence ; Breast Neoplasms/blood supply ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Cell Survival/genetics ; Disease Models, Animal ; Female ; Gene Expression Regulation, Neoplastic ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice, Inbred NOD ; Mice, SCID ; MicroRNAs/genetics ; Neoplasm Invasiveness ; Neovascularization, Pathologic/genetics ; Signal Transduction ; Tumor Stem Cell Assay ; Mice

Hypoxia and oxidative stress significantly contribute to breast cancer (BC) progression. Although hypoxia-inducible factor 1α (Hif-1α) is considered a key effector of the cellular response to hypoxia, nuclear factor erythroid 2-related factor 2 (Nrf2), a master antioxidant transcription factor, is a crucial factor essential for Hif-1α-mediated hypoxic responses. Hence, targeting Nrf2 could provide new treatment strategies for cancer therapy. miRNAs are potential regulators of hypoxia-responsive genes. In a quest to identify novel hypoxia-regulated miRNAs involved in the regulation of Nrf2, we found that miR-140-5p significantly affects the expression of Nrf2 under hypoxia. In our study, miR-140-5p expression is downregulated in BC cells under hypoxic conditions. We have identified Nrf2 as a direct target of miR-140-5p, as confirmed by the luciferase assay. Knockdown of miR-140-5p under normoxic conditions significantly enhanced Nrf2/HO-1 signaling and tumor growth, angiogenesis, migration, and invasion in BC. In contrast, overexpression of miR-140-5p under hypoxic conditions revealed opposite results. Further silencing Nrf2 expression mimicked the miR-140-5p-induced anti-tumor effects. Consistent with the knockdown of miR-140-5p in vitro, mice injected with miR-140-5p-KD cells exhibited dramatically reduced miR-140-5p levels, increased Nrf2 levels, and increased tumor growth. In contrast, tumor growth is potently suppressed in mice injected with miR-140-5p-OE cells. Collectively, the above results demonstrate the importance of the Nrf2/HO-1 axis in cancer progression and, thus, targeting Nrf2 by miR-140-5p could be a better strategy for the treatment of Nrf2-driven breast cancer progression.

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Keywords: Nrf2; angiogenesis; breast cancer; metastasis; miR-140-5p

0 (HIF1A protein, human)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (Kelch-Like ECH-Associated Protein 1)
0 (MicroRNAs)
0 (Mirn140 microRNA, human)
0 (NF-E2-Related Factor 2)
EC 1.14.14.18 (Heme Oxygenase-1)

Date Created: 20220111 Date Completed: 20220303 Latest Revision: 20240226

20250114

PMC8750786

10.3390/cells11010012

35011574