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

Abstract

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.

Picrasidine I Triggers Heme Oxygenase-1-Induced Apoptosis in Nasopharyngeal Carcinoma Cells via ERK and Akt Signaling Pathways

“…It also plays a cytoprotective role in various types of tumor cells. A previous study found that enhanced Nrf2/HO-1 signaling may contribute to breast cancer progression, and miR-140-5p could be a strategy for nuclear factor erythroid 2-related factor 2 (Nrf2)-driven cancer progression [ 46 ]. In KRAS mutant colorectal cancer, Yang et al revealed that cetuximab, an approved chemotherapeutic agent for metastatic colorectal cancer, promoted RSL3-induced ferroptosis by suppressing the p38/Nrf2/HO-1 signaling pathway [ 47 ].…”

MicroRNAs and Gene Regulatory Networks Related to Cleft Lip and Palate

“…On the other hand, overexpression of miR-140-5p suppresses osteogenic differentiation by targeting SATB2 -mediated ERK1/2 and P38MAPK signaling pathways in human vascular smooth muscle cells [ 89 ]. Moreover, miR-140-5p binds to NRF2, which is a key molecule for anti-oxidative stress and cellular toxicity, enhances the NRF2/HO-1 signaling pathway, and suppresses cell proliferation, cell migration, and angiogenesis in breast cancer cells under hypoxia conditions [ 90 ]. In zebrafish, overexpression of miR-140 results in a cleft between lateral elements of the ethmoid plate, a structural analog of the palate in higher vertebrates, through the suppression of Pdgfra [ 91 ]; in mice, miR-140 null mice exhibit submucous cleft palate with hypoplastic palatal bones [ 92 ].…”

Hypoxia-driven ncRNAs in breast cancer

“…This supports cancer cells’ metabolic adaptation via heightened glycolysis, aiding in proliferation and survival ( 60 ). Alternatively, miR-140-5p may suppress hypoxia-driven tumor growth, angiogenesis, invasion, and metastasis via targeting NRF2, but its expression is downregulated upon hypoxia in breast cancer cells ( 61 ). High‐mobility group box protein 1 (HMGB1) works as a positive regulator of hypoxia by directly regulating HIF1α expression.…”