MiR ‐182‐3p targets TRF2 and impairs tumor growth of triple‐negative breast cancer

Abstract

The telomeric repeat‐binding factor 2 (TRF2) is a telomere‐capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti‐cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA‐based approach to reduce TRF2 expression. By performing a high‐throughput luciferase screening of 54 candidate miRNAs, we identified miR‐182‐3p as a specific and efficient post‐transcriptional regulator of TRF2. Ectopic expression of miR‐182‐3p drastically reduced TRF2 protein levels in a panel of telomerase‐ or alternative lengthening of telomeres (ALT)‐positive cancer cell lines. Moreover, miR‐182‐3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR‐182‐3p impaired tumor growth in triple‐negative breast cancer (TNBC) models, including patient‐derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs‐miR‐182‐3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.

MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice

“…Furthermore, oral delivery of LNPs-mRNA demonstrated protective effects in a mouse model of acute colitis induced by DSS . Additionally, LNPs-miRNA-193b exhibited significant delays in leukemia propagation in acute myeloid leukemia xenograft models, while LNPs containing miR-182 impaired tumor growth in triple-negative breast cancer models. , Optimal LNPs should maximize the probability of reaching specific cell types within a target organ and minimize the toxicity and immunogenicity of cargoes . To enhance the stability, transfection efficacy, and safety of LNPs, various optimization strategies such as component selection, surface modification, suitable administration routes, and design of bioinspired compositions and structures have been explored .…”

METTL14/miR‐29c‐3p axis drives aerobic glycolysis to promote triple‐negative breast cancer progression though TRIM9‐mediated PKM2 ubiquitination

“…Pyruvate kinase (PK) is the ultimate rate‐limiting enzyme of glycolysis 24 . PKM2 is a key enzyme in Warburg effect 25,26 . PKM2 has two conformations in cells: high enzyme activity tetramer and low enzyme activity dimer 27 .…”

Identification of Mir-182-3p/FLI-1 Axis as a Key Signaling in Immune Response in Cervical Cancer: A Comprehensive Bioinformatic Analysis

“…Some studies have investigated the role of miR-182-3p in several types of cancer including osteosarcoma [ 6 ], lung [ 7 ], oral [ 8 ], breast [ 9 , 10 ], and ovarian cancer [ 11 ]. In breast cancer, miR-182-3p was found to decrease TRF2 abundance at the telomere, regulating its structure and function and promoting telomeric and pericentromeric DNA damage [ 9 ]. In addition, the circulating levels of miR-182-3p were increased in the sera and peripheral blood mononuclear cells with high predictive value [ 10 ].…”

“…In addition, the circulating levels of miR-182-3p were increased in the sera and peripheral blood mononuclear cells with high predictive value [ 10 ]. The above suggests miR-182-3p as a biomarker and therapeutic target [ 9 , 10 ].…”