MicroRNA-1246 Mediates Drug Resistance and Metastasis in Breast Cancer by Targeting NFE2L3

Abstract

MicroRNA (miR)-1246 is abnormally expressed and has pro-oncogenic functions in multiple types of cancer. In the present study, its functions in breast cancer and the underlying mechanisms were further elucidated. The clinical relevance of miR-1246 was analyzed and its expression in clinical specimens and cell lines was examined by reverse transcription-quantitat000000ive PCR analysis. FACS was used to detect cell apoptosis and mitochondrial transmembrane potential. A Transwell system was used to detect cell migration and invasion. Luciferase assay was used to confirm the target gene of miR-1246. Xenograft and metastasis mouse models were constructed to determine the function of miR-1246 in vivo. miR-1246 was found to be negatively associated with overall survival in breast cancer. miR-1246 inhibitor could effectively increase the cytotoxicity of docetaxel (Doc) by inducing apoptosis, and impair cell migration and invasion by suppressing epithelial-to-mesenchymal transition. Nuclear factor (erythroid 2)-like factor 3 (NFE2L3) was confirmed as a new target gene of miR-1246, and its overexpression was shown to reduce drug resistance and migration of MDA-MB-231 cells. More importantly, NFE2L3-silencing attenuated the effect of miR-1246 inhibitor. Finally, the inhibition of miR-1246 effectively enhanced the cytotoxicity of Doc in xenografts and impaired breast cancer metastasis. Therefore, miR-1246 may promote drug resistance and metastasis in breast cancer by targeting NFE2L3.

MiR‐1246 is responsible for lung cancer cells‐derived exosomes‐mediated promoting effects on lung cancer stemness via targeting TRIM17

“…Since one miRNA can bind to several transcripts and one transcript can be bound by several miRNAs, we could not exclude that CSC‐derived exosomal miR‐1246 might act through other transcripts in lung cancer stemness, for example, the previous studies have indicated that glioma‐derived exosomal miR‐1246 could induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF‐κB pathways, 25 and exosome miR‐1246 conferred chemoresistance via targeting Cav1/p‐gp/M2‐type macrophage axis in ovarian cancer 26 . In additionally, miR‐1246 was found to contribute drug resistance and metastasis in breast cancer by targeting NFE2L3 27 . Therefore, future works should be conducted to reveal other targets or pathways essential for miR‐1246‐mediated effects on lung cancer stemness.…”

“…26 In additionally, miR-1246 was found to contribute drug resistance and metastasis in breast cancer by targeting NFE2L3. 27 Therefore, future works should be conducted to reveal other targets or pathways essential for miR-1246-mediated effects on lung cancer stemness. Notably, a previous study has shown that miR-1246 was associated with the stemness of lung cancer, this effect is consistent with our results; however, the underlying mechanisms were not revealed in this work, which was supplemented by our work.…”

Circulating miR-1246 and miR-485-3p as Promising Biomarkers of Clinical Response and Outcome in Melanoma Patients Treated with Targeted Therapy

“…A large body of experimental evidence indicates that miR-1246 acts as an oncomiR in most, although not all, types of cancer, and that its expression in the tumor tissue and/or in patients’ plasma/serum can have a diagnostic and prognostic value [ 50 ]. Indeed, with respect to normal adjacent tissue, overexpression of miR-1246 has been described in breast, colorectal, lung and ovarian cancer, as well as in hepatocellular and oral squamous cell carcinoma [ 50 , 51 ]. Moreover, increased levels of miR-1246 have been detected in plasma/serum of patients with those types of cancer as compared with healthy controls [ 50 ].…”

“…Moreover, increased levels of miR-1246 have been detected in plasma/serum of patients with those types of cancer as compared with healthy controls [ 50 ]. In patients with colorectal, lung, esophageal and breast cancer and hepatocellular and oral squamous cell carcinoma, worse disease-free survival and/or OS were also found to be associated with high miR-1246 expression in the tumor tissue and/or in plasma/serum [ 50 , 51 ]. An elevated level of circulating miR-1246 was also demonstrated to be a marker of therapy resistance in colorectal and breast cancer [ 52 , 53 ].…”

“…Similarly, Cooks et al [ 63 ] demonstrated that CRC cells with specific gain of function mutations in p53 can reprogram neighboring macrophages into a tumor-promoting state by releasing miR-1246-enriched exosomes. Several other target genes of miR-1246 involved in its oncogenic activity have been experimentally identified, including, among others, GSK3B (Glycogen Synthase Kinase 3 Beta) in lung cancer cells, SPRED2 (Sprouty Related EVH1 Domain Containing 2) in CRC cells, CADM1 (Cell Adhesion Molecule 1) in hepatocellular carcinoma cells [ 50 ], NFE2L3 (NFE2-like bZIP transcription factor 3) in breast cancer cells [ 51 ].…”