lncRNA NEAT1 Interacts with miR-218 and miR-146b to Promote the Progression of Breast Cancer
Introduction: Despite the availability of new primary and adjuvant therapies, certain breast cancers are refractory and continue to progress.1,2 The lncRNA, nuclear-enriched abundant transcript 1 (NEAT1) has been identified to be dysregulated in various solid cancers and can induce breast cancer progression by associating with various miRNAs in the nucleus.3,4 A recent study set out to further investigate the interaction between NEAT1 and miR-218 and how this interaction might affect breast cancer promoting genes. TPD52 is a conserved protein that has been shown to have elevated mRNA and protein levels in prostate, breast, and colorectal cancer. It’s interaction of NEAT1 and miR-218 was shown to play a role in breast cancer proliferation and migration.4 Methods: To confirm lncRNA dysregulation in BC cells, qRT-PCR was used on human tumor specimens and adjacent non-tumor tissues.2,3,4 Breast cancer cell lines, MCF-7 and SK-BR-3 were collected along with normal breast cell line, MCF-10A from surgical resections of patients.2 MCF-7 and SK-BR-3 cells were transfected with si-NC, si-NEAT1-1, or si-NEAT1-1 + miR-218 inhibitor.2 The CCK8 assay and Transwell cell invasion assay were used to assess the proliferation and invasion of breast cancer cells.2,4 A luciferase assay was used to determine the functional relationship between the cancer cells transfected with NEAT1 and miR-218.2,4 To demonstrate the oncogenic nature of TPD52, the effect of overexpression or knockdown was observed in BT474 and MDA-MB-231 breast cancer cell lines.4 StarBase database was used for further analysis of expression values and binding sites of miR-218-5p, TPD52, and NEAT1.4 A wound healing assay, colony formation assay, and 5’-ethynyl-2’ deoxyuridine assay were used to test BT474 and MDA-MB-231 migration, colony formation, and proliferation in vitro.4 For the in vivo tumor formation assay, shRNA-mediated silencing of TPD52 was performed by lentiviral infection of MDA-MB-231 cells.4 Suspension containing 1×106 cells was injected on the right flank of the mice and tumor growth was observed for 30 days and tumor volume was measured every 4 days.4 Results: Expression of lncRNA NEAT1 was found to be significantly upregulated in human BC tissues compared to adjacent non-tumor tissues.2,3,4 Further, these data indicate that NEAT1 expression is negatively associated with the level of miR-218 expression and that NEAT1 acts as a ceRNA for miR-218 leading to increased cell proliferation and invasion of breast cancer cells. NEAT1 expression was up-regulated in the presence of the miR-218 inhibitor and down-regulated in the presence of the miR-218 mimic, indicating that NEAT1 mediated regulation of miR-218 in breast cancer cells.2 It was revealed that overexpression of TPD52 promoted BT474 migration and that TPD52 knockdown suppressed MDA-MB-231 cell migration in vitro and in vivo. miR-218-5p inhibition increased breast cancer cell proliferation and migration, however, silencing of TPD52 decreased these stimulatory effects of miR-218-5p inhibition. This indicates that miR-218-5p regulation of TPD52 expression can inhibit breast cancer cell proliferation and migration. Since miR-218 negatively regulated TPD52, it was shown that NEAT1 can increase TPD52 expression by binding and repressing miR-218. This promotes the proliferation and migration of breast cancer cells.5 Conclusion: Upregulation of NEAT1, as seen in breast cancer cells, suppresses the action of miR-218 by directly binding to the miRNA response element and preventing suppression of oncogenic gene products, thereby promoting breast cancer cell migration, proliferation, and metastasis. The ability of NEAT1 to directly interact with many miRNAs and secondarily effect other pro-cancer genes makes it a promising therapeutic target for the treatment of human breast cancer.
- Zhang M, Wu WB, Wang ZW, Wang XH. lncRNA NEAT1 is closely related with progression of breast cancer via promoting proliferation and EMT. Eur Rev Med Pharmacol Sci. 2017;21(5):1020-1026.
- Zhao D, Zhang Y, Wang N, Yu N. NEAT1 negatively regulates miR-218 expression and promotes breast cancer progression. Cancer Biomark. 2017;20(3):247-254. doi:10.3233/CBM-170027
- Shin VY, Chen J, Cheuk IWY, et al. Long non-coding RNA NEAT1 confers oncogenic role in triple-negative breast cancer through modulating chemoresistance and cancer stemness. Cell Death Dis. 2019;10(4):270. doi:10.1038/s41419-019-1513-5
- Ren J, Chen Y, Kong W, Li Y, Lu F. Tumor protein D52 promotes breast cancer proliferation and migration via the long non-coding RNA NEAT1/microRNA-218-5p axis. Ann Transl Med. 2021;9(12):1008-1008. doi:10.21037/atm-21-2668