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The miR-23a/27a/24-2 cluster promotes postoperative progression of early-stage non-small cell lung cancer.

ABSTRACT: Even with optimal surgery, many early-stage non-small cell lung cancer (NSCLC) patients die of recurrence. Unfortunately, there are no precise predictors for postoperative recurrence in early-stage NSCLC, and the recurrence mechanism is still unclear. In this study, we found that simultaneous overexpression of all miRNAs in the miR-23a/27a/24-2 cluster was closely associated with postoperative recurrence, β-catenin upregulation and promoter methylation of p16 and CDH13 in early-stage NSCLC patients. In addition, in vitro and in vivo experiments show that overexpression or inhibition of all miRNAs in the miR-23a/27a/24-2 cluster significantly stimulated or inhibited NSCLC cell stemness, tumorigenicity and metastasis. Furthermore, we demonstrated that the miR-23a/27a/24-2 cluster miRNAs activated Wnt/β-catenin signaling by targeting their suppressors and stimulated promoter methylation-induced silencing of p16 and CDH13 by affecting DNA methylation-related genes expression. Our findings suggest that simultaneous high expression of all miRNAs in the miR-23a/27a/24-2 cluster represents a new biomarker for predicting postoperative recurrence in early-stage NSCLC. The miR-23a/27a/24-2 cluster miRNAs stimulate early-stage NSCLC progression through simultaneously stimulating Wnt/β-catenin signaling, and promoter methylation-induced tumor suppressor genes silencing. In addition, simultaneous inhibition of all miRNAs in the miR-23a/27a/24-2 cluster may be a useful strategy for treatment of early-stage NSCLC recurrence.

SUBMITTER: Fan X

PROVIDER: S-EPMC8760463 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MicroRNA cluster mirn23a has previously been shown to promote myeloid development at the expense of lymphoid development in overexpression and knockout mouse models. This polarization is observed early in hematopoietic development, with an increase in common lymphoid progenitors (CLPs) and a decrease in all myeloid progenitor subsets in adult bone marrow. The pool size of multipotential progenitors (MPPs) is unchanged; however, in this report we observe by flow cytometry that polarized subsets of MPPs are changed in the absence of mirn23a. Additionally, in vitro culture of MPPs and sorted MPP transplants showed that these cells have decreased myeloid and increased lymphoid potential in vitro and in vivo. We investigated the mechanism by which mirn23a regulates hematopoietic differentiation and observed that mirn23a promotes myeloid development of hematopoietic progenitors through regulation of hematopoietic transcription factors and signaling pathways. Early transcription factors that direct the commitment of MPPs to CLPs (Ikzf1, Runx1, Satb1, Bach1 and Bach2) are increased in the absence of mirn23a miRNAs as well as factors that commit the CLP to the B cell lineage (FoxO1, Ebf1, and Pax5). Mirn23a appears to buffer transcription factor levels so that they do not stochastically reach a threshold level to direct differentiation. Intriguingly, mirn23a also inversely regulates the PI3 kinase (PI3K)/Akt and BMP/Smad signaling pathways. Pharmacological inhibitor studies, coupled with dominant active/dominant negative biochemical experiments, show that both signaling pathways are critical to mirn23a's regulation of hematopoietic differentiation. Lastly, consistent with mirn23a being a physiological inhibitor of B cell development, we observed that the essential B cell transcription factor EBF1 represses expression of mirn23a. In summary, our data demonstrates that mirn23a regulates a complex array of transcription and signaling pathways to modulate adult hematopoiesis.

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The miR-23a/27a/24-2 cluster promotes postoperative progression of early-stage non-small cell lung cancer.

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