MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

Abstract

The Runx1 transcription factor, known for its essential role normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx 1 increases concomitant with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant down-regulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mouse, and in human breast cancer cell lines MCF7 and triple negative MDA-MB-231 that represent early and late stage disease, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3′UTR and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion; while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer.

Retracted: LncRNA HOTAIR influences cell growth, migration, invasion, and apoptosis via the miR‐20a‐5p/HMGA2 axis in breast cancer

“…Dysregulation of miRNAs is a major culprit of tumorigenesis in breast cancers because their loss leads to the increased expression of targeted genes, including oncogenes. For example, Browne et al [19] showed that miR-378-mediated suppression of Runx1 alleviated the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells. Playing the role of cancer inhibitor, miR-20a-5p has been found to be downregulated in the majority of cancer cells.…”

miR-378 suppresses the proliferation, migration and invasion of colon cancer cells by inhibiting SDAD1

“…Studies have demonstrated that miR-378 has biological functions that can regulate a variety of tumor cells, including cell proliferation [24], migration and invasion [25], and drug resistance [26]. …”

Molecular mechanisms of suppressor of fused in regulating the hedgehog signalling pathway (Review)

“…Furthermore, microRNA-214 can directly target Sufu mRNA and compromise its function, which facilitates lung adenocarcinoma metastasis and the epithelial-mesenchymal transition (EMT), which are most likely attributed to deregulated Hh signalling (100). Shown here, microRNA-214 and microRNA-378 display tumour-promoting roles, whereas some studies reported tumour-suppressive roles in cervical and breast cancer cells (101,102), implying the intrinsic complexity of multi-cellular organisms and the considerable influence of the microenvironment on gene functions.…”