MicroRNA-1246 suppresses the metastasis of breast cancer cells by targeting the DYRK1A/PGRN axis to prevent the epithelial-mesenchymal transition

Abstract

Objective. Breast cancer is one of the most common malignant and highly heterogeneous tumors in women. MicroRNAs (miRNAs), such as miR-1246, play important roles in various types of malignant cancers, including triple-negative breast cancer (TNBC). However, the biological role of miR-1246 in TNBChas not yet been fully elucidated. In this study, we studied the role of miR-1246 in the occurrence and development of TNBC and its mechanism of action.Methods. Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays were performed to observe the effects of miR-1246 on TNBC cell proliferation, migration, and invasion, respectively. The expression of epithelial-mesenchymal transition (EMT) markers was detected by western blotting. Dual luciferase reporter assays were performed to determine whether DYRK1A is a novel target of miR-1246. In addition, an immunoprecipitation experiment was performed to verify the binding of DYRK1A to PGRN. Rescue experiments were performed to determine whether DYRK1A is a novel target of miR-1246 and whether miR-1246 suppresses the metastasis of breast cancer cells by targeting the DYRK1A/PGRN axis to prevent the epithelial-mesenchymal transition.Results. Our results show that miR-1246 suppresses the proliferation, migration, and invasion of TNBC cells and that DYRK1A is a novel target of miR-1246. MiR-1246 plays a suppressive role in the regulation of the EMT of TNBC cells by targeting DYRK1A. DYRK1A mediates the metastasis of triple-negative breast cancer via activation of the EMT. We identi ed PGRN as a novel DYRK1A-interacting protein. DYRK1A and PGRN act together to regulate the occurrence and development of breast cancer through miR-1246. Conclusion. miR-1246 attenuates TNBC cell invasion and the EMT by targeting the DYRK1A/PGRN axis.Our data suggest that miR-1246 may be used to develop novel early-stage diagnostic and therapeutic strategies for TNBC.

Targeting the DYRK1A kinase prevents cancer progression and metastasis and promotes cancer cells response to G1/S targeting chemotherapy drugs

“…Using preclinical models of colon cancer in vivo, we also found that DYRK1A inhibition not only led to restriction of tumor growth but also significantly inhibited the spread of the tumors to distant secondary organs such as the lungs, liver and kidney. These findings clearly define DYRK1A as a pro-tumorigenic and pro-metastatic kinase and could explain results from a recent study in which microRNA miR-1246 was found to suppress epithelial-to-mesenchymal transition (EMT) and metastasis by targeting DYRK1A in metastatic breast cancer 42 . Similarly, DYRK1A was found to induce EMT by activating STAT3 and SMAD in hepatocellular carcinoma 43 .…”

Organotypic 3D Cell-Architecture Impacts the Expression Pattern of miRNAs–mRNAs Network in Breast Cancer SKBR3 Cells

“…However, some of these downregulated DE-microRNAs, such as hsa-miR-449a, hsa-miR-4739, hsa-miR-449a, hsa-miR-34c-5p, hsa-miR-219a-5p, hsa-miR-34c-5p, hsa-miR-34c-5p, hsa-miR-219a-5p, has-miR-5091, and has-miR-943 have been previously associated with poor breast cancer prognosis [39], among other processes [40][41][42][43][44][45]. In addition, the upregulated miRNAs hsa-miR-127-3p, hsa-miR-223-3p, has-miR-4458, hsa-miR-10b-5p, hsa-miR-381-3p, has-miR-451a, hsa-miR-142-5p, has-miR-1246, hsa-miR-375-3p, and hsa-miR-4739, have been associated with several breast cancer processes, such as malignancy [40,46], tumor progression [41], and poor prognosis [47], as well as, cancer hallmarks' activation as proliferation [48,49], apoptosis [49] and metastasis [49][50][51], among others [51][52][53][54][55][56].…”

MicroRNAs associated with postoperative outcomes in patients with limited stage neuroendocrine carcinoma of the esophagus

“…As for biological pathways of these m iR NAs, miR-1246 has been reported to play a suppressive role in the regulation of the EMT by targeting dual-specificity tyro-sine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) and progranulin (PGRN) in a breast cancer cell line (36). DYRK1A is linked to a number of cellular processes, including self-renewal, DNA damage, apoptosis, and cancer stem cell maintenance (37).…”