MiR-34a regulates the invasive capacity of canine osteosarcoma cell lines

Abstract

BackgroundOsteosarcoma (OSA) is the most common bone tumor in children and dogs; however, no substantial improvement in clinical outcome has occurred in either species over the past 30 years. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and play a fundamental role in cancer. The purpose of this study was to investigate the potential contribution of miR-34a loss to the biology of canine OSA, a well-established spontaneous model of the human disease.Methodology and principal findingsRT-qPCR demonstrated that miR-34a expression levels were significantly reduced in primary canine OSA tumors and canine OSA cell lines as compared to normal canine osteoblasts. In canine OSA cell lines stably transduced with empty vector or pre-miR-34a lentiviral constructs, overexpression of miR-34a inhibited cellular invasion and migration but had no effect on cell proliferation or cell cycle distribution. Transcriptional profiling of canine OSA8 cells possessing enforced miR-34a expression demonstrated dysregulation of numerous genes, including significant down-regulation of multiple putative targets of miR-34a. Moreover, gene ontology analysis of down-regulated miR-34a target genes showed enrichment of several biological processes related to cell invasion and motility. Lastly, we validated changes in miR-34a putative target gene expression, including decreased expression of KLF4, SEM3A, and VEGFA transcripts in canine OSA cells overexpressing miR-34a and identified KLF4 and VEGFA as direct target genes of miR-34a. Concordant with these data, primary canine OSA tumor tissues demonstrated increased expression levels of putative miR-34a target genes.ConclusionsThese data demonstrate that miR-34a contributes to invasion and migration in canine OSA cells and suggest that loss of miR-34a may promote a pattern of gene expression contributing to the metastatic phenotype in canine OSA.

Synergistic effect of microRNA and albumin-bound nanoparticles for inhibition of glioblastoma cancer cell proliferation

“…MiR-34a expression is diminished in most of the human cancers, in which it counteracts tumor progression (Slabáková, Eva et al, 2017). MiR-34a belongs to the miR-34 family consisting of miR-34a, b and c. Although miR-34a derives from a polycistronic transcript, miR-34b and miR-34c share a common transcript at 11q23 loci (Lopez et al, 2018). MiR-34a is an abundant miRNA, ubiquitously expressed in normal human tissue, whereas miR-34b/c expression patterns is more tissue specific.…”

Epigenetic Mechanisms in Canine Cancer

“…Ten miRNA (cfa-let-7c, cfa-miR-10b, cfa-miR-26a, cfa-miR-26b, cfa-miR-29c, cfa-miR-30a, cfamiR-30b, cfa-miR-30c, cfa-miR-148a, and cfa-miR-299) were validated and showed significant different expression in metastatic and non-metastatic mammary tumors (130). MiR-9 was found to be overexpressed and associated with metastasis in mast cells tumors and osteosarcoma (121,122), while miR-34a also appeared to be associated with invasion ability in canine osteosarcoma cell lines (131). Some miRNAs also correlated with tumor grading in canine splenic lymphoma (132).…”

MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

“…miR‐34a was shown to contribute to senescence regulation triggered via ionizing radiation in human non‐small cell lung cancer cells . miR‐34a also affects the migration and invasion of osteosarcoma cells, and miR‐34a exhaustion could enhance their expression pattern, resulting in osteosarcoma metastasis . However, more efforts are needed to examine the mechanism underlying miR‐34a‐mediated modulation of AML stem cell features.…”