Abstract
MiR-34a-5p has been implicated in the tumorigenesis and progression of several types of cancer. However, the role of miR-34a-5p in osteosarcoma (OS) remains largely unknown. This study was performed in two multi-chemosensitive (G-292 and MG63.2) and two resistant (SJSA-1 and MNNG/HOS) OS cell lines. MiR-34a-5p promotes OS multi-chemoresistance via its repression of the Delta-like ligand 1 (DLL1) gene, the ligand of the Notch pathway, and thus negatively correlates with OS chemoresistance. The siRNA-mediated repression of the DLL1 gene suppressed cell apoptosis and de-sensitized G-292 and MG63.2 cells, while overexpression of DLL1 sensitized SJSA-1 and MNNG/HOS cells to drug-induced cell death. In agreement with the changes in the drug-induced cell death, the activity of the ATF2/ATF3/ATF4 signaling pathway was significantly altered by a forced reversal of miR-34a-5p or DLL1 levels in OS cells. DLL1 is a target of miR-34a-5p and negatively regulates the multi-chemoresistance of OS. This study suggested that miR-34a-5p, DLL1 and the ATF2/ATF3/ATF4 signaling pathway-associated genes are the potential diagnostic and/or therapeutic targets for an effective chemotherapy of OS. Our results also provide novel insights into the effective chemotherapy for OS patients.
Highlights
Agent for brain tumors[19]
To identify the mechanisms that govern the multi-chemoresistance of OS cells, we performed an RNA-seq-based miR-omic analysis of G-292, MG63.2 and SJSA-1 cells (GEO accession number: GSE89930)
The results showed that a dozen of miRNAs were differentially expressed in the multi-chemoresistant OS cells SJSA-1 and the multi-chemosensitive OS cells G-292 and MG63.2 (Additional File 1A)
Summary
Agent for brain tumors[19]. MiR-34a-5p, derived from miR-34a, has been found to inhibit cell invasion and migration[20,21,22,23], which suggests that miR-34a-5p might be involved in inhibiting tumor recurrence. OS is the most common malignant primary bone tumor in children and adolescents[9,24], and the mechanism for OSchemoresistanceremains largely unknown. We performed a RNA-seq-based-omic analysis to detect the differentially expressed genes in two multi-chemosensitive (G-292 and MG63.2) versus two resistant (SJSA-1 and MNNG/HOS) OS cell lines. We showed that miR-34a-5p promoted OS multi-chemoresistance via repression of the DLL1 gene, a new target of miR-34a-5p. We further performed a systematic analysis of the DLL1 gene for its role in and mechanisms by which the multi-chemoresistance of OS cells is regulated
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