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Abstract
BackgroundChemoresistance hinders the curative cancer chemotherapy. MicroRNAs (miRNAs) are key players in diverse biological processes including the chemoresistance of cancers.MethodsA RNA-seq-based miR-omic analysis of osteosarcoma (OS) cells was performed to detect the levels of miR-34a-5p. Bioinformatics analysis revealed that AGTR1 is one of the target genes of miR-34a-5p. The mRNA and protein levels of AGTR1 were detected in both the miR-34a-5p-mimic transfected G-292 and miR-34a-5p-antagomiR transfected SJSA-1 cells. The involvement of AGTR1 with OS chemoresistance was validated by the experiments with siRNA-mediated repression or overexpression of the AGTR1 gene.ResultsWe showed that miR-34a-5p promotes the multi- chemoresistance of OS. The angiotensin II type 1 receptor (AGTR1) gene, is one of the targets of miR-34a-5p in OS and thus negatively correlates with OS chemoresistance by systematic investigations of a multi-drug sensitive (G-292) and resistant (SJSA-1) OS cell lines. Down-regulation of the AGTR1 expression by siRNA passivates G-292 cells and suppresses cell apoptosis, while over-expression of AGTR1 sensitizes SJSA-1 cells and thus promotes the drug-triggered cell death.ConclusionsThe miR-34a-5p and its target gene AGTR1 are the potential targets for an effective chemotherapy of OS. Our results also provide novel insights into the effective chemotherapy for OS patients.
Highlights
In hepatocellular carcinoma (HCC) cells, miR-193a-3p contributes to the 5-FU resistance regulated by the DNA methylation in particular via repressing SRSF2 expression [10]
We showed that miR-34a-5p promotes the OS multi-chemoresistance via its repression of the AGTR1 gene, a new target of miR-34a-5p
AGTR1 negatively regulates the multi-chemoresistance of OS Our previous result suggested that G-292 and SJSA-1 cell lines are the multi-chemosensitive and multi-drug resistant OS cell lines, respectively [29]
Summary
MicroRNAs (miRNAs) are key players in diverse biological processes including the chemoresistance of cancers. MiRNAs regulate the expression of a variety of target genes and their dysregulation is closely related to the development of diseases including cancer. The abnormal expression of miRNAs in cancer contributes to almost every field of tumor pathology [2, 3], including drug resistance [4], which remains a major obstacle to effective therapy of patients [5]. Our knowledge of the multichemoresistance of cancers remains very poor due to the diverse mechanisms that induce the multi-chemoresistance [7, 8]. Overexpressed miR-21 in colorectal cancer tissues contributes to the resistance to 5-FU [11]. The miR-140 participates in the drug resistance to osteosarcoma (OS)
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