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MARK2 enhances cisplatin resistance via PI3K/AKT/NF-?B signaling pathway in osteosarcoma cells.

ABSTRACT: Osteosarcoma is the most common primary bone malignancy found in children and young adults. Chemotherapy resistance, especially to cisplatin, presents a major clinical challenge in the treatment and prognosis of osteosarcoma. New biomarkers and mechanisms of cisplatin resistance in osteosarcoma are urgently needed due to poor survival outcomes and currently inadequate treatments. In this study, we investigate the role and potential mechanisms of microtubule-affinity regulating kinase2 (MARK2) during osteosarcoma cisplatin resistance. Gene Expression Omnibus dataset analyses indicated that high MARK2 expression was associated with poor prognosis and may positively correlate with chemoresistance. Moreover, we showed that MARK2 was significantly upregulated in osteosarcoma cells compared with normal cells. The overexpression and inhibition of MARK2 promoted and suppressed, respectively, cisplatin resistance in osteosarcoma cells in vitro and in vivo. Mechanistically, MARK2 overexpression enhanced P-glycoprotein expression and decreased cell apoptosis through PI3K/AKT/NF-?B signaling pathway activation, resulting in cisplatin resistance. Our results suggest that high MARK2 expression can enhance cisplatin resistance in osteosarcoma cells, supporting the potential of MARK2 as a new therapeutic target and biomarker for predicting cisplatin resistance in osteosarcoma.

SUBMITTER: Wei X

PROVIDER: S-EPMC7270034 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MARK2 enhances cisplatin resistance via PI3K/AKT/NF-κB signaling pathway in osteosarcoma cells.

Wei Xianfu X Xu Liang L Jeddo Salim Fa SF Li Ka K Li Xin X Li Jianmin J

American journal of translational research 20200515 5

Osteosarcoma is the most common primary bone malignancy found in children and young adults. Chemotherapy resistance, especially to cisplatin, presents a major clinical challenge in the treatment and prognosis of osteosarcoma. New biomarkers and mechanisms of cisplatin resistance in osteosarcoma are urgently needed due to poor survival outcomes and currently inadequate treatments. In this study, we investigate the role and potential mechanisms of microtubule-affinity regulating kinase2 (MARK2) du ...[more]

PMID: 32509178

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Project description:BackgroundMicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional and/or translational level and are deeply involved in the pathogenesis of several types of cancers. Specifically, microRNA-221 (miR-221) is overexpressed in many human cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-221 in human osteosarcoma has not been totally elucidated. In the present study, the effects of miR-221 on osteosarcoma and the possible mechanism by which miR-221 affected the survival, apoptosis, and cisplatin resistance of osteosarcoma were investigated.Methodology/principal findingsReal-time quantitative PCR analysis revealed miR-221 was significantly upregulated in osteosarcoma cell lines than in osteoblasts. Both human osteosarcoma cell lines SOSP-9607 and MG63 were transfected with miR-221 mimic or inhibitor to regulate miR-221 expression. The effects of miR-221 were then assessed by cell viability, cell cycle analysis, apoptosis assay, and cisplatin resistance assay. In both cells, upregulation of miR-221 induced cell survival and cisplatin resistance and reduced cell apoptosis. In addition, knockdown of miR-221 inhibited cell growth and cisplatin resistance and induced cell apoptosis. Potential target genes of miR-221 were predicted using bioinformatics. Moreover, luciferase reporter assay and western blot confirmed that PTEN was a direct target of miR-221. Furthermore, introduction of PTEN cDNA lacking 3'-UTR or PI3K inhibitor LY294002 abrogated miR-221-induced cisplatin resistance. Finally, both miR-221 and PTEN expression levels in osteosarcoma samples were examined by using real-time quantitative PCR and immunohistochemistry. High miR-221 expression level and inverse correlation between miR-221 and PTEN levels were revealed in osteosarcoma tissues.Conclusions/significanceThese results for the first time demonstrate that upregulation of miR-221 induces the malignant phenotype of human osteosarcoma whereas knockdown of miR-221 reverses this phenotype, suggesting that miR-221 could be a potential target for osteosarcoma treatment.

Dataset Information

MARK2 enhances cisplatin resistance via PI3K/AKT/NF-?B signaling pathway in osteosarcoma cells.

Publications

MARK2 enhances cisplatin resistance via PI3K/AKT/NF-κB signaling pathway in osteosarcoma cells.

Similar Datasets

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