Dataset Information

Overexpression of Rad51 predicts poor prognosis and silencing of Rad51 increases chemo-sensitivity to doxorubicin in neuroblastoma.

ABSTRACT: Outcome for children with high-risk neuroblastoma (NB) remains suboptimal. Recurrence and metastasis caused by chemo-resistance is an underlying mechanism contributing to the poor prognosis. Aberrant expression of Rad51 is implicated in both radio- and chemo-sensitivity in many human malignancies. However, its clinical significance and relationship with chemo-sensitivity in NB remain undefined. In this study, Rad51 expression was first evaluated in 70 surgically resected NB specimens by immunochemistry using tissue microarray and the correlation with clinic-pathologic features including survival was assessed. We then conducted microarray-based search with the Tumor Neuroblastoma public datasets to validate the immunochemistry results. Furthermore, the role of Rad51 in drug sensitivity was studied by using short hairpin RNA in the human NB SK-N-BE(2) and SH-SY5Y cells with treatment of doxorubicin. Our findings demonstrated for the first time that Rad51 is a prognostic marker in NB and down-regulation of Rad51 can lead to chemo-sensitizing effect in human NB cells.

SUBMITTER: Xu Y

PROVIDER: S-EPMC6789219 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Overexpression of Rad51 predicts poor prognosis and silencing of Rad51 increases chemo-sensitivity to doxorubicin in neuroblastoma.

Xu Yonghu Y Chen Kai K Cai Yuanxia Y Cheng Cheng C Zhang Zihan Z Xu Guofeng G

American journal of translational research 20190915 9

Outcome for children with high-risk neuroblastoma (NB) remains suboptimal. Recurrence and metastasis caused by chemo-resistance is an underlying mechanism contributing to the poor prognosis. Aberrant expression of Rad51 is implicated in both radio- and chemo-sensitivity in many human malignancies. However, its clinical significance and relationship with chemo-sensitivity in NB remain undefined. In this study, Rad51 expression was first evaluated in 70 surgically resected NB specimens by immunoch ...[more]

PMID: 31632548

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Project description:Chemotherapy is the most common treatment for cancer. However, multidrug resistance (MDR) remains a major obstacle to effective chemotherapy, limiting the efficacy of both conventional chemotherapeutic and novel biologic agents. The constitutive androstane receptor (CAR), a xenosensor, is a key regulator of MDR. It functions in xenobiotic detoxification by regulating the expression of phase I drug-metabolizing enzymes and ATP-binding cassette (ABC) transporters, whose overexpression in cancers and whose role in drug resistance make them potential therapeutic targets for reducing MDR. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes, including drug resistance. Here, we report the inversely related expression of miR-137 and CAR in parental and doxorubicin-resistant neuroblastoma cells, wherein miR-137 is downregulated in resistant cells. miR-137 overexpression resulted in downregulation of CAR protein and mRNA (via mRNA degradation); it sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis and increased G2-phase cell cycle arrest) and reduced the in vivo growth rate of neuroblastoma xenografts. We observed similar results in cellular models of hepatocellular and colon cancers, indicating that the doxorubicin-sensitizing effect of miR-137 is not tumor type-specific. Finally, we show for the first time a negative feedback loop whereby miR-137 downregulates CAR expression and CAR downregulates miR-137 expression. Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells. These findings demonstrate that miR-137 is a crucial regulator of cancer response to doxorubicin treatment, and they identify miR-137 as a highly promising target to reduce CAR-driven doxorubicin resistance.

Dataset Information

Overexpression of Rad51 predicts poor prognosis and silencing of Rad51 increases chemo-sensitivity to doxorubicin in neuroblastoma.

Publications

Overexpression of Rad51 predicts poor prognosis and silencing of Rad51 increases chemo-sensitivity to doxorubicin in neuroblastoma.

Similar Datasets

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