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The expression of miRNAs is associated with tumour genome instability and predicts the outcome of ovarian cancer patients treated with platinum agents.

ABSTRACT: miRNAs, a class of short but stable noncoding RNA molecules, have been revealed to play important roles in the DNA damage response (DDR). However, their functions in cancer genome instability and the consequent clinical effect as the response to chemotherapy have not been fully elucidated. In this study, we utilized multidimensional TCGA data and the known miRNAs involved in DDR to identify a miRNA-regulatory network that responds to DNA damage. Additionally, based on the expression of ten miRNAs in this network, we developed a 10-miRNA-score that predicts defects in the homologous recombination (HR) pathway and genome instability in ovarian cancer. Importantly, consistent with the association between HR defects and improved response to chemotherapeutic agents, the 10-miRNA-score predicts the outcome of ovarian cancer patients treated with platinum agents, with a surprisingly better performance than the indexes of DNA damage. Therefore, our study demonstrates the implication of miRNA expression on cancer genome instability and provides an alternative method to identify DDR defects in patients who show the best effect with platinum drug treatment.

SUBMITTER: Wang T

PROVIDER: S-EPMC5677022 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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The expression of miRNAs is associated with tumour genome instability and predicts the outcome of ovarian cancer patients treated with platinum agents.

Wang Tianzhen T Wang Guangyu G Zhang Xiaoxiao X Wu Di D Yang Lei L Wang Guangyou G Hao Dapeng D

Scientific reports 20171107 1

miRNAs, a class of short but stable noncoding RNA molecules, have been revealed to play important roles in the DNA damage response (DDR). However, their functions in cancer genome instability and the consequent clinical effect as the response to chemotherapy have not been fully elucidated. In this study, we utilized multidimensional TCGA data and the known miRNAs involved in DDR to identify a miRNA-regulatory network that responds to DNA damage. Additionally, based on the expression of ten miRNA ...[more]

PMID: 29116111

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Project description:Although epithelial ovarian cancers (EOCs) are initially treated with platinum-based chemotherapy, EOCs vary in platinum responsiveness. Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive EOC cell lines is valuable for development of therapeutic strategies to avoid platinum inefficacy and to exploit platinum sensitivity. TOV-21G devoid of FANCF expression, OV-90 and SKOV-3 were employed as examples of platinum-sensitive, platinum-intermediate and platinum-resistant cell lines, respectively. Antineoplastic agents examined included mitomycin C, doxorubicin, etoposide, gemcitabine, chlorambucil, paclitaxel, triapine and X-rays. Their effectiveness against cell lines was analyzed by clonogenic assays. Cytotoxic profiles of mitomycin C and carboplatin were similar, with mitomycin C exhibiting greater potency and selectivity against TOV-21G than carboplatin. Cytotoxic profiles of doxorubicin, etoposide and X-rays overlapped with that of carboplatin, while OV-90 overexpressing Rad51 was more resistant to chlorambucil than SKOV-3. The efficacy of paclitaxel and triapine was independent of platinum sensitivity or resistance. Consistent with these cytotoxic profiles, cisplatin/mitomycin C, triapine, and paclitaxel differed in the capacity to induce phosphorylation of H2AX, and produced unique inhibitory patterns of DNA/RNA syntheses in HL-60 human leukemia cells. Paclitaxel and triapine in combination produced additive antitumor effects in M109 murine lung carcinoma. In conclusion, mitomycin C is potentially more effective against Fanconi anemia pathway-deficient EOCs than carboplatin. Doxorubicin and etoposide, because of their overlapping cytotoxic properties with carboplatin, are unlikely to be efficacious against platinum-refractory EOCs. Paclitaxel and triapine are effective regardless of platinum sensitivity status, and promising in combination for both platinum-sensitive and platinum-refractory EOCs.

Dataset Information

The expression of miRNAs is associated with tumour genome instability and predicts the outcome of ovarian cancer patients treated with platinum agents.

Publications

The expression of miRNAs is associated with tumour genome instability and predicts the outcome of ovarian cancer patients treated with platinum agents.

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