Dataset Information

MiR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF-?B in high-grade serous ovarian carcinoma.

ABSTRACT: Activation of mammalian target of rapamycin (mTOR) signaling pathway is associated with poor prognosis of epithelial ovarian cancer. The TSC1-TSC2 complex is a critical negative regulator of mTOR signaling. Here, we demonstrated that TSC1 was frequently downregulated in high-grade serous ovarian carcinoma (HGSOC) and low TSC1 expression level is associated with advanced tumor stage. We next identified miR-130a to be a negative regulator of TSC1 by targeting its 3'UTR. miR-130a was overexpressed in HGSOC and could drive proliferation and invasion/metastasis of ovarian cancer cells. miR-130a could also attenuate rapamycin/starvation-induced autophagy. Ectopic TSC1 expression could block the effects of miR-130a on cell proliferation, migration and autophagy. Finally, we found that miR-130a expression could be upregulated by inflammatory factors and was transactivated by NF-?B. Therefore, our findings establish a crosstalk between inflammation and mTOR signaling that is mediated by miR-130a, which might have a pivotal role in the initiation and progression of HGSOC.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5686346 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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miR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF-κB in high-grade serous ovarian carcinoma.

Wang Yuqiong Y Zhang Xiyu X Tang Wei W Lin Zhenghong Z Xu Limei L Dong Ruifen R Li Yinuo Y Li Jieyin J Zhang Zaixin Z Li Xiangzhi X Zhao Ling L Wei Jian-Jun JJ Shao Changshun C Kong Beihua B Liu Zhaojian Z

Cell death and differentiation 20170811 12

Activation of mammalian target of rapamycin (mTOR) signaling pathway is associated with poor prognosis of epithelial ovarian cancer. The TSC1-TSC2 complex is a critical negative regulator of mTOR signaling. Here, we demonstrated that TSC1 was frequently downregulated in high-grade serous ovarian carcinoma (HGSOC) and low TSC1 expression level is associated with advanced tumor stage. We next identified miR-130a to be a negative regulator of TSC1 by targeting its 3'UTR. miR-130a was overexpressed ...[more]

PMID: 28800130

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Project description:High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.

Project description:BackgroundDevelopment of resistance against first line drug therapy including cisplatin and paclitaxel in high-grade serous ovarian cancer (HGSOC) presents a major challenge. Identifying drug candidates breaking resistance, ideally combined with predictive biomarkers allowing precision use are needed for prolonging progression free survival of ovarian cancer patients. Modeling of molecular processes driving drug resistance in tumor tissue further combined with mechanism of action of drugs provides a strategy for identification of candidate drugs and associated predictive biomarkers.ResultsConsolidation of transcriptomics profiles and biomedical literature mining results provides 1242 proteins linked with ovarian cancer drug resistance. Integrating this set on a protein interaction network followed by graph segmentation results in a molecular process model representation of drug resistant HGSOC embedding 409 proteins in 24 molecular processes. Utilizing independent transcriptomics profiles with follow-up data on progression free survival allows deriving molecular biomarker-based classifiers for predicting recurrence under first line therapy. Biomarkers of specific relevance are identified in a molecular process encapsulating TGF-beta, mTOR, Jak-STAT and Neurotrophin signaling. Mechanism of action molecular model representations of cisplatin and paclitaxel embed the very same signaling components, and specifically proteins afflicted with the activation status of the mTOR pathway become evident, including VEGFA. Analyzing mechanism of action interference of the mTOR inhibitor sirolimus shows specific impact on the drug resistance signature imposed by cisplatin and paclitaxel, further holding evidence for a synthetic lethal interaction to paclitaxel mechanism of action involving cyclin D1.ConclusionsStratifying drug resistant high grade serous ovarian cancer via VEGFA, and specifically treating with mTOR inhibitors in case of activation of the pathway may allow adding precision for overcoming resistance to first line therapy.

Dataset Information

MiR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF-?B in high-grade serous ovarian carcinoma.

Publications

miR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF-κB in high-grade serous ovarian carcinoma.

Similar Datasets

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