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Systematic analysis of ovarian cancer platinum-resistance mechanisms via text mining.

ABSTRACT: BACKGROUND:Platinum resistance is an important cause of clinical recurrence and death for ovarian cancer. This study tries to systematically explore the molecular mechanisms for platinum resistance in ovarian cancer and identify regulatory genes and pathways via text mining and other methods. METHODS:Genes in abstracts of associated literatures were identified. Gene ontology and protein-protein interaction (PPI) network analysis were performed. Then co-occurrence between genes and ovarian cancer subtypes were carried out followed by cluster analysis. RESULTS:Genes with highest frequencies are mostly involved in DNA repair, apoptosis, metal transport and drug detoxification, which are closely related to platinum resistance. Gene ontology analysis confirms this result. Some proteins such as TP53, HSP90, ESR1, AKT1, BRCA1, EGFR and CTNNB1 work as hub nodes in PPI network. According to cluster analysis, specific genes were highlighted in each subtype of ovarian cancer, indicating that various subtypes may have different resistance mechanisms respectively. CONCLUSIONS:Platinum resistance in ovarian cancer involves complicated signaling pathways and different subtypes may have specific mechanisms. Text mining, combined with other bio-information methods, is an effective way for systematic analysis.

SUBMITTER: Li H

PROVIDER: S-EPMC7066848 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Systematic analysis of ovarian cancer platinum-resistance mechanisms via text mining.

Li Haixia H Li Jinghua J Gao Wanli W Zhen Cheng C Feng Limin L

Journal of ovarian research 20200311 1

<h4>Background</h4>Platinum resistance is an important cause of clinical recurrence and death for ovarian cancer. This study tries to systematically explore the molecular mechanisms for platinum resistance in ovarian cancer and identify regulatory genes and pathways via text mining and other methods.<h4>Methods</h4>Genes in abstracts of associated literatures were identified. Gene ontology and protein-protein interaction (PPI) network analysis were performed. Then co-occurrence between genes and ...[more]

PMID: 32160916

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Project description:Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests that resistant clones exist within a larger drug-sensitive cell population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically derived, intrapatient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 downregulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of histone deacetylase (HDAC) 4, FOLR2, PIK3R1, or STAT1 (P < 0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum-sensitive cells but not in HDAC4 overexpressing platinum-resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum-induced STAT1 activation, and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors [n = 7 of 16 (44%); P = 0.04]. Therefore, clinical selection of HDAC4-overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer.

Dataset Information

Systematic analysis of ovarian cancer platinum-resistance mechanisms via text mining.

Publications

Systematic analysis of ovarian cancer platinum-resistance mechanisms via text mining.

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