Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis

Lum, Elena; Vigliotti, Michele; Banerjee, Nilanjana; Cutter, Noelle; Wrzeszczyński, Kazimierz O.; Khan, Sohail Ahmed; Kamalakaran, Sitharthan; Levine, Douglas A.; Dimitrova, Nevenka; Lucito, Robert

doi:10.1016/j.ygyno.2013.05.002

Cited by 44 publications

(64 citation statements)

References 38 publications

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“…These results indicate that DNA methylation involves the regulation of multidrug resistance in ovarian cancer through apoptosis. The latter finding is in good agreement with that of previous studies (86,87). As shown in Table I, there are at least seven genes, including PTEN, BLU and UCHL1, that participate in the regulation of multidrug resistance in ovarian cancer through cell apoptosis.…”

Section: Discussionsupporting

confidence: 92%

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

et al. 2016

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Abstract.The main obstacle to the successful treatment of ovarian cancer is the development of drug resistance to combined chemotherapy. Among all the factors associated with drug resistance, DNA methylation apparently plays a critical role. In this study, we performed an integrative analysis of the 26 DNA-methylated genes associated with drug resistance in ovarian cancer, and the genes were further evaluated by comprehensive bioinformatics analysis including gene/protein interaction, biological process enrichment and annotation. The results from the protein interaction analyses revealed that at least 20 of these 26 methylated genes are present in the protein interaction network, indicating that they interact with each other, have a correlation in function, and may participate as a whole in the regulation of ovarian cancer drug resistance. There is a direct interaction between the phosphatase and tensin homolog (PTEN) gene and at least half of the other genes, indicating that PTEN may possess core regulatory functions among these genes. Biological process enrichment and annotation demonstrated that most of these methylated genes were significantly associated with apoptosis, which is possibly an essential way for these genes to be involved in the regulation of multidrug resistance in ovarian cancer. In addition, a comprehensive analysis of clinical factors revealed that the methylation level of genes that are associated with the regulation of drug resistance in ovarian cancer was significantly correlated with the prognosis of ovarian cancer. Overall, this study preliminarily explains the potential correlation between the genes with DNA methylation and drug resistance in ovarian cancer. This finding has significance for our understanding of the regulation of resistant ovarian cancer by methylated genes, the treatment of ovarian cancer, and improvement of the prognosis of ovarian cancer. IntroductionOvarian cancer is a malignant tumour posing a serious threat to women's health. As the main type of ovarian cancer, ovarian epithelial carcinoma accounts for 85-90% of all ovarian cancers. The mortality rate of ovarian epithelial carcinoma ranks first among all female reproductive tract malignancies. Approximately 70% of ovarian cancer patients are in the late stage when diagnosed. Most of these tumours easily develop drug resistance in the course of post-surgery chemotherapy; therefore, the therapeutic effect is greatly reduced, leading to a survival rate of just 30% for ovarian cancer (1). Therefore, multidrug resistance is the main cause of ovarian cancer chemotherapy failure. Studies have demonstrated that multidrug resistance is the result of multiple genes or proteins and a multistep process, or cross-reactivity of multiple factors. Multidrug resistance involves several different regulatory mechanisms, and epigenetic regulation is one of the significant regulatory mechanisms in the development of ovarian cancer multidrug resistance (2). Epigenetic modification is a heritable change in gene expression without a DNA...

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Section: Discussionsupporting

confidence: 92%

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

et al. 2016

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“…ErbB signaling (91), focal adhesion (92,93), apoptosis (94,95) and p53 signaling (96,97) have been reported to associate with drug resistance in ovarian cancer. For example, miR-21 regulates drug resistance via apoptosis and cellular survival pathways (94), and loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis (98).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Zhang²,

Gao

et al. 2014

Oncology Reports

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Abstract. The expression of HNF1 homeobox B (HNF1B) is associated with cancer risk in several tumors, including ovarian cancer, and its decreased expression play roles in cancer development. However, the study of HNF1B and cancer is limited, and its association with drug resistance in cancer has never been reported. On the basis of array data retrieved from Oncomine and Gene Expression Omnibus (GEO) online database, we found that the mRNA expression of HNF1B in 586 ovarian serous cystadenocarcinomas and in platinum-resistant A2780 epithelial ovarian cancer cells was significantly decreased, indicating a potential role of HNF1B in drug resistance in ovarian cancer. Based on this finding, comprehensive bioinformatics analyses, including protein/ gene interaction, protein-small molecule/chemical interaction, biological process annotation, gene co-occurrence and pathway enrichment analysis and microRNA-mRNA interaction, were performed to illustrate the association of HNF1B with drug resistance in ovarian cancer. We found that among the proteins/ genes, small molecules/chemicals and microRNAs which directly interacted with HNF1B, the majority was associated with drug resistance in cancer, particularly in ovarian cancer. Biological process annotation revealed that HNF1B closely related to 24 biological processes which were all notably associated with ovarian cancer and drug resistance. These results indicated that the downregulation of HNF1B may contribute to drug resistance in ovarian cancer, via its direct interactions with these drug resistance-related proteins/genes, small molecules/chemicals and microRNAs, and via its regulations on the drug resistance-related biological processes. Pathway enrichment analysis of 36 genes which co-occurred with HNF1B, ovarian cancer and drug resistance indicated that the HNF1B may perform its drug resistance-related functions through 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling. Collectively, in this study, we illustrated for the first time that HNF1B may contribute to drug resistance in ovarian cancer, potentially through the 4 pathways. The present study may pave the way for further investigation of the drug resistance-related functions of HNF1B in ovarian cancer.

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“…A previous study revealed that the loss of DOK2 induces carboplatin resistance in ovarian cancer through the suppression of apoptosis [56]. Moreover, DOK2 was found to act as a potential tumor suppressor in human breast cancer [57].…”

Section: Inferring Putative Cancer Genesmentioning

confidence: 98%

Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach

et al. 2014

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Background: Recently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer. Methods: In this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.

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Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis

Cited by 44 publications

References 38 publications

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach

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