Identification of differentially expressed genes according to chemosensitivity in advanced ovarian serous adenocarcinomas: expression of GRIA2 predicts better survival

Choi, Changhyun; Jj, Choi; Ya, Park; Yy, Lee; Sy, Song; Sung, Chang Ohk; Song, Taejong; Mk, Kim; Tj, Kim; Jw, Lee; Kim, Hyung Jun; Bae, Dong Ho; Kim, B-G.

doi:10.1038/bjc.2012.217

Cited by 43 publications

(36 citation statements)

References 43 publications

(45 reference statements)

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“…Repression of glutamate receptor GRIA4, one of the top upregulated genes in our study, increases cell viability, proliferation, and migratory potential in rhabdomyosarcoma/medulloblastoma and multiple myeloma cells [31]. Another GRIA family member, GRIA2, is downregulated in chemoresistant advanced serous papillary ovarian carcinomas and upregulated in chemosensitive tumors [32]. TOMM40L, also upregulated in our study, is upregulated in epithelial ovarian cancer cell lines overexpressing DOK1, a candidate tumor suppressor associated with cisplatin sensitivity [33].…”

Section: Discussionmentioning

confidence: 57%

Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer

Reyes-González

Quiñones-Díaz

Santana

et al. 2020

Cancers

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Despite good responses to first-line treatment with platinum-based combination chemotherapy, most ovarian cancer patients will relapse and eventually develop platinum-resistant disease with poor prognosis. Although reports suggest that integrin-linked kinase (ILK) is a potential target for ovarian cancer treatment, identification of ILK downstream effectors has not been fully explored. The purpose of this study was to investigate the molecular and biological effects of targeting ILK in cisplatin-resistant ovarian cancer. Western blot analysis showed that phosphorylation levels of ILK were higher in cisplatin-resistant compared with cisplatin-sensitive ovarian cancer cells. Further immunohistochemical analysis of ovarian cancer patient samples showed a significant increase in phosphorylated ILK levels in the tumor tissue when compared to normal ovarian epithelium. Targeting ILK by small-interfering RNA (siRNA) treatment reduced cisplatin-resistant cell growth and invasion ability, and increased apoptosis. Differential gene expression analysis by RNA sequencing (RNA-Seq) upon ILK-siRNA transfection followed by Ingenuity Pathway Analysis (IPA) and survival analysis using the Kaplan–Meier plotter database identified multiple target genes involved in cell growth, apoptosis, invasion, and metastasis, including several non-coding RNAs. Taken together, results from this study support ILK as an attractive target for ovarian cancer and provide potential ILK downstream effectors with prognostic and therapeutic value.

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Section: Discussionmentioning

confidence: 57%

Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer

Reyes-González

Quiñones-Díaz

Santana

et al. 2020

Cancers

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“…More importantly, significantly higher expressed SEMA3A was previously reported in chemosensitive cancers than in chemoresistant tumors [ 28 , 29 ]. Additionally, an identified EZH2-H3K27me3-enriched promoter region of SEMA3A (Chr7:83,814,596-83,835,002) covers a microsatellite marker that is significantly associated with acute adverse effects following radiotherapy in cancer patients [ 30 ] (Figure 3A ).…”

Section: Resultsmentioning

confidence: 85%

Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles

2015

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BackgroundTherapy-related, secondary acute myeloid leukemia (t-AML) is an increasingly frequent complication of intensive chemotherapy. This malignancy is often characterized by abnormalities of chromosome 7, including large deletions or chromosomal loss. A variety of studies suggest that decreased expression of the EZH2 gene located at 7q36.1 is critical in disease pathogenesis. This histone methyltransferase has been implicated in transcriptional repression through modifying histone H3 on lysine 27 (H3k27). However, the critical target genes of EZH2 and their regulatory roles remain unclear.MethodTo characterize the subset of EZH2 target genes that might contribute to t-AML pathogenesis, we developed a novel computational analysis to integrate tissue-specific histone modifications and genome-wide transcriptional regulation. Initial integrative analysis utilized a novel "seq2gene" strategy to explore largely the target genes of chromatin immuneprecipitation sequencing (ChIP-seq) enriched regions. By combining seq2gene with our Phenotype-Genotype-Network (PGNet) algorithm, we enriched genes with similar expression profiles and genomic or functional characteristics into "biomodules".ResultsInitial studies identified SEMA3A (semaphoring 3A) as a novel oncogenic candidate that is regulated by EZH2-silencing, using data derived from both normal and leukemic cell lines as well as murine cells deficient in EZH2. A microsatellite marker at the SEMA3A promoter has been associated with chemosensitivity and radiosensitivity. Notably, our subsequent studies in primary t-AML demonstrate an expected up-regulation of SEMA3A that is EZH2-modulated. Furthermore, we have identified three biomodules that are co-expressed with SEMA3A and up-regulated in t-AML, one of which consists of previously characterized EZH2-repressed gene targets. The other two biomodules include MAPK8 and TATA box targets. Together, our studies suggest an important role for EZH2 targets in t-AML pathogenesis that warrants further study.ConclusionThese developed computational algorithms and systems biology strategies will enhance the knowledge discovery and hypothesis-driven analysis of multiple next generation sequencing data, for t-AML and other complex diseases.

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“…For validation of the four SNPs and seven associated genes in Ov-CCA, we first analyzed gene expression microarray data from our previous studies to investigate whether these genes were expressed differentially among Ov-CCA (n = 19), HGSOC (n = 26), and normal ovarian tissue (n = 7) [19,26]. The samples were collected prospectively from patients at Samsung Medical Center with Institutional Review Board (IRB) approval (2011-04-008, Seoul, South Korea) and informed consent.…”

Section: Analysis Of the Clinical Significance Of The Seven Identifiementioning

confidence: 99%

Identification of Candidate Genes Associated with Susceptibility to Ovarian Clear Cell Adenocarcinoma Using cis-eQTL Analysis

Kim

Chung

Hwang

et al. 2020

JCM

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Ovarian clear cell adenocarcinoma (Ov-CCA) has a higher prevalence in the Japanese ancestry than other populations. The ancestral disparities in Ov-CCA prevalence suggests the presence of Ov-CCA-specific genetic alterations and may provide an opportunity to identify the novel genes associated with Ov-CCA tumorigenesis. Using 94 previously reported genes as the phenotypic trait, we conducted multistep expression quantitative trait loci (eQTL) analysis with the HapMap3 project datasets. Four single-nucleotide polymorphisms (SNPs) (rs4873815, rs12976454, rs11136002, and rs13259097) that had different allele frequencies in the Japanese ancestry and seven genes associated in cis (APBA3, C8orf58, KIAA1967, NAPRT1, RHOBTB2, TNFRSF10B, and ZNF707) were identified. In silico functional annotation analysis and in vitro promoter assay validated the regulatory effect of rs4873815-TT on ZNF707 and rs11136002-TT on TNFRSF10B. Furthermore, ZNF707 was highly expressed in Ov-CCA and had a negative prognostic value in disease recurrence in our sample cohort. This prognostic power was consistently observed in The Cancer Genome Atlas (TCGA) clear cell renal cell carcinoma dataset, suggesting that ZNF707 may have prognostic value in clear cell histology regardless of tissue origin. In conclusion, rs4873815-TT/ZNF707 may have clinical significance in the prognosis and tumorigenesis of Ov-CCA, which may be more relevant to clear cell histology. Besides, this study may underpin the evidence that cis-eQTL analysis based on ancestral disparities can facilitate the discovery of causal genetic alterations in complex diseases, such as cancer.

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Identification of differentially expressed genes according to chemosensitivity in advanced ovarian serous adenocarcinomas: expression of GRIA2 predicts better survival

Cited by 43 publications

References 43 publications

Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer

Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer

Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles

Identification of Candidate Genes Associated with Susceptibility to Ovarian Clear Cell Adenocarcinoma Using cis-eQTL Analysis

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