STAT1 Drives Tumor Progression in Serous Papillary Endometrial Cancer

Kharma, Budiman; Baba, Tsukasa; Matsumura, Noriomi; Kang, Hyun Jung; Hamanishi, Junzo; Murakami, Ryusuke; McConechy, Melissa M.; Leung, Samuel; Yamaguchi, Ken; Hosoe, Yuko; Yoshioka, Yumiko; Murphy, Susan K.; Mandai, Masaki; Hunstman, David G.; Konishi, Ikuo

doi:10.1158/0008-5472.can-14-0847

Cited by 66 publications

(61 citation statements)

References 47 publications

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“…Another example is STAT1, which was identified as a negative regulator in our analysis. It is known that the c-MYC promoter region contains STAT1 binding sites, and that STAT1 increases and maintains the basal expression of MYC during tumorigenesis [50, 51]. We examined the ENCODE ChIP-seq dataset in the UCSC genome browser, but found no STAT1 binding signal in the MYCN promoter region.…”

Section: Resultsmentioning

confidence: 99%

Unveiling MYCN regulatory networks in neuroblastoma via integrative analysis of heterogeneous genomics data

Hsu

Chang

et al. 2016

Oncotarget

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MYCN, an oncogenic transcription factor of the Myc family, is a major driver of neuroblastoma tumorigenesis. Due to the difficulty in drugging MYCN directly, revealing the molecules in MYCN regulatory networks will help to identify effective therapeutic targets for neuroblastoma therapy. Here we perform ChIP-sequencing and small RNA-sequencing of neuroblastoma cells to determine the MYCN-binding sites and MYCN-associated microRNAs, and integrate various types of genomic data to construct MYCN regulatory networks. The overall analysis indicated that MYCN-regulated genes were involved in a wide range of biological processes and could be used as signatures to identify poor-prognosis MYCN-non-amplified patients. Analysis of the MYCN binding sites showed that MYCN principally served as an activator. Using a computational approach, we identified 32 MYCN co-regulators, and some of these findings are supported by previous studies. Moreover, we investigated the interplay between MYCN transcriptional and microRNA post-transcriptional regulations and identified several microRNAs, such as miR-124-3p and miR-93-5p, which may significantly contribute to neuroblastoma pathogenesis. We also found MYCN and its regulated microRNAs acted together to repress the tumor suppressor genes. This work provides a comprehensive view of MYCN regulations for exploring therapeutic targets in neuroblastoma, as well as insights into the mechanism of neuroblastoma tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Unveiling MYCN regulatory networks in neuroblastoma via integrative analysis of heterogeneous genomics data

Hsu

Chang

et al. 2016

Oncotarget

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“…ISGs are inducible by radiation and chemotherapy and regulate therapeutic resistance in preclinical cancer models [11-14]. Interestingly, STAT1 has been reported to have both tumor suppressive [15, 16] and protumorigenic activity [17, 18]. …”

Section: Introductionmentioning

confidence: 99%

MiRNA203 suppresses the expression of protumorigenic STAT1 in glioblastoma to inhibit tumorigenesis

et al. 2016

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MicroRNAs (miRNAs) play critical roles in regulating cancer cell proliferation, migration, survival and sensitivity to chemotherapy. The potential application of using miRNAs for cancer prognosis holds great promise but miRNAs with predictive value remain to be identified and underlying mechanisms of how they promote or suppress tumorigenesis are not completely understood. Here, we show a strong correlation between miR203 expression and brain cancer patient survival. Low miR203 expression is found in subsets of brain cancer patients, especially glioblastoma. Ectopic miR203 expression in glioblastoma cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon or temozolomide in vitro, and inhibited tumorigenesis in vivo. We further show that STAT1 is a direct functional target of miR203, and miR203 level is negatively correlated with STAT1 expression in brain cancer patients. Knockdown of STAT1 expression mimicked the effect of overexpression of miR203 in glioblastoma cell lines, and inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by IFN or temozolomide in vitro, and inhibited glioblastoma tumorigenesis in vivo. High STAT1 expression significantly correlated with poor survival in brain cancer patients. Mechanistically, we found that enforced miR203 expression in glioblastoma suppressed STAT1 expression directly, as well as that of a number of STAT1 regulated genes. Taken together, our data suggest that miR203 acts as a tumor suppressor in glioblastoma by suppressing the pro-tumorigenic action of STAT1. MiR203 may serve as a predictive biomarker and potential therapeutic target in subsets of cancer patients with low miR203 expression.

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“…Indeed, variability can be observed for results from endometrial cancer microarray studies. For example, in total ~1,300 genes have been reported as differentially expressed across microarray studies assessing gene expression profiles between EEC and NEEC tumors910111213141516, however only 160 genes were reported in more than one study and no gene was reported by more than four studies.…”

mentioning

confidence: 99%

Meta-analysis of gene expression studies in endometrial cancer identifies gene expression profiles associated with aggressive disease and patient outcome

O’Mara

Zhao

Spurdle

2016

Sci Rep

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Although endometrioid endometrial cancer (EEC; comprising ~80% of all endometrial cancers diagnosed) is typically associated with favourable patient outcome, a significant portion (~20%) of women with this subtype will relapse. We hypothesised that gene expression predictors of the more aggressive non-endometrioid endometrial cancers (NEEC) could be used to predict EEC patients with poor prognosis. To explore this hypothesis, we performed meta-analysis of 12 gene expression microarray studies followed by validation using RNA-Seq data from The Cancer Genome Atlas (TCGA) and identified 1,253 genes differentially expressed between EEC and NEEC. Analysis found 121 genes were associated with poor outcome among EEC patients. Forward selection likelihood-based modelling identified a 9-gene signature associated with EEC outcome in our discovery RNA-Seq dataset which remained significant after adjustment for clinical covariates, but was not significant in a smaller RNA-Seq dataset. Our study demonstrates the value of employing meta-analysis to improve the power of gene expression microarray data, and highlight genes and molecular pathways of importance for endometrial cancer therapy.

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STAT1 Drives Tumor Progression in Serous Papillary Endometrial Cancer

Cited by 66 publications

References 47 publications

Unveiling MYCN regulatory networks in neuroblastoma via integrative analysis of heterogeneous genomics data

Unveiling MYCN regulatory networks in neuroblastoma via integrative analysis of heterogeneous genomics data

MiRNA203 suppresses the expression of protumorigenic STAT1 in glioblastoma to inhibit tumorigenesis

Meta-analysis of gene expression studies in endometrial cancer identifies gene expression profiles associated with aggressive disease and patient outcome

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