Hypermethylation of SOX2 Gene in Hydatidiform Mole and Choriocarcinoma

Li, Albert S.M.; Siu, Michelle K.Y.; Zhang, Huijuan; Wong, Eric T.T.; Chan, Kelvin Yuen-Kwong; Ngan, Hextan Y.S.; Cheung, Annie N.Y.

doi:10.1177/1933719108322433

Cited by 34 publications

(36 citation statements)

References 48 publications

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“…DNA hypermethylation of tumor-suppressor genes and stem cell transcription factors has indeed been reported in gestational trophoblastic disease. 24,26,30 Moreover, synergistic reactivation of ASPP1 mRNA expression could be observed in combined treatment by the histone deacetylase (HDAC) inhibitor TSA and the demethylating agent 5-aza-dc, as in our previous studies on Oct4 and Sox2. 24,30 Genomic DNA methylation and histone deacetylation are essential but not secluded epigeneticregulating mechanisms.…”

Section: Aberrant Expression and Hypermethylation Of Aspp1 In Gestatimentioning

confidence: 52%

“…24,26,30 Moreover, synergistic reactivation of ASPP1 mRNA expression could be observed in combined treatment by the histone deacetylase (HDAC) inhibitor TSA and the demethylating agent 5-aza-dc, as in our previous studies on Oct4 and Sox2. 24,30 Genomic DNA methylation and histone deacetylation are essential but not secluded epigeneticregulating mechanisms. 31 Methylcytosine-binding proteins, which bind to methylated DNA sequences, can recruit HDAC and histone methyltransferases, 32 whereas DNA methyltransferases can directly bind HDAC, representing an interaction between DNA methylation and histone deacetylation.…”

Section: Aberrant Expression and Hypermethylation Of Aspp1 In Gestatimentioning

confidence: 52%

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Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome

et al. 2011

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Gestational trophoblastic disease encompasses a spectrum of trophoblastic lesions including true neoplasms such as choriocarcinomas and the potentially malignant hydatidiform moles, which may develop persistent disease requiring chemotherapy. ASPP1, a member of apoptosis-stimulating proteins of p53 (ASPPs), is a proapoptotic protein that can stimulate apoptosis through its interaction with p53. We evaluated the promoter methylation and expression profiles of ASPP1 in different trophoblastic tissues and its in vitro functional effect on two choriocarcinoma cell lines, namely JEG-3 and JAR. Significant downregulation of ASPP1 mRNA and protein levels was demonstrated in hydatidiform moles and choriocarcinomas, when compared with normal placentas by quantitative-PCR and immunohistochemistry. The ASPP1 mRNA level was significantly correlated with its hypermethylation status, evaluated with methylation-specific PCR, in placenta and gestational trophoblastic disease samples (P ¼ 0.024). Moreover, lower ASPP1 immunoreactivity was shown in hydatidiform moles that progressed to persistent gestational trophoblastic neoplasms than in those that regressed (P ¼ 0.045). A significant correlation was also found between expression of ASPP1 and proliferative indices (assessed by Ki67 and MCM7), apoptotic activity (M30 CytoDeath antibody), p53 and caspase-8 immunoreactivities. An in vitro study showed that ectopic expression of ASPP1 could trigger apoptosis through intrinsic and extrinsic pathways as indicated by an increase in cleaved caspase-9 and Fas ligand protein expression. The latter suggests a hitherto unreported novel link between ASPP1 and the extrinsic pathway of apoptosis. Our findings suggest that downregulation of ASPP1 by hypermethylation may be involved in the pathogenesis and progress of gestational trophoblastic disease, probably through its effect on apoptosis.

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Section: Aberrant Expression and Hypermethylation Of Aspp1 In Gestatimentioning

confidence: 52%

Section: Aberrant Expression and Hypermethylation Of Aspp1 In Gestatimentioning

confidence: 52%

Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome

et al. 2011

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“…Sox2 was also found to be involved in the later events of carcinogenesis, such as invasion and metastasis, rather than the early progression of pancreatic intraepithelial neoplasias (24). However, decreased expression of Sox2 is also associated with a few types of carcinoma such as gastric cancer and choriocarcinoma (27,28).…”

Section: Discussionmentioning

confidence: 99%

Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy

Yang

Zheng

et al. 2012

Oncol Rep

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Abstract. Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy. Oct4 and Sox2 are essential transcription factors for embryonic development and play key roles in determining the fate of stem cells. In this study, we aimed to investigate the expression of Oct4 and Sox2 in NB tissues, and evaluated their relationship with various clinicopathological parameters. Oct4 and Sox2 expression in 65 samples of NB and paracancerous tissues was examined by real-time PCR. The relationship between Oct4 and Sox2 expression and clinical data was assessed. To detect Oct4 and Sox2 expression at the protein level, western blot analyses and immunohistochemical staining were employed. We found that the expression levels of Oct4 and Sox2 in NB tissues were significantly higher than those in paracancerous tissues (P<0.05). Oct4 and Sox2 expression was significantly correlated to the clinical stage of NB, but not other clinicopathological parameters including patient gender and age, tumor size, location and histological classification. In stage III and IV tumors, Oct4 and Sox2 expression was significantly decreased in the chemotherapy subgroup as compared with that of the non-chemotherapy subgroup (P<0.05). These findings suggest that the expression of Oct4 and Sox2 may correlate with the genesis and progression of NB. In addition, Oct4 and Sox2 expression can be inhibited by chemotherapy.

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“…Molecular mechanism of SOX2 gene transcription in cancer is hardly known. It is reported that hypomethylation of SOX2 promoter enhances SOX2 gene expression in glioblastoma multiforme [7], and that mRNA expression level of SOX2 is correlated with SOX2 hyper-methylation in choriocarcinoma [8]. A study shows that an artificial transcription factor suppressed SOX2 gene expression by inducing SOX2 core promoter methylation [9].…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of human breast cancer cells with SOX2 promoter activity

Liang

Furuhashi

Nakane

et al. 2013

Biochemical and Biophysical Research Communications

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(H.I.) 1. These authors contributed to this work equally. Word count: 4,388 ABSTRACTSex determining region Y-box 2 (SOX2) is well known as one of the "stemness" factors and is often expressed in cancers including breast cancer. In this study, we developed a reporter system using fluorescent protein driven by the promoter for SOX2 gene to detect and isolate living SOX2-positive cells. Using this system, we determined that SOX2 promoter activities were well correlated with SOX2 mRNA expression levels in 5 breast cancer cell lines, and that the cell population with positive SOX2 promoter activity (pSp-T + ) isolated from one of the 5 cell lines, MCF-7 cells, showed a high SOX2 protein expression and high sphere-forming activity compared with very low promoter activity (pSp-T low/-). The pSp-T + population expressed higher mRNA levels of several stemness-related genes such as CD44, ABCB1, NANOG and TWIST1 than the pSp-T low/-population whereas the two populations expressed CD24 at similar levels. These results suggest that the cell population with SOX2 promoter activity contains cancer stem cell (CSC)-like cells which show different expression profiles from those of CSC-marker genes previously recognized in human breast cancers.

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Hypermethylation of SOX2 Gene in Hydatidiform Mole and Choriocarcinoma

Cited by 34 publications

References 48 publications

Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome

Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome

Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy

Isolation and characterization of human breast cancer cells with SOX2 promoter activity

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