MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development

Gjerstorff, Morten F.; Kock, Kirsten; Nielsen, Ole; Ditzel, Henrik J.

doi:10.1093/humrep/del494

Cited by 62 publications

(38 citation statements)

References 16 publications

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“…One possibility is that miR-767 becomes activated upon completion of these DNA demethylation processes, and then inhibits TET activities in order to allow subsequent re-methylation of specific DNA sites. The timeframe of activation of CG genes in developing germline cells is compatible with this proposed role of miR-767 31 - 33 . Experimental validation of this hypothesis can be envisaged in the mouse, where miR-767 location in the X-linked Gabra3 gene, and target sites in the 3′-UTR of Tet genes, are conserved.…”

Section: Discussionsupporting

confidence: 54%

A novel cancer-germline transcript carrying pro-metastatic miR-105 andTET-targeting miR-767 induced by DNA hypomethylation in tumors

et al. 2014

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Genome hypomethylation is a common epigenetic alteration in human tumors, where it often leads to aberrant activation of a group of germline-specific genes, commonly referred to as “cancer-germline” genes. The cellular functions and tumor promoting potential of these genes remain, however, largely uncertain. Here, we report identification of a novel cancer-germline transcript (CT-GABRA3) displaying DNA hypomethylation-dependent activation in various tumors, including melanoma and lung carcinoma. Importantly, CT-GABRA3 harbors a microRNA (miR-105), which has recently been identified as a promoter of cancer metastasis by its ability to weaken vascular endothelial barriers following exosomal secretion. CT-GABRA3 also carries a microRNA (miR-767) with predicted target sites in TET1 and TET3, two members of the ten-eleven-translocation family of tumor suppressor genes, which are involved in the conversion of 5-methylcytosines to 5-hydroxymethylcytosines (5hmC) in DNA. Decreased TET activity is a hallmark of cancer; here, we provide evidence that aberrant activation of miR-767 contributes to this phenomenon. We demonstrate that miR-767 represses TET1/3 mRNA and protein expression and regulates genomic 5hmC levels. Additionally, we show that high CT-GABRA3 transcription correlates with reduced TET1 mRNA levels in vivo in lung tumors. Together, our study identified a cancer-germline gene that produces microRNAs with oncogenic potential. Moreover, our data indicate that DNA hypomethylation in tumors can contribute to reduced 5hmC levels via activation of a TET-targeting microRNA.

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Section: Discussionsupporting

confidence: 54%

A novel cancer-germline transcript carrying pro-metastatic miR-105 andTET-targeting miR-767 induced by DNA hypomethylation in tumors

et al. 2014

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“…It is believed that many CT genes are also expressed during oogenesis, but data on this process are still very sparse [30,31]. There is abundant evidence in the literature that many genes expressed predominantly during gametogenesis, as well as those implicated in reproduction in general (e.g.…”

Section: Discussionmentioning

confidence: 99%

Rapid evolution of cancer/testis genes on the X chromosome

et al. 2007

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Background: Cancer/testis (CT) genes are normally expressed only in germ cells, but can be activated in the cancer state. This unusual property, together with the finding that many CT proteins elicit an antigenic response in cancer patients, has established a role for this class of genes as targets in immunotherapy regimes. Many families of CT genes have been identified in the human genome, but their biological function for the most part remains unclear. While it has been shown that some CT genes are under diversifying selection, this question has not been addressed before for the class as a whole.

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“…Anti-apoptotic properties have been attributed to GAGE antigens [35]. Expression of the GAGE antigens normally occurs in a subset of oocytes in the adult ovary [37], adult male germ cells, and for a few weeks in fetal Leydig and Sertoli cells during the third trimester [38]. …”

Section: Discussionmentioning

confidence: 99%

The unique C- and N-terminal sequences of Metallothionein isoform 3 mediate growth inhibition and Vectorial active transport in MCF-7 cells

Voels¹,

Wang²,

Sens³

et al. 2017

BMC Cancer

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BackgroundThe 3rd isoform of the metallothionein (MT3) gene family has been shown to be overexpressed in most ductal breast cancers. A previous study has shown that the stable transfection of MCF-7 cells with the MT3 gene inhibits cell growth. The goal of the present study was to determine the role of the unique C-terminal and N-terminal sequences of MT3 on phenotypic properties and gene expression profiles of MCF-7 cells.MethodsMCF-7 cells were transfected with various metallothionein gene constructs which contain the insertion or the removal of the unique MT3 C- and N-terminal domains. Global gene expression analysis was performed on the MCF-7 cells containing the various constructs and the expression of the unique C- and N- terminal domains of MT3 was correlated to phenotypic properties of the cells.ResultsThe results of the present study demonstrate that the C-terminal sequence of MT3, in the absence of the N-terminal sequence, induces dome formation in MCF-7 cells, which in cell cultures is the phenotypic manifestation of a cell’s ability to perform vectorial active transport. Global gene expression analysis demonstrated that the increased expression of the GAGE gene family correlated with dome formation. Expression of the C-terminal domain induced GAGE gene expression, whereas the N-terminal domain inhibited GAGE gene expression and that the effect of the N-terminal domain inhibition was dominant over the C-terminal domain of MT3. Transfection with the metallothionein 1E gene increased the expression of GAGE genes. In addition, both the C- and the N-terminal sequences of the MT3 gene had growth inhibitory properties, which correlated to an increased expression of the interferon alpha-inducible protein 6.ConclusionsOur study shows that the C-terminal domain of MT3 confers dome formation in MCF-7 cells and the presence of this domain induces expression of the GAGE family of genes. The differential effects of MT3 and metallothionein 1E on the expression of GAGE genes suggests unique roles of these genes in the development and progression of breast cancer. The finding that interferon alpha-inducible protein 6 expression is associated with the ability of MT3 to inhibit growth needs further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3355-9) contains supplementary material, which is available to authorized users.

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MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development

Cited by 62 publications

References 16 publications

A novel cancer-germline transcript carrying pro-metastatic miR-105 andTET-targeting miR-767 induced by DNA hypomethylation in tumors

A novel cancer-germline transcript carrying pro-metastatic miR-105 andTET-targeting miR-767 induced by DNA hypomethylation in tumors

Rapid evolution of cancer/testis genes on the X chromosome

The unique C- and N-terminal sequences of Metallothionein isoform 3 mediate growth inhibition and Vectorial active transport in MCF-7 cells

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