Epigenetic Regulation Identifies<i>RASEF</i>as a Tumor-Suppressor Gene in Uveal Melanoma

Maat, Willem; Beiboer, Sigrid H.W.; Jager, Martine J.; Luyten, Gré P.M.; Gruis, Nelleke A.; Velden, Pieter A. van der

doi:10.1167/iovs.07-1135

Cited by 48 publications

(31 citation statements)

References 21 publications

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“…They found that all cell lines and samples that did not express RASEF contained a methylated promoter, whereas those with RASEF expression lacked this methylation. Furthermore, they demonstrated methylation not only coincided with low expression but also with a homozygous genotype, suggesting that a combination of methylation and loss of heterozygosity may be the mechanism for loss of expression 63. Additional effects of the loss of heterozygosity seem to be related to the aggressive behavior of the tumor, because homozygous tumors with a methylated RASEF promoter region tend to display decreased survival compared with heterozygous tumors without methylation (P=0.019).…”

Section: Epigenetic Mechanisms In Ummentioning

confidence: 98%

Role of Epigenetics in Uveal Melanoma

Li¹,

Jia²,

Ge³

2017

Int. J. Biol. Sci.

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Uveal melanoma (UM) is a severe human malignancy with a high mortality rate that demands continued research into new and alternative forms of prevention and treatment. The emerging field of epigenetics is beginning to unfold an era of contemporary approaches to reducing the risk and improving the clinical treatment of UM. Epigenetic changes have a high prevalence rate in cancer, are reversible in nature, and can lead to cancer characteristics even in mutation-free cells. The information contained in this review highlights and expands on the main mechanisms of epigenetic dysregulation in UM tumorigenesis, progression and metastasis, including microRNA expression, hypermethylation of genes and histone modification. Epigenetic drugs have been shown to enhance tumor suppressor gene expression and drug sensitivity in many other cancer cell lines and animal models. An increased understanding of epigenetic mechanisms in UM will be invaluable in the design of more potent epigenetic drugs, which when used in combination with traditional therapies, may permit improved therapeutic outcomes.

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Section: Epigenetic Mechanisms In Ummentioning

confidence: 98%

Role of Epigenetics in Uveal Melanoma

Li¹,

Jia²,

Ge³

2017

Int. J. Biol. Sci.

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“…4,5 Tumor suppressor proteins implicated in melanoma include p16 (INK4A) and p14 (ARF) and are lost through chromosomal deletion, germ line mutations, 6 or, in some cases, epigenetic modification. 7 Semaphorins are a large class of secreted and membrane-anchored proteins that play a critical role in neuronal pathfinding, and axon guidance, in selected areas of the developing nervous system. 8 Semaphorins stimulate multiple signaling pathways, and the same semaphorin may repel or attract neuronal processes, promote or inhibit cell migration, or promote and inhibit cell survival, in a cell typespecific fashion.…”

Section: Introductionmentioning

confidence: 99%

The Semaphorin 7A Receptor Plexin C1 Is Lost During Melanoma Metastasis

Lazova¹,

Rothberg²,

Rimm³

et al. 2009

The American Journal of Dermatopathology

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The transformation of normal melanocytes, or melanocyte stem cells, to melanoma, is a complex process involving multiple mechanisms. Loss of tumor suppressor proteins, which function as brakes on cell growth, migration, or cell survival, was recognized early on as an important mechanism for initiation and progression of melanoma. Semaphorins and their cognate receptors, Plexins and neuropilins, are involved in neuronal pathfinding, immune function, and tumor progression through effects on blood vessel growth and cell migration. Semaphorin 7A (Sema7A) is a membrane-linked semaphorin that is expressed by human keratinocytes, and we have shown that Sema7A binds to human melanocytes through beta1-integrins and the Plexin C1 receptor. Functional studies showed that Sema7A stimulates cytoskeletal reorganization in human melanocytes, resulting in adhesion and dendrite formation. Downstream targets of Plexin C1 signaling in human melanocytes include cofilin and LIM kinase II, both of which are critical mediators of cell adhesion and migration. In this report, we analyzed the expression of Plexin C1 using immunohistochemistry on sections of primary and matched metastatic lesions from 19 subjects and in a large melanoma tumor microarray. Our data show a significant loss of Plexin C1 in metastatic melanoma compared with primary melanoma, suggesting the possibility that the Plexin C1 receptor is a tumor suppressor protein for melanoma.

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“…RASEF is described as a member of Rab GTPase family which generally plays important roles in vesicle trafficking. To date, a few studies indicated aberrant expression of RASEF in human cancers, but results were contradictory; RASEF was reported to be downregulated in uveal melanomas, whereas it was overexpressed in esophageal squamous cell carcinomas (48,49). To examine the mechanism of RASEF activation and overexpression in lung cancer, we checked previous publications and databases for RASEF including the data of CGH and genome sequencing (http://cancer.sanger.ac.uk/cosmic/gene/).…”

Section: Discussionmentioning

confidence: 99%

RASEF is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer

Oshita

Nishino

Takano

et al. 2013

Molecular Cancer Research

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Genome-wide gene expression profiling revealed that the Ras and EF-hand domain containing (RASEF) transcript was significantly transactivated in the majority of lung cancers. Using lung cancer cells, transient expression of RASEF promoted cell growth, whereas RASEF knockdown not only reduced its expression but resulted in growth suppression of the cancer cells. Immunohistochemical staining using tumor tissue microarrays consisting of 341 archived non-small cell lung cancers (NSCLC) revealed the association of strong RASEF positivity with poor prognosis (P ¼ 0.0034 by multivariate analysis). Mechanistically, RASEF interacted with extracellular signal-regulated kinase (ERK) 1/2 and enhanced ERK1/2 signaling. Importantly, inhibiting the interaction between RASEF and ERK1/2 using a cell-permeable peptide that corresponded to the ERK1/2-interacting site of RASEF, suppressed growth of lung cancer cells. This study demonstrates that elevated RASEF promoted cell growth via enhanced ERK signaling and is associated with poor prognosis of NSCLC.

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Epigenetic Regulation IdentifiesRASEFas a Tumor-Suppressor Gene in Uveal Melanoma

Abstract: Homozygosity, in combination with methylation, appears to be the mechanism targeting RASEF in uveal melanoma, and allelic imbalance at this locus supports a TSG role for RASEF.

Cited by 48 publications

References 21 publications

Role of Epigenetics in Uveal Melanoma

Role of Epigenetics in Uveal Melanoma

The Semaphorin 7A Receptor Plexin C1 Is Lost During Melanoma Metastasis

RASEF is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer

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