The EPHB6 Receptor Tyrosine Kinase Is a Metastasis Suppressor That Is Frequently Silenced by Promoter DNA Hypermethylation in Non–Small Cell Lung Cancer

Yu, Jun; Bulk, Etmar; Ji, Ping; Hascher, Antje; Tang, Moying; Metzger, Ralf; Marra, Alessandro; Serve, Hubert; Berdel, Wolfgang E.; Wiewroth, Rainer; Koschmieder, Steffen; Müller‐Tidow, Carsten

doi:10.1158/1078-0432.ccr-09-2000

Cited by 69 publications

(59 citation statements)

References 33 publications

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“…Cell culture and 5-azacytidine treatment A549 and HTB56 lung adenocarcinoma cells were cultured and maintained as described (12,13). Cell line identity was confirmed by STR marker analysis.…”

Section: Methodsmentioning

confidence: 99%

DNA Methyltransferase Inhibition Reverses Epigenetically Embedded Phenotypes in Lung Cancer Preferentially Affecting Polycomb Target Genes

Hascher

Haase

Hebestreit

et al. 2014

Clinical Cancer Research

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Purpose: Cancer cell phenotypes are partially determined by epigenetic specifications, such as DNA methylation. Metastasis development is a late event in cancerogenesis and might be associated with epigenetic alterations.Experimental Design: An in vivo selection approach was used to generate highly aggressive non-small cell lung cancer (NSCLC) cell lines (A549 and HTB56) followed by genome-wide DNA methylation analysis. Furthermore, the therapeutic effects of the epigenetic agent azacytidine on DNA methylation patterns and the in vivo phenotypes were explored.Results: Widespread changes of DNA methylation were observed during development of highly aggressive cell lines. Up to 2.5% of the CpG-rich region was differentially methylated as identified by reduced representation bisulfite sequencing compared with the less aggressive parental cell lines. DNA methyltransferase inhibition by azacytidine reversed the prometastatic phenotype; this was highly associated with the preferential loss of DNA methylation at sites that were hypermethylated during the in vivo selection. Of note, polycomb (PRC2) binding sites were particularly affected by DNA methylation changes after azacytidine exposure that persisted over time.Conclusions: We could show that metastatic capability of NSCLC is closely associated with DNA methylome alterations. Because inhibition of DNA methyltransferase reversed metastasis-prone phenotype, epigenetic modulation seems to be a potential therapeutic approach to prevent metastasis formation. Clin Cancer Res; 20(4); 814-26. Ó2013 AACR.

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Section: Methodsmentioning

confidence: 99%

DNA Methyltransferase Inhibition Reverses Epigenetically Embedded Phenotypes in Lung Cancer Preferentially Affecting Polycomb Target Genes

Hascher

Haase

Hebestreit

et al. 2014

Clinical Cancer Research

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“…In addition, expression of MIR335 is lost in the majority of primary breast tumors from patients who relapse and loss of MIR335 expression is associated with poor-distal metastasis-free survival. The loss of EPHB6 expression is associated with an increased risk of developing metastasis (Yu et al, 2010) and is correlated with a poor outcome in non-small cell lung cancer (Fox and Kandpal, 2009). All of these three known TSGs are suggested to be involved in tumor suppression and/or in the regulation of metastasis/development.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of genome‐wide minimally deleted regions in oral squamous cell carcinomas

Chien

Liao

Huang

et al. 2011

Genes Chromosomes & Cancer

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Oral squamous cell carcinoma (OSCC) has the highest rate of increase among male cancers in Taiwan. An understanding of the molecular pathogenesis of this disease as well as the development of prognostic markers for the clinical management of this disease is very important. Thus, a systematic loss of heterozygosity (LOH) analysis was performed to define minimally deleted regions (MDRs) in 63 male OSCCs using 400 polymorphic microsatellite markers. For increasing reliability, genomic DNA was extracted from >90% tumor cells that had been purified by LCM, and only when a microsatellite marker provided LOH information in >30% of the OSCCs was there considered to be successful allelotyping. A correlation of the various MDRs with clinicopathological parameters and prognosis was carried out. In total, 32 MDRs were identified and ten were noted as novel. In addition, six MDRs were found to be associated with cigarette smoking. Among these markers, a loss of MDR c7r2 (7q32.2-q35) was significantly associated with poor disease-free survival (DFS) and ten MDRs were associated with allelic imbalance (AI) in tumors. Among the latter, a loss of MDR c14r1 (14q24.2-q32.12) and c11r1 (11q13.4-q25) had a synergistic effect on poor DFS and were able to reduce further the DFS rate in patients with MDR c7r2 loss. Taken together, the results generated in this study provide new insights that help with exploring the molecular mechanisms associated with OSCC tumorigenesis and cigarette smoking. They also should aid the development of potential prognostic markers for the clinical management of OSCC.

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“…By contrast to these data suggesting a mainly pro-metastatic role, decreased levels of EphB6 are associated with an increased risk of metastases development in early stage non-small cell lung cancer (NSCLC) [54]. Restoration of EphB6 expression increased adhesion and decreased migration and entirely abolished metastasis formation in vivo [55]. In addition to angiogenesis, many biological processes determine cancer cells' metastatic potential, including migration, invasion, adhesion, intravasation, and extravasation.…”

Section: Role Of Ephrins and Ephs In Tumor-associated Angiogenesismentioning

confidence: 99%

The Eph/Ephrin family in cancer metastasis: communication at the service of invasion

Kandouz

2012

Cancer Metastasis Rev

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Cancer cells rely on intercellular communication throughout the different stages of their transformation and progression into metastasis. They do so by co-opting different processes such as cell-cell junctions, growth factors, receptors, and vesicular release. Initially characterized in neuronal and vascular tissues, Ephs and Ephrins, the largest family of receptor tyrosine kinases, comprised of two classes (i.e., A and B types), is increasingly scrutinized by cancer researchers. These proteins possess the particular features of both the receptors and ligands being membrane-bound which, via mandatory direct cell-cell interactions, undergo a bidirectional signal transduction initiated from both the receptor and the ligand. Following cell-cell interactions, Ephs/Ephrins behave as guidance molecules which trigger both repulsive and attractive signals, so as to direct the movement of cells through their immediate microenvironment. They also direct processes which include sorting and positioning and cytoskeleton rearrangements, thus making them perfect candidates for the control of the metastatic process. In fact, the role of Ephs and Ephrins in cancer progression has been demonstrated for many of the family members and they, surprisingly, have both tumor promoter and suppressor functions in different cellular contexts. They are also able to coordinate between multiple processes including cell survival, proliferation, differentiation, adhesion, motility, and invasion. This review is an attempt to summarize the data available on these Ephs/Ephrins' biological functions which contribute to the onset of aggressive cancers. I will also provide an overview of the factors which could explain the functional differences demonstrated by Ephs and Ephrins at different stages of tumor progression and whose elucidation is warranted for any future therapeutic targeting of this signaling pathway in cancer metastasis.

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The EPHB6 Receptor Tyrosine Kinase Is a Metastasis Suppressor That Is Frequently Silenced by Promoter DNA Hypermethylation in Non–Small Cell Lung Cancer

Cited by 69 publications

References 33 publications

DNA Methyltransferase Inhibition Reverses Epigenetically Embedded Phenotypes in Lung Cancer Preferentially Affecting Polycomb Target Genes

DNA Methyltransferase Inhibition Reverses Epigenetically Embedded Phenotypes in Lung Cancer Preferentially Affecting Polycomb Target Genes

Clinical significance of genome‐wide minimally deleted regions in oral squamous cell carcinomas

The Eph/Ephrin family in cancer metastasis: communication at the service of invasion

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