Distinct TPEF/HPP1 gene methylation patterns in gastric cancer indicate a field effect in gastric carcinogenesis

Ivanauskas, Audrius; Hoffmann, Juliane; Jonaitis, Laimas Virginijus; Markelis, Rytis; Juozaitytė, Elona; Kupčinskas, Limas; Lofton–Day, Catherine; Röcken, Christoph; Malfertheiner, Peter

doi:10.1016/j.dld.2008.05.004

Cited by 16 publications

(9 citation statements)

References 18 publications

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“…These findings are in line with the Maastricht IV consensus, which states that host genetic polymorphisms still do not have a clinical role in the management of individual patients [8]. The importance of epigenetic changes was stated in the study by Ivanauskas et al [45], showing that TPEF/HPP1 methylation is partly associated with gene silencing in gastric cancer tissue, and this epigenetic alteration may play a role in the early phase of gastric carcinogenesis. In addition, tumor-free gastric mucosa distal to histological cancer lesions might not be ‘healthy' indeed, resulting in a ﬁeld effect which is characterized by distinct genetic and epigenetic changes.…”

Section: Basic Research Insights Into the Pathogenesis Of H Pylori-rsupporting

confidence: 72%

Management of Helicobacter pylori-Related Diseases in the Baltic States

Kupčinskas

Leja²

2014

Dig Dis

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Helicobacter pylori infection has been recognized as the main trigger of stomach-related diseases. The huge variation in H. pylori infection patterns across the globe requires targeted research and close monitoring of this infection in different regions. The Baltic countries have witnessed enormous changes in socioeconomic conditions in the last years. Evolution of H. pylori infection and related diseases has been a key interest of gastroenterology centers in the Baltic States over the last two decades, translating into up-to-date scientific data that are valuable locally and on the European level. The East-West gradient in the prevalence of H. pylori infection is still evident in the Baltic countries, but the gap is becoming smaller, and similar trends are expected for the coming years. Clarithromycin-based triple therapy remains the first-line treatment of H. pylori in the region; however, careful monitoring of resistance rates in the future remains highly relevant, though routine resistance testing is not available in all the countries. A high prevalence of gastric cancer is still notable in the Baltic States; nevertheless, a steady decline in gastric cancer incidence in Lithuania, Latvia and Estonia is present and expected to be continuing during the coming decades. Currently, H. pylori-related diseases still constitute a substantial part of gastroenterologists' workload in the region. This paper reviews epidemiological, diagnostic, treatment as well as basic research trends on H. pylori infection and related diseases in the Baltic States during the last two decades.

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Section: Basic Research Insights Into the Pathogenesis Of H Pylori-rsupporting

confidence: 72%

Management of Helicobacter pylori-Related Diseases in the Baltic States

Kupčinskas

Leja²

2014

Dig Dis

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“…Deregulated expression of TMEFF2 has been documented in a variety of tumor types (3,8,(11)(12)(13)(14)(15)(16)25, and references therein). However, the relationship of TMEFF2 to the biology of tumor development or suppression and the molecular bases of these activities remain unknown.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor Activity of the Transmembrane Protein with Epidermal Growth Factor and Two Follistatin Motifs 2 (TMEFF2) Correlates with Its Ability to Modulate Sarcosine Levels

Chen¹,

Overcash²,

Green

et al. 2011

Journal of Biological Chemistry

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The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed in brain and prostate and overexpressed in prostate cancer, but its role in this disease is unclear. Several studies have suggested that TMEFF2 plays a role in suppressing the growth and invasive potential of human cancer cells, whereas others suggest that the shed portion of TMEFF2, which lacks the cytoplasmic region, has a growth-promoting activity. Here we show that TMEFF2 has a dual mode of action. Ectopic expression of wild-type fulllength TMEFF2 inhibits soft agar colony formation, cellular invasion, and migration and increases cellular sensitivity to apoptosis. However, expression of the ectodomain portion of TMEFF2 increases cell proliferation. Using affinity chromatography and mass spectrometry, we identify sarcosine dehydrogenase (SARDH), the enzyme that converts sarcosine to glycine, as a TMEFF2-interacting protein. Co-immunoprecipitation and immunofluorescence analysis confirms the interaction of SARDH with full-length TMEFF2. The ectodomain does not bind to SARDH. Moreover, expression of the full-length TMEFF2 but not the ectodomain results in a decreased level of sarcosine in the cells. These results suggest that the tumor suppressor activity of TMEFF2 requires the cytoplasmic/transmembrane portion of the protein and correlates with its ability to bind to SARDH and to modulate the level of sarcosine.The transmembrane protein with an epidermal growth factor and two follistatin motifs 2 (TMEFF2) 3 is an evolutionarily conserved type I transmembrane protein expressed in the embryo (1, 2) and selectively in the adult brain and prostate (3-5). The extracellular (ecto-) domain can be cleaved from the membrane in an ADAM17/␥-secretase-dependent fashion (6, 7) and consists of an epidermal growth factor-like motif and two follistatin motifs. The cytoplasmic domain contains a potential G-protein activation motif (2). A critical role for this protein in tumorigenesis is suggested by the fact that it is upregulated in a significant fraction of primary and metastatic prostate tumors (3)(4)(5)8). In fact, ectopic expression or the addition of purified recombinant TMEFF2 ectodomain promotes neuronal cell survival (9), cell growth (6), and phosphorylation of erbB4 and ERK1/2 (2, 6). However, it has also been suggested that TMEFF2 functions as a tumor suppressor because ectopic expression of full-length TMEFF2 demonstrates in vitro antiproliferative effects (4, 10) and suppresses tumor growth in vivo in nude mouse xenografts (10). Consistent with a tumor suppressor activity, Tmeff2 has been shown to be hypermethylated in a number of cancer types (Refs. 11-16 and references therein), and the Tmeff2 promoter is repressed by c-Myc (17).Recently, sarcosine, a glycine derivative, was identified as a potential marker of prostate cancer progression (18). Sarcosine levels were highest in metastatic cancer, and in urine, its levels were higher in men with prostate cancer than in controls. Importantly, using cell ...

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“…Aberrant methylation has been implicated in the development of gastric adenocarcinomas. Our data suggest that methylation is present in the majority of gastric adenocarcinomas and in the surrounding tumour-free area, indicating that this epigenetic change may indicate a field effect in the gastric mucosa (33).…”

Section: Molecular Alterations Related To H Pylori Induced Premalignmentioning

confidence: 63%

Helicobacter pylori infection, premalignant gastric lesions and gastric cancer in the Baltic States: a review

Kupčinskas¹,

Malfertheiner²

2011

AML

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Helicobacter pylori (H. pylori) infection has been recognized as a human class I carcinogen in 1994 and linked with the development of gastric cancer in numerous studies. Gastric cancer still ranks as the second leading mortality cause among all cancers in the world and in the fourth place in Europe. High prevalence of H. pylori infection and high incidence of gastric cancer in adults are still characteristic of the Baltic States and resemble patterns in the Western and Northern European countries several decades ago. The recent decline in gastric cancer incidence and mortality as well as H. pylori prevalence in Lithuania, Latvia and Estonia reflects the worldwide trends. H. pylori induced diseases, however, still remain a significant burden for health care systems in the Baltic States. The relevance of H. pylori induced gastric diseases in the Baltic States has stimulated epidemiological, clinical as well as fundamental research on H. pylori infection, premalignant gastric conditions and gastric cancer. This paper reviews original research on H. pylori infection and related diseases in Lithuania, Latvia and Estonia during the period 1992–2011. Keywords: Helicobacter pylori, atrophic gastritis, gastric cancer, Baltic States

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Distinct TPEF/HPP1 gene methylation patterns in gastric cancer indicate a field effect in gastric carcinogenesis

Cited by 16 publications

References 18 publications

Management of <b><i>Helicobacter pylori</i></b>-Related Diseases in the Baltic States

Management of <b><i>Helicobacter pylori</i></b>-Related Diseases in the Baltic States

The Tumor Suppressor Activity of the Transmembrane Protein with Epidermal Growth Factor and Two Follistatin Motifs 2 (TMEFF2) Correlates with Its Ability to Modulate Sarcosine Levels

Helicobacter pylori infection, premalignant gastric lesions and gastric cancer in the Baltic States: a review

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