Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion
Identifieur interne : 000E47 ( Istex/Corpus ); précédent : 000E46; suivant : 000E48Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion
Auteurs : Mirang Kim ; Hay-Ran Jang ; Jeong-Hwan Kim ; Seung-Moo Noh ; Kyu-Sang Song ; June-Sik Cho ; Hyun-Yong Jeong ; Jim C. Norman ; Patrick T. Caswell ; Gyeong Hoon Kang ; Seon-Young Kim ; Hyang-Sook Yoo ; Yong Sung KimSource :
- Carcinogenesis [ 0143-3334 ] ; 2008-02-17.
Abstract
Protein kinase D (PKD) 1 influences cell migration by mediating both trans-Golgi vesicle fission and integrin recycling to the cell surface. Using restriction landmark genomic scanning methods, we found that the promoter region of PKD1 was aberrantly methylated in gastric cancer cell lines. Silencing of PKD1 expression was detected in 72.7% of gastric cancer cell lines examined, and the silencing was associated with CpG hypermethylation in the promoter region of PKD1. Treatment with 5-aza-2-deoxycytidine and trichostatin A partially reversed PKD1 methylation and restored gene expression in PKD1-silenced cell lines. Real-time reverse transcriptionpolymerase chain reaction analysis of 96 paired clinical primary gastric cancer samples revealed that 59% of the analyzed tumors had a >2-fold decrease in PKD1 expression compared with each normal-appearing tissue and that this downregulation of PKD1 expression was significantly correlated with increased methylation. We also observed a gradual increase in the level of promoter methylation of PKD1 in aging, normal-appearing mucosal tissues, suggesting that PKD1 methylation may be one of the earliest events that predispose an individual to gastric cancer. PKD1 expression was required for directional migration of gastric cancer cells. Furthermore, knock down of PKD1 by RNA interference promoted the invasiveness of cell lines that expressed PKD1 at relatively high levels. Based on these results, we propose that PKD1 is frequently silenced by epigenetic regulation, which plays a role in cell migration and metastasis in gastric cancer.
Url:
DOI: 10.1093/carcin/bgm291
Links to Exploration step
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<front><div type="abstract">Protein kinase D (PKD) 1 influences cell migration by mediating both trans-Golgi vesicle fission and integrin recycling to the cell surface. Using restriction landmark genomic scanning methods, we found that the promoter region of PKD1 was aberrantly methylated in gastric cancer cell lines. Silencing of PKD1 expression was detected in 72.7% of gastric cancer cell lines examined, and the silencing was associated with CpG hypermethylation in the promoter region of PKD1. Treatment with 5-aza-2-deoxycytidine and trichostatin A partially reversed PKD1 methylation and restored gene expression in PKD1-silenced cell lines. Real-time reverse transcriptionpolymerase chain reaction analysis of 96 paired clinical primary gastric cancer samples revealed that 59% of the analyzed tumors had a >2-fold decrease in PKD1 expression compared with each normal-appearing tissue and that this downregulation of PKD1 expression was significantly correlated with increased methylation. We also observed a gradual increase in the level of promoter methylation of PKD1 in aging, normal-appearing mucosal tissues, suggesting that PKD1 methylation may be one of the earliest events that predispose an individual to gastric cancer. PKD1 expression was required for directional migration of gastric cancer cells. Furthermore, knock down of PKD1 by RNA interference promoted the invasiveness of cell lines that expressed PKD1 at relatively high levels. Based on these results, we propose that PKD1 is frequently silenced by epigenetic regulation, which plays a role in cell migration and metastasis in gastric cancer.</div>
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<abstract><p>Protein kinase D (PKD) 1 influences cell migration by mediating both trans-Golgi vesicle fission and integrin recycling to the cell surface. Using restriction landmark genomic scanning methods, we found that the promoter region of PKD1 was aberrantly methylated in gastric cancer cell lines. Silencing of PKD1 expression was detected in 72.7% of gastric cancer cell lines examined, and the silencing was associated with CpG hypermethylation in the promoter region of PKD1. Treatment with 5-aza-2-deoxycytidine and trichostatin A partially reversed PKD1 methylation and restored gene expression in PKD1-silenced cell lines. Real-time reverse transcriptionpolymerase chain reaction analysis of 96 paired clinical primary gastric cancer samples revealed that 59% of the analyzed tumors had a >2-fold decrease in PKD1 expression compared with each normal-appearing tissue and that this downregulation of PKD1 expression was significantly correlated with increased methylation. We also observed a gradual increase in the level of promoter methylation of PKD1 in aging, normal-appearing mucosal tissues, suggesting that PKD1 methylation may be one of the earliest events that predispose an individual to gastric cancer. PKD1 expression was required for directional migration of gastric cancer cells. Furthermore, knock down of PKD1 by RNA interference promoted the invasiveness of cell lines that expressed PKD1 at relatively high levels. Based on these results, we propose that PKD1 is frequently silenced by epigenetic regulation, which plays a role in cell migration and metastasis in gastric cancer.</p>
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<issn pub-type="epub">1460-2180</issn>
<issn pub-type="ppub">0143-3334</issn>
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<article-meta><article-id pub-id-type="doi">10.1093/carcin/bgm291</article-id>
<article-categories><subj-group><subject>CARCINOGENESIS</subject>
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<title-group><article-title>Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Mirang</given-names>
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<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff8">8</xref>
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<contrib contrib-type="author"><name><surname>Jang</surname>
<given-names>Hay-Ran</given-names>
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<xref ref-type="aff" rid="aff1">1</xref>
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<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Jeong-Hwan</given-names>
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<xref ref-type="aff" rid="aff1">1</xref>
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<contrib contrib-type="author"><name><surname>Noh</surname>
<given-names>Seung-Moo</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
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<contrib contrib-type="author"><name><surname>Song</surname>
<given-names>Kyu-Sang</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cho</surname>
<given-names>June-Sik</given-names>
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<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jeong</surname>
<given-names>Hyun-Yong</given-names>
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<xref ref-type="aff" rid="aff5">5</xref>
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<contrib contrib-type="author"><name><surname>Norman</surname>
<given-names>Jim C.</given-names>
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<xref ref-type="aff" rid="aff6">6</xref>
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<contrib contrib-type="author"><name><surname>Caswell</surname>
<given-names>Patrick T.</given-names>
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<xref ref-type="aff" rid="aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kang</surname>
<given-names>Gyeong Hoon</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
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<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Seon-Young</given-names>
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<xref ref-type="aff" rid="aff1">1</xref>
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<contrib contrib-type="author"><name><surname>Yoo</surname>
<given-names>Hyang-Sook</given-names>
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<xref ref-type="aff" rid="aff1">1</xref>
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<contrib contrib-type="author" corresp="yes"><name><surname>Kim</surname>
<given-names>Yong Sung</given-names>
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<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff8">8</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
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<aff id="aff1"><label>1</label>
Medical Genomics Research Center, KRIBB, Daejeon 305-806, Korea</aff>
<aff id="aff2"><label>2</label>
Department of General Surgery</aff>
<aff id="aff3"><label>3</label>
Department of Pathology</aff>
<aff id="aff4"><label>4</label>
Department of Diagnostic Radiology and</aff>
<aff id="aff5"><label>5</label>
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 301-747, Korea</aff>
<aff id="aff6"><label>6</label>
Integrin Cell Biology Laboratory, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK</aff>
<aff id="aff7"><label>7</label>
Department of Pathology, Seoul National University College of Medicine, Seoul 110-744, Korea</aff>
<aff id="aff8"><label>8</label>
Department of Functional Genomics, University of Science and Technology, Daejeon 305-806, Korea</aff>
<author-notes><corresp id="cor1"><label>*</label>
To whom correspondence should be addressed. Tel: +82 42 879 8110; Fax: +82 42 879 8119; Email: <email>yongsung@kribb.re.kr</email>
</corresp>
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<pub-date pub-type="epub-ppub"><month>3</month>
<year>2008</year>
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<pub-date pub-type="epub"><day>17</day>
<month>2</month>
<year>2008</year>
</pub-date>
<volume>29</volume>
<issue>3</issue>
<fpage>629</fpage>
<lpage>637</lpage>
<history><date date-type="received"><day>3</day>
<month>9</month>
<year>2007</year>
</date>
<date date-type="rev-recd"><day>27</day>
<month>11</month>
<year>2007</year>
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<date date-type="accepted"><day>27</day>
<month>11</month>
<year>2007</year>
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<permissions><copyright-statement>© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement>
<copyright-year>2008</copyright-year>
<license license-type="open-access"><p>The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org</p>
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<abstract><p>Protein kinase D (PKD) 1 influences cell migration by mediating both <italic>trans</italic>
-Golgi vesicle fission and integrin recycling to the cell surface. Using restriction landmark genomic scanning methods, we found that the promoter region of <italic>PKD1</italic>
was aberrantly methylated in gastric cancer cell lines. Silencing of <italic>PKD1</italic>
expression was detected in 72.7% of gastric cancer cell lines examined, and the silencing was associated with CpG hypermethylation in the promoter region of <italic>PKD1</italic>
. Treatment with 5-aza-2′-deoxycytidine and trichostatin A partially reversed <italic>PKD1</italic>
methylation and restored gene expression in <italic>PKD1</italic>
-silenced cell lines. Real-time reverse transcription–polymerase chain reaction analysis of 96 paired clinical primary gastric cancer samples revealed that 59% of the analyzed tumors had a >2-fold decrease in <italic>PKD1</italic>
expression compared with each normal-appearing tissue and that this downregulation of <italic>PKD1</italic>
expression was significantly correlated with increased methylation. We also observed a gradual increase in the level of promoter methylation of <italic>PKD1</italic>
in aging, normal-appearing mucosal tissues, suggesting that <italic>PKD1</italic>
methylation may be one of the earliest events that predispose an individual to gastric cancer. PKD1 expression was required for directional migration of gastric cancer cells. Furthermore, knock down of PKD1 by RNA interference promoted the invasiveness of cell lines that expressed PKD1 at relatively high levels. Based on these results, we propose that <italic>PKD1</italic>
is frequently silenced by epigenetic regulation, which plays a role in cell migration and metastasis in gastric cancer.</p>
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