Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis
Identifieur interne : 000053 ( Pmc/Checkpoint ); précédent : 000052; suivant : 000054Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis
Auteurs : Aruz Mesci [Canada] ; Xiaoyong Huang [Canada] ; Samira Taeb [Canada] ; Sahar Jahangiri [Canada] ; Yohan Kim [Canada] ; Emmanouil Fokas [Royaume-Uni] ; Jeff Bruce [Canada] ; Hon S. Leong [Canada] ; Stanley K. Liu [Canada]Source :
- British Journal of Cancer [ 0007-0920 ] ; 2017.
Abstract
MicroRNAs (miRs) are involved in the regulation of many processes that contribute to malignancy, including cell proliferation, radiation resistance, invasion and metastasis. The role of miR-330-3p, an miR upregulated in breast cancer, remains unclear.
We examine the association of miR-330-3p with distant relapse-free survival in the Oxford cohort of breast cancer patients. We also study miR-330-3p function using
miR-330-3p is enriched in breast cancer, and higher levels of miR-330-3p expression are associated with lower distant relapse-free survival in a cohort of breast cancer patients. Consistent with these observations, overexpression of miR-330-3p in breast cancer cell lines results in greater invasiveness
We show for the first time that miR-330-3p targets CCBE1 to promote invasion and metastasis. miR-330-3p and CCBE1 may represent promising biomarkers in breast cancer.
Url:
DOI: 10.1038/bjc.2017.105
PubMed: 28419078
PubMed Central: 5482727
Affiliations:
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<author><name sortKey="Leong, Hon S" sort="Leong, Hon S" uniqKey="Leong H" first="Hon S" last="Leong">Hon S. Leong</name>
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<author><name sortKey="Huang, Xiaoyong" sort="Huang, Xiaoyong" uniqKey="Huang X" first="Xiaoyong" last="Huang">Xiaoyong Huang</name>
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<country xml:lang="fr">Canada</country>
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<author><name sortKey="Leong, Hon S" sort="Leong, Hon S" uniqKey="Leong H" first="Hon S" last="Leong">Hon S. Leong</name>
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, London, Ontario,<country>Canada</country>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<front><div type="abstract" xml:lang="en"><sec><title>Background:</title>
<p>MicroRNAs (miRs) are involved in the regulation of many processes that contribute to malignancy, including cell proliferation, radiation resistance, invasion and metastasis. The role of miR-330-3p, an miR upregulated in breast cancer, remains unclear.</p>
</sec>
<sec><title>Methods:</title>
<p>We examine the association of miR-330-3p with distant relapse-free survival in the Oxford cohort of breast cancer patients. We also study miR-330-3p function using <italic>in vitro</italic>
invasion and <italic>ex ovo</italic>
metastasis assays. Using <italic>in vitro</italic>
luciferase assays, we validate a novel target gene for miR-330-3p, Collagen And Calcium Binding EGF Domains 1 (CCBE1). We assess functional consequences of CCBE1 loss by using siRNA-mediated knockdown followed by <italic>in vitro</italic>
invasion assays. Lastly, we examine the expression profile of CCBE1 in breast carcinomas in the Curtis and TCGA Breast Cancer data sets using Oncomine Platform as well as distant relapse-free and overall survival of patients in the Helsinki University breast cancer data set according to CCBE1 expression status.</p>
</sec>
<sec><title>Results:</title>
<p>miR-330-3p is enriched in breast cancer, and higher levels of miR-330-3p expression are associated with lower distant relapse-free survival in a cohort of breast cancer patients. Consistent with these observations, overexpression of miR-330-3p in breast cancer cell lines results in greater invasiveness <italic>in vitro</italic>
, and miR-330-3p-overexpressing cells also metastasise more aggressively <italic>ex ovo</italic>
. We identify CCBE1 as a direct target of miR-330-3p, and show that knockdown of CCBE1 results in a greater invasive capacity. Accordingly, in breast cancer patients CCBE1 is frequently downregulated, and its loss is associated with reduced distant relapse-free and overall survival.</p>
</sec>
<sec><title>Conclusions:</title>
<p>We show for the first time that miR-330-3p targets CCBE1 to promote invasion and metastasis. miR-330-3p and CCBE1 may represent promising biomarkers in breast cancer.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Cancer</journal-id>
<journal-id journal-id-type="iso-abbrev">Br. J. Cancer</journal-id>
<journal-title-group><journal-title>British Journal of Cancer</journal-title>
</journal-title-group>
<issn pub-type="ppub">0007-0920</issn>
<issn pub-type="epub">1532-1827</issn>
<publisher><publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">28419078</article-id>
<article-id pub-id-type="pmc">5482727</article-id>
<article-id pub-id-type="pii">bjc2017105</article-id>
<article-id pub-id-type="doi">10.1038/bjc.2017.105</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Molecular Diagnostics</subject>
</subj-group>
</article-categories>
<title-group><article-title>Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis</article-title>
<alt-title alt-title-type="running">Targeting of CCBE1 by miR-330-3p</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Mesci</surname>
<given-names>Aruz</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Xiaoyong</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Taeb</surname>
<given-names>Samira</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jahangiri</surname>
<given-names>Sahar</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Yohan</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fokas</surname>
<given-names>Emmanouil</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bruce</surname>
<given-names>Jeff</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Leong</surname>
<given-names>Hon S</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Stanley K</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff6">6</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
</contrib>
<aff id="aff1"><label>1</label>
<institution>Sunnybrook Research Institute, Sunnybrook Health Sciences Centre</institution>
, Toronto, Ontario,<country>Canada</country>
</aff>
<aff id="aff2"><label>2</label>
<institution>Department of Radiation Oncology, University of Toronto</institution>
, Toronto, Ontario,<country>Canada</country>
</aff>
<aff id="aff3"><label>3</label>
<institution>Pathology and Lab Medicine, University of Western Ontario</institution>
, London, Ontario,<country>Canada</country>
</aff>
<aff id="aff4"><label>4</label>
<institution>Oxford Institute for Radiation Oncology, University of Oxford</institution>
, Oxford,<country>UK</country>
</aff>
<aff id="aff5"><label>5</label>
<institution>Princess Margaret Cancer Centre</institution>
, Toronto, Ontario,<country>Canada</country>
</aff>
<aff id="aff6"><label>6</label>
<institution>Department of Medical Biophysics, University of Toronto</institution>
, Toronto, Ontario,<country>Canada</country>
</aff>
</contrib-group>
<author-notes><corresp id="caf1"><label>*</label>
E-mail: <email>stanley.liu@sunnybrook.ca</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>09</day>
<month>05</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="epub"><day>18</day>
<month>04</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>9</day>
<month>5</month>
<year>2017</year>
</pub-date>
<volume>116</volume>
<issue>10</issue>
<fpage>1350</fpage>
<lpage>1357</lpage>
<history><date date-type="received"><day>25</day>
<month>09</month>
<year>2016</year>
</date>
<date date-type="rev-recd"><day>21</day>
<month>03</month>
<year>2017</year>
</date>
<date date-type="accepted"><day>23</day>
<month>03</month>
<year>2017</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2017 The Author(s)</copyright-statement>
<copyright-year>2017</copyright-year>
<copyright-holder>The Author(s)</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-sa/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-sa/4.0/">http://creativecommons.org/licenses/by-nc-sa/4.0/</ext-link>
</license-p>
</license>
</permissions>
<abstract><sec><title>Background:</title>
<p>MicroRNAs (miRs) are involved in the regulation of many processes that contribute to malignancy, including cell proliferation, radiation resistance, invasion and metastasis. The role of miR-330-3p, an miR upregulated in breast cancer, remains unclear.</p>
</sec>
<sec><title>Methods:</title>
<p>We examine the association of miR-330-3p with distant relapse-free survival in the Oxford cohort of breast cancer patients. We also study miR-330-3p function using <italic>in vitro</italic>
invasion and <italic>ex ovo</italic>
metastasis assays. Using <italic>in vitro</italic>
luciferase assays, we validate a novel target gene for miR-330-3p, Collagen And Calcium Binding EGF Domains 1 (CCBE1). We assess functional consequences of CCBE1 loss by using siRNA-mediated knockdown followed by <italic>in vitro</italic>
invasion assays. Lastly, we examine the expression profile of CCBE1 in breast carcinomas in the Curtis and TCGA Breast Cancer data sets using Oncomine Platform as well as distant relapse-free and overall survival of patients in the Helsinki University breast cancer data set according to CCBE1 expression status.</p>
</sec>
<sec><title>Results:</title>
<p>miR-330-3p is enriched in breast cancer, and higher levels of miR-330-3p expression are associated with lower distant relapse-free survival in a cohort of breast cancer patients. Consistent with these observations, overexpression of miR-330-3p in breast cancer cell lines results in greater invasiveness <italic>in vitro</italic>
, and miR-330-3p-overexpressing cells also metastasise more aggressively <italic>ex ovo</italic>
. We identify CCBE1 as a direct target of miR-330-3p, and show that knockdown of CCBE1 results in a greater invasive capacity. Accordingly, in breast cancer patients CCBE1 is frequently downregulated, and its loss is associated with reduced distant relapse-free and overall survival.</p>
</sec>
<sec><title>Conclusions:</title>
<p>We show for the first time that miR-330-3p targets CCBE1 to promote invasion and metastasis. miR-330-3p and CCBE1 may represent promising biomarkers in breast cancer.</p>
</sec>
</abstract>
<kwd-group><kwd>miR-330-3p</kwd>
<kwd>metastasis</kwd>
<kwd>invasion</kwd>
<kwd>CCBE1</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="fig1"><label>Figure 1</label>
<caption><p><bold>miR-330-3p is elevated in human breast cancer and is associated with reduced distant relapse-free survival.</bold>
(<bold>A</bold>
) Expression levels of miR-330-3p in a cohort of human breast cancer patients (GSE22216; cancer <italic>versus</italic>
normal tissue). (<bold>B</bold>
) The Kaplan–Meier curve of distant relapse-free survival in the early-stage breast cancer patient cohort: lowest quartile of miR-330-3p expression (solid) <italic>versus</italic>
higher three quartiles (dashed) of miR-330-3p expression. A log-rank test was performed for statistical significance, and the hazard ratio was calculated between the two groups (*<italic>P</italic>
<0.05, **<italic>P</italic>
<0.01).</p>
</caption>
<graphic xlink:href="bjc2017105f1"></graphic>
</fig>
<fig id="fig2"><label>Figure 2</label>
<caption><p><bold>miR-330-3p increases invasiveness, extravasation and metastases.</bold>
(<bold>A</bold>
) MDA-MB-231 or MCF10.DCIS were transiently transfected with the miR-330-3p or the control mimic, followed by a Matrigel transwell invasion assay. Means, standard deviations and statistical significance are shown (*<italic>P</italic>
<0.05; <italic>n</italic>
=3 independent experiments). Representative images of the invasion assays for MDA-MB-231 are shown. Scale bar denotes 100 <italic>μ</italic>
m. (<bold>B</bold>
) MDA-MB-231 cells were transduced with a lentivirus encoding for the control (MDA.ctrl) or the miR-330-3p (MDA.330p) mimic, followed by the chick CAM assay. Extravasation efficiency, actin stress fibres per cell and number metastatic colonies are shown with means, standard deviations and statistical significance (*<italic>P</italic>
<0.05, ***<italic>P</italic>
<0.001; <italic>n</italic>
=3 independent experiments). Representative images are shown; green: MDA.ctrl or MDA.330p transductants (as labelled) expressing GFP; red: stroma stained with lectin; blue: stroma stained with dextran. Representative image shows three different planes of view (XY, XZ and YZ as labelled) Scale bar=20 <italic>μ</italic>
m, magnification: × 60.</p>
</caption>
<graphic xlink:href="bjc2017105f2"></graphic>
</fig>
<fig id="fig3"><label>Figure 3</label>
<caption><p><bold>miR-330-3p targets CCBE1, and CCBE1 downregulation results in increased invasiveness.</bold>
(<bold>A</bold>
) Pearson correlation test of miR-330-3p expression with CCBE1 transcript expression from Oxford breast cohort (GSE22216 for miR and GSE22219 for mRNA); Pearson’s rho=−0.129, ***<italic>P</italic>
<0.005. (<bold>B</bold>
) MDA-MB-231 were transiently transfected with the miR-330-3p or the control mimic. Left panel: qPCR analysis of CCBE1 transcripts (normalised to GAPDH). Means and standard deviations are shown. Middle panel: representative western blot of CCBE1 protein levels (with <italic>β</italic>
-actin control; numbers shown represent molecular weight markers in kDa). Right panel: densitometry analyses of CCBE1 protein normalised to <italic>β</italic>
-actin control). (<bold>C</bold>
) Sequence alignment of miR-330-3p with the wild type (wt) or mutated (mut) 3′UTR of CCBE1 showing the putative miR-330-3p binding site. MDA-MB-231 cells were transiently transfected with control or the miR-330-3p mimic, in combination with the wild type (wt; middle panel) or the mutated (mut; right panel) 3′UTR CCBE1 luciferase reporter. Luciferase activity was normalised to a renilla control. Means, standard deviations and statistical significance are shown. <italic>n</italic>
=3 independent experiments. (<bold>D</bold>
) MDA-MB-231 or MCF10DCIS.COM cells were transfected with a pool of CCBE1-specific siRNA (siCCBE1) or control (control) mimic, followed by qPCR analysis of CCBE1 transcripts (normalised to GAPDH) (left panel) or western blot analysis (normalised to <italic>β</italic>
-actin) (middle panel – representative blot shown). Densitometry is shown in the right panel. (<bold>E</bold>
) Matrigel transwell invasion assay of MDA-MB-231 or MCF10DCIS.COM cell lines transfected with siCCBE1 or Control as above. Means, standard deviations, and statistical significance are shown from <italic>n</italic>
=3 independent experiments. Representative images are displayed (scale bar: MDA-MB-231: 200 <italic>μ</italic>
m; MCF10DCIS.COM: 500 <italic>μ</italic>
m).</p>
</caption>
<graphic xlink:href="bjc2017105f3"></graphic>
</fig>
<fig id="fig4"><label>Figure 4</label>
<caption><p><bold>CCBE1 is downregulated in a cohort of patients with DCIS and invasive ductal carcinoma, and CCBE1 levels inversely correlate with survival.</bold>
(<bold>A</bold>
) Oncotype Platform was searched for differential expression of CCBE1 in normal <italic>versus</italic>
cancer tissues (gene keyword: CCBE1, search limited by breast cancer, cancer <italic>versus</italic>
normal analysis). Results were ordered by fold change (reduction). Comparison of normal <italic>versus</italic>
DCIS (left panel), normal <italic>versus</italic>
invasive ductal carcinoma (middle panel) from Curtis Breast Cancer data set, as well as normal <italic>versus</italic>
invasive ductal carcinoma from the TCGA Breast Cancer data set (right panel) are shown. 25–75 percentile range is shown by the box; median is indicated by the line inside the 25–75 percentile. Also shown are 10–90 percentile range (lines above and below the 25–75 percentile) and minimum/maximum values (dots). Fold change in CCBE1 expression and <italic>P</italic>
-values is indicated. ***<italic>P</italic>
<0.001. (<bold>B</bold>
) Kaplan–Meier distant relapse-free survival (left panel) and overall survival (middle panel) curves of the Helsinki University breast cancer patient cohort (GSE24450) as well as distant relapse-free survival in the Oxford breast cohort (right panel; GSE22219) are shown as lower quartile of CCBE1 expression (dashed line) <italic>versus</italic>
higher three quartiles of CCBE1 (solid line) expression. Log-rank test was performed for statistical significance (**<italic>P</italic>
<0.01; *<italic>P</italic>
<0.05; NS, nonsignificant, <italic>P</italic>
>0.05).</p>
</caption>
<graphic xlink:href="bjc2017105f4"></graphic>
</fig>
</floats-group>
</pmc>
<affiliations><list><country><li>Canada</li>
<li>Royaume-Uni</li>
</country>
</list>
<tree><country name="Canada"><noRegion><name sortKey="Mesci, Aruz" sort="Mesci, Aruz" uniqKey="Mesci A" first="Aruz" last="Mesci">Aruz Mesci</name>
</noRegion>
<name sortKey="Bruce, Jeff" sort="Bruce, Jeff" uniqKey="Bruce J" first="Jeff" last="Bruce">Jeff Bruce</name>
<name sortKey="Huang, Xiaoyong" sort="Huang, Xiaoyong" uniqKey="Huang X" first="Xiaoyong" last="Huang">Xiaoyong Huang</name>
<name sortKey="Jahangiri, Sahar" sort="Jahangiri, Sahar" uniqKey="Jahangiri S" first="Sahar" last="Jahangiri">Sahar Jahangiri</name>
<name sortKey="Kim, Yohan" sort="Kim, Yohan" uniqKey="Kim Y" first="Yohan" last="Kim">Yohan Kim</name>
<name sortKey="Leong, Hon S" sort="Leong, Hon S" uniqKey="Leong H" first="Hon S" last="Leong">Hon S. Leong</name>
<name sortKey="Liu, Stanley K" sort="Liu, Stanley K" uniqKey="Liu S" first="Stanley K" last="Liu">Stanley K. Liu</name>
<name sortKey="Liu, Stanley K" sort="Liu, Stanley K" uniqKey="Liu S" first="Stanley K" last="Liu">Stanley K. Liu</name>
<name sortKey="Liu, Stanley K" sort="Liu, Stanley K" uniqKey="Liu S" first="Stanley K" last="Liu">Stanley K. Liu</name>
<name sortKey="Mesci, Aruz" sort="Mesci, Aruz" uniqKey="Mesci A" first="Aruz" last="Mesci">Aruz Mesci</name>
<name sortKey="Taeb, Samira" sort="Taeb, Samira" uniqKey="Taeb S" first="Samira" last="Taeb">Samira Taeb</name>
</country>
<country name="Royaume-Uni"><noRegion><name sortKey="Fokas, Emmanouil" sort="Fokas, Emmanouil" uniqKey="Fokas E" first="Emmanouil" last="Fokas">Emmanouil Fokas</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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