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Overexpression of PPT2 Represses the Clear Cell Renal Cell Carcinoma Progression by Reducing Epithelial-to-mesenchymal Transition

Identifieur interne : 000648 ( Pmc/Curation ); précédent : 000647; suivant : 000649

Overexpression of PPT2 Represses the Clear Cell Renal Cell Carcinoma Progression by Reducing Epithelial-to-mesenchymal Transition

Auteurs : Changfei Yuan [République populaire de Chine] ; Zhiyong Xiong [République populaire de Chine] ; Jian Shi [République populaire de Chine] ; Jingtao Peng [République populaire de Chine] ; Xiangui Meng [République populaire de Chine] ; Cheng Wang [République populaire de Chine] ; Wenjun Hu [République populaire de Chine] ; Zeyuan Ru [République populaire de Chine] ; Kairu Xie [République populaire de Chine] ; Hongmei Yang [République populaire de Chine] ; Ke Chen [République populaire de Chine] ; Xiaoping Zhang [République populaire de Chine]

Source :

RBID : PMC:6959065

Abstract

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors of the urinary system and has a poor response to radiotherapy and chemotherapy. To date, it is urgent to find effective biomarkers for the prevention and treatment of ccRCC. The occurrence and development of ccRCC is closely related to metabolic disturbances. Palmitoyl protein thioesterase 2 (PPT2) is a lysosomal thioesterase which is highly associated with metabolism, and it has never been studied in ccRCC. In this study, we first revealed PPT2 is significantly downregulated in ccRCC, and its expression level is highly correlated with clinicopathological parameters of ccRCC patients. Our ROC curve analyses evaluated the potential of PPT2 as a novel diagnostic marker and prognostic factor. Functional experiment results showed overexpression of PPT2 represses the proliferation, migration and invasion of ccRCC cells in vitro. Mechanistic investigations demonstrated that overexpression of PPT2 represses the ccRCC progression by reducing epithelial-to-mesenchymal transition (EMT). In conclusion, PPT2 is downregulated in ccRCC. Decreased PPT2 expression may be considered as a novel diagnostic marker and prognostic factor and serve as a therapeutic target for ccRCC.


Url:
DOI: 10.7150/jca.36477
PubMed: 31956361
PubMed Central: 6959065

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PMC:6959065

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<p>Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors of the urinary system and has a poor response to radiotherapy and chemotherapy. To date, it is urgent to find effective biomarkers for the prevention and treatment of ccRCC. The occurrence and development of ccRCC is closely related to metabolic disturbances. Palmitoyl protein thioesterase 2 (PPT2) is a lysosomal thioesterase which is highly associated with metabolism, and it has never been studied in ccRCC. In this study, we first revealed PPT2 is significantly downregulated in ccRCC, and its expression level is highly correlated with clinicopathological parameters of ccRCC patients. Our ROC curve analyses evaluated the potential of PPT2 as a novel diagnostic marker and prognostic factor. Functional experiment results showed overexpression of PPT2 represses the proliferation, migration and invasion of ccRCC cells
<italic>in vitro</italic>
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<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">J Cancer</journal-id>
<journal-id journal-id-type="iso-abbrev">J Cancer</journal-id>
<journal-id journal-id-type="publisher-id">jca</journal-id>
<journal-title-group>
<journal-title>Journal of Cancer</journal-title>
</journal-title-group>
<issn pub-type="epub">1837-9664</issn>
<publisher>
<publisher-name>Ivyspring International Publisher</publisher-name>
<publisher-loc>Sydney</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">31956361</article-id>
<article-id pub-id-type="pmc">6959065</article-id>
<article-id pub-id-type="doi">10.7150/jca.36477</article-id>
<article-id pub-id-type="publisher-id">jcav11p1151</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Research Paper</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Overexpression of PPT2 Represses the Clear Cell Renal Cell Carcinoma Progression by Reducing Epithelial-to-mesenchymal Transition</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Yuan</surname>
<given-names>ChangFei</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="author-notes" rid="FNA_number">#</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Xiong</surname>
<given-names>ZhiYong</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="author-notes" rid="FNA_number">#</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Shi</surname>
<given-names>Jian</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Peng</surname>
<given-names>JingTao</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Meng</surname>
<given-names>XianGui</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Cheng</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hu</surname>
<given-names>WenJun</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ru</surname>
<given-names>ZeYuan</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Xie</surname>
<given-names>KaiRu</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Yang</surname>
<given-names>HongMei</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Ke</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="corresp" rid="FNA_envelop"></xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Zhang</surname>
<given-names>XiaoPing</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="corresp" rid="FNA_envelop"></xref>
</contrib>
</contrib-group>
<aff id="A1">
<label>1</label>
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.</aff>
<aff id="A2">
<label>2</label>
Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China.</aff>
<author-notes>
<corresp id="FNA_envelop">✉ Corresponding authors: Tel.: +86-27-8535-1625. E-mail addresses:
<email>shenke@hust.edu.cn</email>
(K. Chen),
<email>xzhang@hust.edu.cn</email>
(X. Zhang).</corresp>
<fn fn-type="equal" id="FNA_number">
<p># These authors contributed equally to this study.</p>
</fn>
<fn fn-type="COI-statement">
<p>Competing Interests: The authors have declared that no competing interest exists.</p>
</fn>
</author-notes>
<pub-date pub-type="collection">
<year>2020</year>
</pub-date>
<pub-date pub-type="epub">
<day>1</day>
<month>1</month>
<year>2020</year>
</pub-date>
<volume>11</volume>
<issue>5</issue>
<fpage>1151</fpage>
<lpage>1161</lpage>
<history>
<date date-type="received">
<day>8</day>
<month>5</month>
<year>2019</year>
</date>
<date date-type="accepted">
<day>25</day>
<month>10</month>
<year>2019</year>
</date>
</history>
<permissions>
<copyright-statement>© The author(s)</copyright-statement>
<copyright-year>2020</copyright-year>
<license license-type="open-access">
<license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (
<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>
). See
<ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link>
for full terms and conditions.</license-p>
</license>
</permissions>
<abstract>
<p>Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors of the urinary system and has a poor response to radiotherapy and chemotherapy. To date, it is urgent to find effective biomarkers for the prevention and treatment of ccRCC. The occurrence and development of ccRCC is closely related to metabolic disturbances. Palmitoyl protein thioesterase 2 (PPT2) is a lysosomal thioesterase which is highly associated with metabolism, and it has never been studied in ccRCC. In this study, we first revealed PPT2 is significantly downregulated in ccRCC, and its expression level is highly correlated with clinicopathological parameters of ccRCC patients. Our ROC curve analyses evaluated the potential of PPT2 as a novel diagnostic marker and prognostic factor. Functional experiment results showed overexpression of PPT2 represses the proliferation, migration and invasion of ccRCC cells
<italic>in vitro</italic>
. Mechanistic investigations demonstrated that overexpression of PPT2 represses the ccRCC progression by reducing epithelial-to-mesenchymal transition (EMT). In conclusion, PPT2 is downregulated in ccRCC. Decreased PPT2 expression may be considered as a novel diagnostic marker and prognostic factor and serve as a therapeutic target for ccRCC.</p>
</abstract>
<kwd-group>
<kwd>PPT2</kwd>
<kwd>ccRCC</kwd>
<kwd>EMT</kwd>
<kwd>Biomarker</kwd>
<kwd>Prognosis</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption>
<p>
<bold> PPT2 is downregulated in ccRCC and has significant correlations with patients' survival.</bold>
(A) Heat map depicting PPT family mRNA expression of all cases from TCGA database; red signifies high expression, yellow signifies medium expression, blue signifies low expression. (B) Comparison of PPT family mRNA expression in paired and in non-paired groups. (C-D) The mRNA expression of PPT2 and PPT1 was divided into low expression group and high expression group respectively on the basis of the median, the survival rate of two corresponding groups was evaluated with Kaplan Meier method and tested by using log rank test.</p>
</caption>
<graphic xlink:href="jcav11p1151g001"></graphic>
</fig>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption>
<p>
<bold> PPT2 mRNA expression is lower in ccRCC comparing with normal tissues and is closely related to various clinicopathological parameters.</bold>
(A) The mRNA expression of PPT2 in statistics by Yusenko et al., Jones et al., and Beroukhim et al. were downloaded from Oncomine datasets and analyzed. In addition, the mRNA expression of PPT2 in ccRCC downloaded from the TCGA-KIRC datasets was compared with different clinicopathological parameters: (B) age, (C) gender, (D) metastasis, (E) survival status, (F) T stage, (G) pathological grade, (H) TNM stage, data differences were tested with Student's T-test.</p>
</caption>
<graphic xlink:href="jcav11p1151g002"></graphic>
</fig>
<fig id="F3" position="float">
<label>Figure 3</label>
<caption>
<p>
<bold> The PPT2 expression may be considered as a diagnostic biomarker for ccRCC patients.</bold>
The ROC curve analyses of PPT2 mRNA expression in subgroups of ccRCC patients show PPT2 expression is of significance in distinguishing ccRCC from normal renal tissues (A), M0 from M1 (B), G1+G2 from G3+G4 (C), T1+T2 from T3+T4 (D), TNM I+II from TNM III+IV (E), the recurred/progressed from the disease-free (F).</p>
</caption>
<graphic xlink:href="jcav11p1151g003"></graphic>
</fig>
<fig id="F4" position="float">
<label>Figure 4</label>
<caption>
<p>
<bold> PPT2 expression is downregulated both in clinical ccRCC samples and in renal cancer cell lines.</bold>
32 pairs of postoperative clinical samples were collected, Western Blot (A), qRT-PCR (B) and IHC (C) were conducted in clinical ccRCC samples and in matched adjacent normal tissues. (D-E) Western Blot and qRT-PCR were also conducted to investigate PPT2 expression in cell lines 293, 786-O, A-498, ACHN, CAKi-1 and OS-RC.</p>
</caption>
<graphic xlink:href="jcav11p1151g004"></graphic>
</fig>
<fig id="F5" position="float">
<label>Figure 5</label>
<caption>
<p>
<bold> Overexpression of PPT2 inhibits cell proliferation, migration and invasion
<italic>in vitro</italic>
.</bold>
(A-B) The efficiency of PPT2 overexpression in cell lines A-498 and CAKi-1 transfected with expression vectors of PPT2 was verified with Western Blot and qRT-PCR, relative gene expression was determined using the comparative delta-delta CT method. (C) CCK-8 assays revealed cell growth curves of A498 and CAKi-1 cells. (D-E) Migration and invasion assays for ccRCC cell lines A498 and CAKi-1, representative photographs were taken at ×200 magnification; number of cells was counted in ten random images from each group. (F-G) Representative micrographs of wound healing assays of cell lines A-498 and CAKi-1, wound closures were photographed at 0, 12 and 24 hours after wounding, representative photographs were taken at ×100 magnification.</p>
</caption>
<graphic xlink:href="jcav11p1151g005"></graphic>
</fig>
<fig id="F6" position="float">
<label>Figure 6</label>
<caption>
<p>
<bold> Decreased expression of PPT2 facilitates EMT in ccRCC
<italic>in vitro</italic>
.</bold>
(A-C) GSEA was performed to investigate the biological pathways involved in PPT2 regulation on the basis of TCGA database. (D-E) The alterations of EMT markers (E-cadherin, Vimentin, Snail1 and N-cadherin) were tested with Western Blot and qRT-PCR.</p>
</caption>
<graphic xlink:href="jcav11p1151g006"></graphic>
</fig>
<table-wrap id="T1" position="float">
<label>Table 1</label>
<caption>
<p>Clinicopathological parameters and their correlations with PPT2 mRNA expression</p>
</caption>
<table frame="hsides" rules="groups">
<thead valign="top">
<tr>
<th rowspan="2" colspan="1">Parameter</th>
<th rowspan="2" colspan="1"></th>
<th colspan="3" rowspan="1">PPT2 mRNA expression</th>
<th rowspan="2" colspan="1">P value</th>
</tr>
<tr>
<th rowspan="1" colspan="1">Number</th>
<th rowspan="1" colspan="1">Low(n=266)</th>
<th rowspan="1" colspan="1">High(n=266)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td rowspan="1" colspan="1">Age(years)</td>
<td rowspan="1" colspan="1">≤60</td>
<td rowspan="1" colspan="1">264</td>
<td rowspan="1" colspan="1">134</td>
<td rowspan="1" colspan="1">130</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">>60</td>
<td rowspan="1" colspan="1">268</td>
<td rowspan="1" colspan="1">132</td>
<td rowspan="1" colspan="1">136</td>
<td rowspan="1" colspan="1">.729</td>
</tr>
<tr>
<td rowspan="1" colspan="1">Gender</td>
<td rowspan="1" colspan="1">male</td>
<td rowspan="1" colspan="1">344</td>
<td rowspan="1" colspan="1">180</td>
<td rowspan="1" colspan="1">164</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">female</td>
<td rowspan="1" colspan="1">188</td>
<td rowspan="1" colspan="1">86</td>
<td rowspan="1" colspan="1">102</td>
<td rowspan="1" colspan="1">.147</td>
</tr>
<tr>
<td rowspan="1" colspan="1">Metastasis</td>
<td rowspan="1" colspan="1">M0</td>
<td rowspan="1" colspan="1">421</td>
<td rowspan="1" colspan="1">201</td>
<td rowspan="1" colspan="1">220</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">M1</td>
<td rowspan="1" colspan="1">79</td>
<td rowspan="1" colspan="1">58</td>
<td rowspan="1" colspan="1">21</td>
<td rowspan="1" colspan="1">.000*</td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">(MX)</td>
<td rowspan="1" colspan="1">(32)</td>
<td rowspan="1" colspan="1">(7)</td>
<td rowspan="1" colspan="1">(25)</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1">Survival status</td>
<td rowspan="1" colspan="1">Disease-free</td>
<td rowspan="1" colspan="1">308</td>
<td rowspan="1" colspan="1">134</td>
<td rowspan="1" colspan="1">174</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Recurred/Progressed</td>
<td rowspan="1" colspan="1">126</td>
<td rowspan="1" colspan="1">80</td>
<td rowspan="1" colspan="1">46</td>
<td rowspan="1" colspan="1">.000*</td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">(Missing)</td>
<td rowspan="1" colspan="1">(98)</td>
<td rowspan="1" colspan="1">(52)</td>
<td rowspan="1" colspan="1">(46)</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1">T stage</td>
<td rowspan="1" colspan="1">T1+T2</td>
<td rowspan="1" colspan="1">343</td>
<td rowspan="1" colspan="1">147</td>
<td rowspan="1" colspan="1">196</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">T3+T4</td>
<td rowspan="1" colspan="1">189</td>
<td rowspan="1" colspan="1">119</td>
<td rowspan="1" colspan="1">70</td>
<td rowspan="1" colspan="1">.000*</td>
</tr>
<tr>
<td rowspan="1" colspan="1">Grade</td>
<td rowspan="1" colspan="1">G1+G2</td>
<td rowspan="1" colspan="1">242</td>
<td rowspan="1" colspan="1">96</td>
<td rowspan="1" colspan="1">146</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">G3+G4</td>
<td rowspan="1" colspan="1">282</td>
<td rowspan="1" colspan="1">165</td>
<td rowspan="1" colspan="1">117</td>
<td rowspan="1" colspan="1">.000*</td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">(GX)</td>
<td rowspan="1" colspan="1">(8)</td>
<td rowspan="1" colspan="1">(5)</td>
<td rowspan="1" colspan="1">(3)</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1">TNM stage</td>
<td rowspan="1" colspan="1">I+II</td>
<td rowspan="1" colspan="1">323</td>
<td rowspan="1" colspan="1">134</td>
<td rowspan="1" colspan="1">189</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">III+IV</td>
<td rowspan="1" colspan="1">209</td>
<td rowspan="1" colspan="1">132</td>
<td rowspan="1" colspan="1">77</td>
<td rowspan="1" colspan="1">.000*</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T2" position="float">
<label>Table 2</label>
<caption>
<p>Univariate and multivariate analyses for patient overall survival</p>
</caption>
<table frame="hsides" rules="groups">
<thead valign="top">
<tr>
<th rowspan="2" colspan="1">Risk factor</th>
<th colspan="3" rowspan="1">Univariate analysis</th>
<th colspan="3" rowspan="1">Multivariate analysis</th>
</tr>
<tr>
<th rowspan="1" colspan="1">HR</th>
<th rowspan="1" colspan="1">p-Value</th>
<th rowspan="1" colspan="1">95% CI</th>
<th rowspan="1" colspan="1">HR</th>
<th rowspan="1" colspan="1">p-Value</th>
<th rowspan="1" colspan="1">95% CI</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td rowspan="1" colspan="1">PPT2 expression</td>
<td rowspan="1" colspan="1">0.712</td>
<td rowspan="1" colspan="1">0.030</td>
<td rowspan="1" colspan="1">0.525-0.967</td>
<td rowspan="1" colspan="1">0.942</td>
<td rowspan="1" colspan="1">0.047</td>
<td rowspan="1" colspan="1">0.687-1.292</td>
</tr>
<tr>
<td rowspan="1" colspan="1">Age</td>
<td rowspan="1" colspan="1">1.771</td>
<td rowspan="1" colspan="1">0.000</td>
<td rowspan="1" colspan="1">1.298-2.416</td>
<td rowspan="1" colspan="1">1.670</td>
<td rowspan="1" colspan="1">0.002</td>
<td rowspan="1" colspan="1">1.215-2.295</td>
</tr>
<tr>
<td rowspan="1" colspan="1">Gender</td>
<td rowspan="1" colspan="1">0.940</td>
<td rowspan="1" colspan="1">0.700</td>
<td rowspan="1" colspan="1">0.688-1.285</td>
<td rowspan="1" colspan="1">0.912</td>
<td rowspan="1" colspan="1">0.570</td>
<td rowspan="1" colspan="1">0.662-1.225</td>
</tr>
<tr>
<td rowspan="1" colspan="1">Metastasis</td>
<td rowspan="1" colspan="1">4.275</td>
<td rowspan="1" colspan="1">0.000</td>
<td rowspan="1" colspan="1">3.128-5.843</td>
<td rowspan="1" colspan="1">2.454</td>
<td rowspan="1" colspan="1">0.000</td>
<td rowspan="1" colspan="1">1.661-3.625</td>
</tr>
<tr>
<td rowspan="1" colspan="1">T stage</td>
<td rowspan="1" colspan="1">3.033</td>
<td rowspan="1" colspan="1">0.000</td>
<td rowspan="1" colspan="1">2.232-4.121</td>
<td rowspan="1" colspan="1">0.938</td>
<td rowspan="1" colspan="1">0.842</td>
<td rowspan="1" colspan="1">0.501-1.757</td>
</tr>
<tr>
<td rowspan="1" colspan="1">TNM stage</td>
<td rowspan="1" colspan="1">3.639</td>
<td rowspan="1" colspan="1">0.000</td>
<td rowspan="1" colspan="1">2.645-5.006</td>
<td rowspan="1" colspan="1">2.106</td>
<td rowspan="1" colspan="1">0.045</td>
<td rowspan="1" colspan="1">1.018-4.354</td>
</tr>
<tr>
<td rowspan="1" colspan="1">G stage</td>
<td rowspan="1" colspan="1">2.559</td>
<td rowspan="1" colspan="1">0.000</td>
<td rowspan="1" colspan="1">1.820-3.600</td>
<td rowspan="1" colspan="1">1.631</td>
<td rowspan="1" colspan="1">0.009</td>
<td rowspan="1" colspan="1">1.131-2.353</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>HR, hazard ratio, estimated from Cox proportional hazard regression model; CI, confidence interval of the estimated HR.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
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