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MicroRNAs in Animal Models of HCC

Identifieur interne : 000580 ( Pmc/Checkpoint ); précédent : 000579; suivant : 000581

MicroRNAs in Animal Models of HCC

Auteurs : Francesca Fornari [Italie] ; Laura Gramantieri ; Elisa Callegari ; Ram C. Shankaraiah ; Fabio Piscaglia [Italie] ; Massimo Negrini ; Catia Giovannini [Italie]

Source :

RBID : PMC:6966618

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.


Url:
DOI: 10.3390/cancers11121906
PubMed: 31805631
PubMed Central: 6966618


Affiliations:


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PMC:6966618

Le document en format XML

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<p>Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.</p>
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</author>
<author>
<name sortKey="Kotiyal, S" uniqKey="Kotiyal S">S. Kotiyal</name>
</author>
<author>
<name sortKey="Conley, C" uniqKey="Conley C">C. Conley</name>
</author>
<author>
<name sortKey="Phan, C" uniqKey="Phan C">C. Phan</name>
</author>
<author>
<name sortKey="Young, A" uniqKey="Young A">A. Young</name>
</author>
<author>
<name sortKey="Evason, K J" uniqKey="Evason K">K.J. Evason</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="review-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Cancers (Basel)</journal-id>
<journal-id journal-id-type="iso-abbrev">Cancers (Basel)</journal-id>
<journal-id journal-id-type="publisher-id">cancers</journal-id>
<journal-title-group>
<journal-title>Cancers</journal-title>
</journal-title-group>
<issn pub-type="epub">2072-6694</issn>
<publisher>
<publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">31805631</article-id>
<article-id pub-id-type="pmc">6966618</article-id>
<article-id pub-id-type="doi">10.3390/cancers11121906</article-id>
<article-id pub-id-type="publisher-id">cancers-11-01906</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Review</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>MicroRNAs in Animal Models of HCC</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4302-4411</contrib-id>
<name>
<surname>Fornari</surname>
<given-names>Francesca</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01906">1</xref>
<xref ref-type="aff" rid="af2-cancers-11-01906">2</xref>
<xref rid="c1-cancers-11-01906" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gramantieri</surname>
<given-names>Laura</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01906">1</xref>
<xref rid="c1-cancers-11-01906" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Callegari</surname>
<given-names>Elisa</given-names>
</name>
<xref ref-type="aff" rid="af3-cancers-11-01906">3</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-9824-0560</contrib-id>
<name>
<surname>Shankaraiah</surname>
<given-names>Ram C.</given-names>
</name>
<xref ref-type="aff" rid="af3-cancers-11-01906">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Piscaglia</surname>
<given-names>Fabio</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01906">1</xref>
<xref ref-type="aff" rid="af2-cancers-11-01906">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Negrini</surname>
<given-names>Massimo</given-names>
</name>
<xref ref-type="aff" rid="af3-cancers-11-01906">3</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-1904-1577</contrib-id>
<name>
<surname>Giovannini</surname>
<given-names>Catia</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01906">1</xref>
<xref ref-type="aff" rid="af2-cancers-11-01906">2</xref>
</contrib>
</contrib-group>
<aff id="af1-cancers-11-01906">
<label>1</label>
Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy;
<email>fabio.piscaglia@unibo.it</email>
(F.P.);
<email>catia.giovannini4@unibo.it</email>
(C.G.)</aff>
<aff id="af2-cancers-11-01906">
<label>2</label>
Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy</aff>
<aff id="af3-cancers-11-01906">
<label>3</label>
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Bologna, Italy;
<email>elisa.callegari@unife.it</email>
(E.C.);
<email>shnrch@unife.it</email>
(R.C.S.);</aff>
<author-notes>
<corresp id="c1-cancers-11-01906">
<label>*</label>
Correspondence:
<email>francesca.fornari2@unibo.it</email>
(F.F.);
<email>laura.gramantieri@aosp.bo.it</email>
(L.G.); Tel.: +39-0512-143-902 (F.F.)</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>01</day>
<month>12</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection">
<month>12</month>
<year>2019</year>
</pub-date>
<volume>11</volume>
<issue>12</issue>
<elocation-id>1906</elocation-id>
<history>
<date date-type="received">
<day>04</day>
<month>11</month>
<year>2019</year>
</date>
<date date-type="accepted">
<day>28</day>
<month>11</month>
<year>2019</year>
</date>
</history>
<permissions>
<copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access">
<license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract>
<p>Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.</p>
</abstract>
<kwd-group>
<kwd>HCC</kwd>
<kwd>microRNA</kwd>
<kwd>animal models</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group>
<fig id="cancers-11-01906-f001" orientation="portrait" position="float">
<label>Figure 1</label>
<caption>
<p>miRNA deregulated in human and rodent human hepatocellular carcinomas (HCCs) and miRNA-based approaches in preclinical models. Top panel depicts miRNA involved in human hepatocarcinogenesis from early development to advanced stages. Downregulated miRNAs are in green; upregulated miRNAs are in red. Bottom panel depicts experimental animal models of HCC and successful miRNA treatments reducing tumor burden. miRNA mimics treatments are in green; anti-miRNA (AM) treatments are in red [
<xref rid="B3-cancers-11-01906" ref-type="bibr">3</xref>
,
<xref rid="B4-cancers-11-01906" ref-type="bibr">4</xref>
,
<xref rid="B5-cancers-11-01906" ref-type="bibr">5</xref>
,
<xref rid="B6-cancers-11-01906" ref-type="bibr">6</xref>
,
<xref rid="B7-cancers-11-01906" ref-type="bibr">7</xref>
,
<xref rid="B8-cancers-11-01906" ref-type="bibr">8</xref>
,
<xref rid="B9-cancers-11-01906" ref-type="bibr">9</xref>
,
<xref rid="B12-cancers-11-01906" ref-type="bibr">12</xref>
,
<xref rid="B15-cancers-11-01906" ref-type="bibr">15</xref>
,
<xref rid="B16-cancers-11-01906" ref-type="bibr">16</xref>
,
<xref rid="B17-cancers-11-01906" ref-type="bibr">17</xref>
,
<xref rid="B18-cancers-11-01906" ref-type="bibr">18</xref>
,
<xref rid="B19-cancers-11-01906" ref-type="bibr">19</xref>
,
<xref rid="B20-cancers-11-01906" ref-type="bibr">20</xref>
,
<xref rid="B21-cancers-11-01906" ref-type="bibr">21</xref>
,
<xref rid="B22-cancers-11-01906" ref-type="bibr">22</xref>
,
<xref rid="B23-cancers-11-01906" ref-type="bibr">23</xref>
,
<xref rid="B24-cancers-11-01906" ref-type="bibr">24</xref>
,
<xref rid="B25-cancers-11-01906" ref-type="bibr">25</xref>
,
<xref rid="B26-cancers-11-01906" ref-type="bibr">26</xref>
,
<xref rid="B27-cancers-11-01906" ref-type="bibr">27</xref>
].</p>
</caption>
<graphic xlink:href="cancers-11-01906-g001"></graphic>
</fig>
<fig id="cancers-11-01906-f002" orientation="portrait" position="float">
<label>Figure 2</label>
<caption>
<p>Features of human and rat hepatocellular carcinoma. Hematoxylin-eosin staining of human (
<bold>H1–H3</bold>
) and rat (
<bold>R1–R3</bold>
) HCC showing common histopathological features. (H1–R1) Clear cell variant caused by glycogen or lipid accumulation. (H2–R2) Trabecular growth pattern. Neoplastic hepatocytes, with nuclear irregularity, are arranged in trabeculae larger than three cell plates. (H3–R3) Progression toward less-differentiated histopathological grades is marked by the appearance of irregular nuclei, nuclear, and cellular pleomorphism, frequent mitosis, and loss of trabecular or pseudoglandular structures. Original magnification 40×. Scale bars: 100 µm.</p>
</caption>
<graphic xlink:href="cancers-11-01906-g002"></graphic>
</fig>
<table-wrap id="cancers-11-01906-t001" orientation="portrait" position="float">
<object-id pub-id-type="pii">cancers-11-01906-t001_Table 1</object-id>
<label>Table 1</label>
<caption>
<p>miRNA downregulated in the Diethylnitrosamine-Hepatocellular carcinoma (DEN-HCC) rat model.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Rat Deregulated miRNA</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Fold Change (HCC/Surrounding Liver)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">
<italic>p</italic>
-Value</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Deregulation in Human HCC</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Target Genes in Human HCC</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-378a-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">18.3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-22-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11.9</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.012</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-338-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0017</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>HIF1A</italic>
;
<break></break>
<italic>PKLR</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B80-cancers-11-01906" ref-type="bibr">80</xref>
,
<xref rid="B81-cancers-11-01906" ref-type="bibr">81</xref>
,
<xref rid="B82-cancers-11-01906" ref-type="bibr">82</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-455-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0011</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>STK17B</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B83-cancers-11-01906" ref-type="bibr">83</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-144-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0011</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>SMAD4; CCNB1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B84-cancers-11-01906" ref-type="bibr">84</xref>
,
<xref rid="B85-cancers-11-01906" ref-type="bibr">85</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-203a-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">7.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.014</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>GPC3</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B86-cancers-11-01906" ref-type="bibr">86</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-352</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6.3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0098</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Rodent-specific miRNA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-30b-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6.2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0040</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-10b-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.012</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>HOXD10</italic>
;
<italic>CSMD1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B87-cancers-11-01906" ref-type="bibr">87</xref>
,
<xref rid="B88-cancers-11-01906" ref-type="bibr">88</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-99a-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0016</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-210-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0083</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>VMP1</italic>
;
<italic>HIF3A</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B89-cancers-11-01906" ref-type="bibr">89</xref>
,
<xref rid="B90-cancers-11-01906" ref-type="bibr">90</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-362-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0083</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>TOB2</italic>
;
<italic>RAB23</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B91-cancers-11-01906" ref-type="bibr">91</xref>
,
<xref rid="B92-cancers-11-01906" ref-type="bibr">92</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-30e-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0061</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-511-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0083</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>AKT1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B93-cancers-11-01906" ref-type="bibr">93</xref>
,
<xref rid="B94-cancers-11-01906" ref-type="bibr">94</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-193-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>SPOCK1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B95-cancers-11-01906" ref-type="bibr">95</xref>
,
<xref rid="B96-cancers-11-01906" ref-type="bibr">96</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-33-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0021</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-192-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0056</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-3547</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0059</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Not annotated human miRNA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-145-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.011</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>IRS1</italic>
;
<italic>IRS2</italic>
; NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B3-cancers-11-01906" ref-type="bibr">3</xref>
,
<xref rid="B58-cancers-11-01906" ref-type="bibr">58</xref>
,
<xref rid="B97-cancers-11-01906" ref-type="bibr">97</xref>
,
<xref rid="B98-cancers-11-01906" ref-type="bibr">98</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-378b</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0039</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-122-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0068</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>MDM2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B99-cancers-11-01906" ref-type="bibr">99</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-339-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.016</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-30a-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.012</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B100-cancers-11-01906" ref-type="bibr">100</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-101a-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0010</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>MCl-1</italic>
;
<italic>SOX9</italic>
;
<italic>EZH2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B101-cancers-11-01906" ref-type="bibr">101</xref>
,
<xref rid="B102-cancers-11-01906" ref-type="bibr">102</xref>
,
<xref rid="B103-cancers-11-01906" ref-type="bibr">103</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-193-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.4</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0011</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN;
<break></break>
DOWN; NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>uPA</italic>
; NA;
<italic>CCND1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B95-cancers-11-01906" ref-type="bibr">95</xref>
,
<xref rid="B104-cancers-11-01906" ref-type="bibr">104</xref>
,
<xref rid="B105-cancers-11-01906" ref-type="bibr">105</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-365-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.013</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>ADAM10</italic>
;
<italic>RAC1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B106-cancers-11-01906" ref-type="bibr">106</xref>
,
<xref rid="B107-cancers-11-01906" ref-type="bibr">107</xref>
,
<xref rid="B108-cancers-11-01906" ref-type="bibr">108</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-347</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0047</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Not annotated human miRNA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-7a-1-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.017</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Not annotated human miRNA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-125b-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0044</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>LIN28B</italic>
;
<break></break>
<italic>PlGF</italic>
;
<italic>Bcl-2</italic>
;
<break></break>
NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B109-cancers-11-01906" ref-type="bibr">109</xref>
,
<xref rid="B110-cancers-11-01906" ref-type="bibr">110</xref>
,
<xref rid="B111-cancers-11-01906" ref-type="bibr">111</xref>
,
<xref rid="B112-cancers-11-01906" ref-type="bibr">112</xref>
,
<xref rid="B113-cancers-11-01906" ref-type="bibr">113</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-122-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>CGN1</italic>
;
<italic>ADAM10</italic>
,
<italic>SRF</italic>
,
<italic>Igf1R</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B3-cancers-11-01906" ref-type="bibr">3</xref>
,
<xref rid="B114-cancers-11-01906" ref-type="bibr">114</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-140-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.016</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>GRN</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B115-cancers-11-01906" ref-type="bibr">115</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-101b-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.9</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0054</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>MCl-1</italic>
;
<italic>SOX9</italic>
;
<break></break>
<italic>EZH2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B101-cancers-11-01906" ref-type="bibr">101</xref>
,
<xref rid="B102-cancers-11-01906" ref-type="bibr">102</xref>
,
<xref rid="B103-cancers-11-01906" ref-type="bibr">103</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-10a-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.015</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>EphA4</italic>
;
<italic>NCOR2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B116-cancers-11-01906" ref-type="bibr">116</xref>
,
<xref rid="B117-cancers-11-01906" ref-type="bibr">117</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-22-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0041</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>HDAC4</italic>
;
<italic>YWHAZ</italic>
;
<italic>CD147</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B118-cancers-11-01906" ref-type="bibr">118</xref>
,
<xref rid="B119-cancers-11-01906" ref-type="bibr">119</xref>
,
<xref rid="B120-cancers-11-01906" ref-type="bibr">120</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-26b-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>CDK6</italic>
,
<italic>CCNE1</italic>
;
<italic>USP9X</italic>
;
<italic>SMAD1</italic>
;
<italic>ULK1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B27-cancers-11-01906" ref-type="bibr">27</xref>
,
<xref rid="B121-cancers-11-01906" ref-type="bibr">121</xref>
,
<xref rid="B122-cancers-11-01906" ref-type="bibr">122</xref>
,
<xref rid="B123-cancers-11-01906" ref-type="bibr">123</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-26a-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.013</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN; DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>CCND2</italic>
,
<italic>CCNE2</italic>
;
<italic>CDK6</italic>
,
<italic>CCNE1</italic>
;
<break></break>
<italic>IL6</italic>
;
<italic>VEGFA</italic>
;
<italic>ITGA5</italic>
;
<italic>ULK1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B26-cancers-11-01906" ref-type="bibr">26</xref>
,
<xref rid="B27-cancers-11-01906" ref-type="bibr">27</xref>
,
<xref rid="B121-cancers-11-01906" ref-type="bibr">121</xref>
,
<xref rid="B124-cancers-11-01906" ref-type="bibr">124</xref>
,
<xref rid="B125-cancers-11-01906" ref-type="bibr">125</xref>
,
<xref rid="B126-cancers-11-01906" ref-type="bibr">126</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-99a-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0013</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>MTOR</italic>
,
<italic>IGF-1R</italic>
;
<italic>PLK1</italic>
;
<italic>AGO2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B127-cancers-11-01906" ref-type="bibr">127</xref>
,
<xref rid="B128-cancers-11-01906" ref-type="bibr">128</xref>
,
<xref rid="B129-cancers-11-01906" ref-type="bibr">129</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-451-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.011</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>IKBKB</italic>
;
<italic>ATF2</italic>
;
<italic>c-Myc</italic>
;
<italic>YWHAZ</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B130-cancers-11-01906" ref-type="bibr">130</xref>
,
<xref rid="B131-cancers-11-01906" ref-type="bibr">131</xref>
,
<xref rid="B132-cancers-11-01906" ref-type="bibr">132</xref>
,
<xref rid="B133-cancers-11-01906" ref-type="bibr">133</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-30e-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.003</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>MTA1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B134-cancers-11-01906" ref-type="bibr">134</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-192-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>ZEB1</italic>
;
<italic>SLC39A6</italic>
;
<italic>HOTTIP</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B135-cancers-11-01906" ref-type="bibr">135</xref>
,
<xref rid="B136-cancers-11-01906" ref-type="bibr">136</xref>
,
<xref rid="B137-cancers-11-01906" ref-type="bibr">137</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-140-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0028</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>TGFBR1</italic>
,
<italic>FGF9</italic>
;
<italic>Pin1</italic>
;
<italic>FEN1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B138-cancers-11-01906" ref-type="bibr">138</xref>
,
<xref rid="B139-cancers-11-01906" ref-type="bibr">139</xref>
,
<xref rid="B140-cancers-11-01906" ref-type="bibr">140</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-345-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0046</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>IRF1</italic>
;
<italic>YAP1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B141-cancers-11-01906" ref-type="bibr">141</xref>
,
<xref rid="B142-cancers-11-01906" ref-type="bibr">142</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-30d-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0097</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>GNAI2</italic>
;
<italic>GLDC</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B8-cancers-11-01906" ref-type="bibr">8</xref>
,
<xref rid="B143-cancers-11-01906" ref-type="bibr">143</xref>
]</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>NA: data not available; UP: upregulated miRNAs in human cohorts; DOWN: downregulated miRNAs in human cohorts. </p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="cancers-11-01906-t002" orientation="portrait" position="float">
<object-id pub-id-type="pii">cancers-11-01906-t002_Table 2</object-id>
<label>Table 2</label>
<caption>
<p>miRNA upregulated in the DEN-HCC rat model.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Rat Deregulated miRNA</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Fold Change (HCC/Surrounding Liver)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">
<italic>p</italic>
-Value</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Deregulation in Human HCC</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Target Genes in Human HCC</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-146b-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">55.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>TRAF6</italic>
; NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B3-cancers-11-01906" ref-type="bibr">3</xref>
,
<xref rid="B144-cancers-11-01906" ref-type="bibr">144</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-183-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">45.4</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>PDCD4</italic>
;
<italic>FOXO1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B145-cancers-11-01906" ref-type="bibr">145</xref>
,
<xref rid="B146-cancers-11-01906" ref-type="bibr">146</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-18a-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14.2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>ESR1</italic>
;
<italic>KLF4</italic>
;
<italic>SOCS5</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B147-cancers-11-01906" ref-type="bibr">147</xref>
,
<xref rid="B148-cancers-11-01906" ref-type="bibr">148</xref>
,
<xref rid="B149-cancers-11-01906" ref-type="bibr">149</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-211-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12.9</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0073</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-125a-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10.8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0059</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-182</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8.3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>MTSS1</italic>
;
<italic>FOXO1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B146-cancers-11-01906" ref-type="bibr">146</xref>
,
<xref rid="B150-cancers-11-01906" ref-type="bibr">150</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-1249</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.018</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>HNRNPK</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B151-cancers-11-01906" ref-type="bibr">151</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-3473</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0050</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Rodent-specific family</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-466b-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.016</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Rodent-specific family</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-466c-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.043</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Rodent-specific family</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-1949</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Rodent-specific family</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-96-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>FOXO1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B12-cancers-11-01906" ref-type="bibr">12</xref>
,
<xref rid="B146-cancers-11-01906" ref-type="bibr">146</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-15b-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>Rab1A</italic>
;
<break></break>
NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B152-cancers-11-01906" ref-type="bibr">152</xref>
,
<xref rid="B153-cancers-11-01906" ref-type="bibr">153</xref>
,
<xref rid="B154-cancers-11-01906" ref-type="bibr">154</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-93-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.9</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>PDCD4</italic>
; NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B12-cancers-11-01906" ref-type="bibr">12</xref>
,
<xref rid="B155-cancers-11-01906" ref-type="bibr">155</xref>
,
<xref rid="B156-cancers-11-01906" ref-type="bibr">156</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-130a-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA; NA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B3-cancers-11-01906" ref-type="bibr">3</xref>
,
<xref rid="B157-cancers-11-01906" ref-type="bibr">157</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-106b-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>DR4</italic>
;
<break></break>
<italic>PTEN</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B158-cancers-11-01906" ref-type="bibr">158</xref>
,
<xref rid="B159-cancers-11-01906" ref-type="bibr">159</xref>
,
<xref rid="B160-cancers-11-01906" ref-type="bibr">160</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-25-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><0.0001</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; UP</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>RhoGDI-1</italic>
;
<italic>SOCS5</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B149-cancers-11-01906" ref-type="bibr">149</xref>
,
<xref rid="B161-cancers-11-01906" ref-type="bibr">161</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-31a-5p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0076</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UP; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA;
<italic>HDAC2</italic>
,
<italic>CDK2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B162-cancers-11-01906" ref-type="bibr">162</xref>
,
<xref rid="B163-cancers-11-01906" ref-type="bibr">163</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">rno-miR-29b-3p</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.023</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOWN; DOWN</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>Bcl-2</italic>
,
<italic>Mcl-1</italic>
;
<italic>LOXL2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B164-cancers-11-01906" ref-type="bibr">164</xref>
,
<xref rid="B165-cancers-11-01906" ref-type="bibr">165</xref>
]</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>NA: data not available; UP: upregulated miRNAs in human cohorts; DOWN: downregulated miRNAs in human cohorts.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations>
<list>
<country>
<li>Italie</li>
</country>
</list>
<tree>
<noCountry>
<name sortKey="Callegari, Elisa" sort="Callegari, Elisa" uniqKey="Callegari E" first="Elisa" last="Callegari">Elisa Callegari</name>
<name sortKey="Gramantieri, Laura" sort="Gramantieri, Laura" uniqKey="Gramantieri L" first="Laura" last="Gramantieri">Laura Gramantieri</name>
<name sortKey="Negrini, Massimo" sort="Negrini, Massimo" uniqKey="Negrini M" first="Massimo" last="Negrini">Massimo Negrini</name>
<name sortKey="Shankaraiah, Ram C" sort="Shankaraiah, Ram C" uniqKey="Shankaraiah R" first="Ram C." last="Shankaraiah">Ram C. Shankaraiah</name>
</noCountry>
<country name="Italie">
<noRegion>
<name sortKey="Fornari, Francesca" sort="Fornari, Francesca" uniqKey="Fornari F" first="Francesca" last="Fornari">Francesca Fornari</name>
</noRegion>
<name sortKey="Giovannini, Catia" sort="Giovannini, Catia" uniqKey="Giovannini C" first="Catia" last="Giovannini">Catia Giovannini</name>
<name sortKey="Piscaglia, Fabio" sort="Piscaglia, Fabio" uniqKey="Piscaglia F" first="Fabio" last="Piscaglia">Fabio Piscaglia</name>
</country>
</tree>
</affiliations>
</record>

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