CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation
Identifieur interne : 000823 ( Pmc/Curation ); précédent : 000822; suivant : 000824CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation
Auteurs : Yi-Fan Lian [République populaire de Chine] ; Yan-Lin Huang [République populaire de Chine] ; Yao-Jun Zhang [République populaire de Chine] ; Dong-Mei Chen [République populaire de Chine] ; Jia-Liang Wang [République populaire de Chine] ; Huan Wei [République populaire de Chine] ; Yan-Hua Bi [République populaire de Chine] ; Zhi-Wu Jiang [République populaire de Chine] ; Peng Li [République populaire de Chine] ; Min-Shan Chen [République populaire de Chine] ; Yue-Hua Huang [République populaire de Chine]Source :
- Theranostics [ 1838-7640 ] ; 2019.
Abstract
Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.
Url:
DOI: 10.7150/thno.36838
PubMed: 31754404
PubMed Central: 6857042
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">CACYBP Enhances Cytoplasmic Retention of P27<sup>Kip1</sup>
to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation</title>
<author><name sortKey="Lian, Yi Fan" sort="Lian, Yi Fan" uniqKey="Lian Y" first="Yi-Fan" last="Lian">Yi-Fan Lian</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Huang, Yan Lin" sort="Huang, Yan Lin" uniqKey="Huang Y" first="Yan-Lin" last="Huang">Yan-Lin Huang</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
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<author><name sortKey="Zhang, Yao Jun" sort="Zhang, Yao Jun" uniqKey="Zhang Y" first="Yao-Jun" last="Zhang">Yao-Jun Zhang</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou</wicri:regionArea>
</affiliation>
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<author><name sortKey="Chen, Dong Mei" sort="Chen, Dong Mei" uniqKey="Chen D" first="Dong-Mei" last="Chen">Dong-Mei Chen</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wang, Jia Liang" sort="Wang, Jia Liang" uniqKey="Wang J" first="Jia-Liang" last="Wang">Jia-Liang Wang</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wei, Huan" sort="Wei, Huan" uniqKey="Wei H" first="Huan" last="Wei">Huan Wei</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bi, Yan Hua" sort="Bi, Yan Hua" uniqKey="Bi Y" first="Yan-Hua" last="Bi">Yan-Hua Bi</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Jiang, Zhi Wu" sort="Jiang, Zhi Wu" uniqKey="Jiang Z" first="Zhi-Wu" last="Jiang">Zhi-Wu Jiang</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou</wicri:regionArea>
</affiliation>
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<author><name sortKey="Li, Peng" sort="Li, Peng" uniqKey="Li P" first="Peng" last="Li">Peng Li</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chen, Min Shan" sort="Chen, Min Shan" uniqKey="Chen M" first="Min-Shan" last="Chen">Min-Shan Chen</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Huang, Yue Hua" sort="Huang, Yue Hua" uniqKey="Huang Y" first="Yue-Hua" last="Huang">Yue-Hua Huang</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Theranostics</title>
<idno type="eISSN">1838-7640</idno>
<imprint><date when="2019">2019</date>
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<front><div type="abstract" xml:lang="en"><p>Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.</p>
<p><bold>Methods</bold>
: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation. Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP. The regulatory mechanism of RNF41-CACYBP signaling axis on P27<sup>Kip1</sup>
was investigated by western blotting and immunofluorescence.</p>
<p><bold>Results</bold>
: CACYBP was highly expressed and associated with poor prognosis in HCC. CACYBP expression was required for HCC cell growth<italic> in vitro</italic>
and <italic>in vivo</italic>
. Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels. RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome- and lysosome-dependent pathways. In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression. Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27<sup>Kip1</sup>
and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon. CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells. P27<sup>Kip1</sup>
-S10D but not P27<sup>Kip1</sup>
-S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.</p>
<p><bold>Conclusion</bold>
: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.</p>
</div>
</front>
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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">Theranostics</journal-id>
<journal-id journal-id-type="iso-abbrev">Theranostics</journal-id>
<journal-id journal-id-type="publisher-id">thno</journal-id>
<journal-title-group><journal-title>Theranostics</journal-title>
</journal-title-group>
<issn pub-type="epub">1838-7640</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">31754404</article-id>
<article-id pub-id-type="pmc">6857042</article-id>
<article-id pub-id-type="doi">10.7150/thno.36838</article-id>
<article-id pub-id-type="publisher-id">thnov09p8392</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>CACYBP Enhances Cytoplasmic Retention of P27<sup>Kip1</sup>
to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Lian</surname>
<given-names>Yi-Fan</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="author-notes" rid="FNA_star">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Yan-Lin</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="author-notes" rid="FNA_star">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Yao-Jun</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="author-notes" rid="FNA_star">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Dong-Mei</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Jia-Liang</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wei</surname>
<given-names>Huan</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bi</surname>
<given-names>Yan-Hua</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jiang</surname>
<given-names>Zhi-Wu</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Peng</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Min-Shan</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="corresp" rid="FNA_envelop">✉</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Yue-Hua</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="corresp" rid="FNA_envelop">✉</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</aff>
<aff id="A2"><label>2</label>
Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China</aff>
<aff id="A3"><label>3</label>
Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China</aff>
<aff id="A4"><label>4</label>
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China</aff>
<author-notes><corresp id="FNA_envelop">✉ Corresponding authors: Yue-Hua Huang, MD, PhD; Guangdong Provincial Key Laboratory of Liver Disease Research and Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Rd., Guangzhou, China, 510630; Tel: 8620-85252702, Fax: 8620-85253305, Yue-Hua Huang, <email>huangyh53@mail.sysu.edu.cn</email>
. Min-Shan Chen, MD, PhD; Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Rd. East, Guangzhou, China, 510030; Tel: 8620-87343585, Min-Shan Chen, <email>chenmsh@sysucc.org.cn</email>
.</corresp>
<fn fn-type="equal" id="FNA_star"><p>*These authors contributed equally to this work.</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>2019</year>
</pub-date>
<pub-date pub-type="epub"><day>22</day>
<month>10</month>
<year>2019</year>
</pub-date>
<volume>9</volume>
<issue>26</issue>
<fpage>8392</fpage>
<lpage>8408</lpage>
<history><date date-type="received"><day>19</day>
<month>5</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>3</day>
<month>9</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The author(s)</copyright-statement>
<copyright-year>2019</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>Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.</p>
<p><bold>Methods</bold>
: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation. Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP. The regulatory mechanism of RNF41-CACYBP signaling axis on P27<sup>Kip1</sup>
was investigated by western blotting and immunofluorescence.</p>
<p><bold>Results</bold>
: CACYBP was highly expressed and associated with poor prognosis in HCC. CACYBP expression was required for HCC cell growth<italic> in vitro</italic>
and <italic>in vivo</italic>
. Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels. RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome- and lysosome-dependent pathways. In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression. Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27<sup>Kip1</sup>
and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon. CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells. P27<sup>Kip1</sup>
-S10D but not P27<sup>Kip1</sup>
-S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.</p>
<p><bold>Conclusion</bold>
: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.</p>
</abstract>
<kwd-group><kwd>Hepatocellular carcinoma</kwd>
<kwd>CACYBP/SIP</kwd>
<kwd>RNF41/Nrdp1</kwd>
<kwd>P27<sup>Kip1</sup>
</kwd>
<kwd>Cell cycle</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="F1" position="float"><label>Figure 1</label>
<caption><p><bold> Increasing expression of CACYBP is associated with poor prognosis in HCC.</bold>
(A) CACYBP mRNA levels in global human cancer tissues (red) and non-tumor tissues (blue) were analyzed using the TCGA database (<ext-link ext-link-type="uri" xlink:href="http://firebrowse.org/">http://firebrowse.org/</ext-link>
). Noticeably, the fold change of tumor <italic>vs</italic>
normal tissue in hepatocellular carcinoma was 1.90. CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; LUSC: Lung squamous cell carcinoma; UCEC: Uterine corpus endometrial carcinoma; BRCA: Breast invasive carcinoma; BLCA: Bladder urothelial carcinoma; COAD: Colon adenocarcinoma; COADREAD: Colon and rectum adenocarcinoma; THYM: Thymoma; READ: Rectum adenocarcinoma; SKCM: Skin cutaneous melanoma; LUAD: Lung adenocarcinoma; LIHC: Liver hepatocellular carcinoma; PCPG: Pheochromocytoma and paraganglioma; GBMLGG: Glioblastoma multiforme and brain lower grade glioma (GBM + LGG); CHOL: Cholangiocarcinoma; SARC: Sarcoma; HNSC: Head and neck squamous cell carcinoma; GBM: Glioblastoma multiforme; STAD: Stomach adenocarcinoma; STES: Stomach and esophageal carcinoma; ESCA: Esophageal carcinoma; PAAD: Pancreatic adenocarcinoma; KIRC: Kidney renal clear cell carcinoma; KICH: Kidney chromophobe; KIRP: Kidney renal; KIPAN: Pan-kidney cohort (KICH + KIRC+ KIRP); PRAD: Prostate adenocarcinoma; THCA: Thyroid carcinoma. (B) CACYBP mRNA was elevated in HCC tissues compared with normal tissues in four datasets from ONCOMINE (<ext-link ext-link-type="uri" xlink:href="https://www.oncomine.org/">https://www.oncomine.org/</ext-link>
). The fold change and P value of the t-test for each dataset are shown. (C) CACYBP mRNA levels from 33 pairs of HCC tissues and matched adjacent non-tumor tissues were tested by qPCR. GAPDH was used as an internal control. (D) CACYBP protein levels from 7 pairs of HCC tissues and matched adjacent non-tumor tissues were tested by western blotting. (E) CACYBP expression in immortalized hepatic cell lines and HCC cell lines was analyzed by western blotting. (F) Representative images of CACYBP expression from three HCC tissues and their matched adjacent tissues by immunohistochemistry analysis. Scale bar for the left column: 400 μm; Scale bar for the middle and right columns: 100 μm. T: tumor; N: non-tumor. (G) Quantification of CACYBP expression scores in tumor tissues and non-tumor tissues from 52 HCC slices. (H) CACYBP expression was significantly associated with OS (upper panel) and DFS (lower panel) in the HCC cohort according to Kaplan-Meier analysis. CACYBP high: 71 samples; CACYBP low: 65 samples. ***P < 0.001.</p>
</caption>
<graphic xlink:href="thnov09p8392g001"></graphic>
</fig>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><p><bold> Knockdown of CACYBP expression impairs HCC cell growth<italic> in vitro</italic>
and <italic>in vivo</italic>
.</bold>
(A) Western blotting analysis of the knockdown efficacy of shCACYBP#1 and shCACYBP#2 in SK-Hep-1 and Huh7 cells. (B) Representative images of control and CACYBP depletion cells under light field. Red arrows indicate the apoptotic-like cells. (C) Viability of SK-Hep-1 and Huh7 cells after CACYBP depletion was assessed by CCK-8 assay at indicated times. (D) Representative images of colony formation assays of SK-Hep-1 and Huh7 cells after CACYBP depletion. (E) Quantification of the colony numbers in (D). (F) All tumors isolated from NSI mice were shown. (G-H) Growth curves (G) and weights (H) of xenograft tumors from NSI mice injected with control and CACYBP-depleted SK-Hep-1 cells. Changes in tumor volumes measured on the indicated days are shown. **P < 0.01; ***P < 0.001.</p>
</caption>
<graphic xlink:href="thnov09p8392g002"></graphic>
</fig>
<fig id="F3" position="float"><label>Figure 3</label>
<caption><p><bold> E3 ubiquitin ligase RNF41 co-immunoprecipitates with CACYBP.</bold>
(A) Silver-stained SDS-PAGE gel of protein marker only (lane 1) and the immunoprecipitated complex after a two-step TAP from SFB-CACYBP expressing 293T cells (lane 2). Bands were excised from the gel, trypsin-digested, and analyzed by MALDI-TOF. Identified proteins are indicated by lines. (B) Protein coverage of RNF41 in the MS result. The blue lines under the amino acid sequence indicate the supporting peptides matching RNF41. (C) MS sequencing of the best unique peptide (indicated by a red asterisk in (B)) of RNF41 protein. (D-E) Immunoprecipitation and western blotting experiments were performed using anti-HA agarose on lysates derived from 293T cells exogenously expressing Flag-tagged RNF41 and HA-tagged CACYBP (D), or Flag-tagged CACYBP and HA-tagged RNF41 (E). The asterisk indicates a nonspecific band. (F) An endogenous immunoprecipitation assay was performed using Huh7 cell extract and anti-CACYBP antibody. Rabbit normal anti-IgG was used as a control. Western blotting was performed with the indicated anti-CACYBP or anti-RNF41 antibody. (G-H) Immunoprecipitation and western blotting experiments were performed using anti-HA agarose on lysates derived from 293T cells exogenously expressing Flag-tagged CACYBP and the indicated HA-tagged RNF41 truncated mutants (G), or Flag-tagged RNF41 and the indicated HA-tagged CACYBP truncated mutants (H).</p>
</caption>
<graphic xlink:href="thnov09p8392g003"></graphic>
</fig>
<fig id="F4" position="float"><label>Figure 4</label>
<caption><p><bold> RNF41 promotes the degradation of CACYBP.</bold>
(A) Expression level of Flag-tagged CACYBP was steadily reduced with increasing amounts of RNF41 in Huh7 and SK-Hep-1 cells. (B) RNF41 with E3 ligase activity reduced the accumulation of exogenously expressed CACYBP, but this did not occur in the presence of the proteasome inhibitor MG132 or the lysosome inhibitors chloroquine or 3-MA. 293T cells were transfected with the indicated plasmids and incubated for 24 h. The cells were then incubated in fresh medium with none, 10 μM MG-132, 50 μM chloroquine, or 5 mM 3-MA for an additional 12 h. The cell lysates were analyzed by immunoblotting using the indicated antibody. Tubulin was used as a loading control. (C) Quantification of the expression level of Flag-tagged CACYBP after normalization to Tubulin. (D) Protein turnover of exogenously expressing Flag-tagged CACYBP in the presence of RNF41 WT or D56V mutant over the course of 8 h following the addition of 10 μg/mL cycloheximide. Tubulin was used as a loading control. (E) Quantification of the percentage of Flag-tagged CACYBP in the presence of RNF41 WT or D56V mutant for each time point compared to 0 h in (D). (F) RNF41 stimulates the poly-ubiquitination of CACYBP<italic> in vivo</italic>
. 293T cells were transfected with the indicated plasmids and incubated for 24 h. Cell lysates were subjected to immunoprecipitation with His affinity nickel beads. Immunoblotting analysis was conducted for the indicated proteins. The red asterisks in lane 3 indicate nonspecific bands. (G) Representative images of RNF41 expression from the same sample slices used for examining CACYBP expression by immunohistochemistry analysis. Scale bar for the left column: 400 μm; Scale bar for the middle and right columns: 100 μm. T: tumor; N: non-tumor. (H) Scatterplot of expression scores of CACYBP <italic>vs</italic>
RNF41 with a regression line showing a negative correlation. (I) RNF41 expression showed no significant association with OS (upper panel) and DFS (lower panel) in the HCC cohort according to Kaplan-Meier analysis. RNF41 high: 76 samples; RNF41 low: 54 samples. *P < 0.05; ***P < 0.001.</p>
</caption>
<graphic xlink:href="thnov09p8392g004"></graphic>
</fig>
<fig id="F5" position="float"><label>Figure 5</label>
<caption><p><bold> RNF41-CACYBP axis regulates the cytoplasm-nucleus transit of P27<sup>Kip1</sup>
in HCC cells.</bold>
(A) CACYBP caused phosphorylation-like modification of P27<sup>Kip1</sup>
, whereas RNF41 co-expression decreased it. Huh7 cells were transfected with the indicated plasmids and incubated for 24 h. Cell lysates were subjected to immunoblotting analysis with the indicated antibodies. β-catenin or tubulin was used as a negative control or loading control, respectively. S.E., short exposure; L.E., long exposure. (B) P27<sup>Kip1</sup>
level was increased in the cytoplasmic fraction upon CACYBP overexpression but decreased after RNF41 co-expression. Huh7 cells were transfected with the indicated plasmids and incubated for 24 h. Nuclear and cytoplasmic extracts were prepared by subcellular fractionation and subjected to immunoblotting analysis with the indicated antibodies. β-catenin was used as a negative control. (C) Immunofluorescence analysis of the cellular localization of P27<sup>Kip1</sup>
after overexpression of CACYBP and/or RNF41. Huh7 cells were transfected with the indicated plasmids and incubated for 24 h. After cell fixation, P27<sup>Kip1</sup>
was detected by anti-Flag immunostaining (green staining). CACYBP and RNF41 were detected by anti-HA immunostaining (red staining). Exogenous HA-tagged CACYBP showed a ubiquitous expression pattern in the nucleus and cytoplasm, and exogenous HA-tagged RNF41 showed a dotted expression pattern. Nuclear staining was performed using DAPI (blue staining). Scale bar: 10 μm. (D) Quantification of the percentage of cells with P27<sup>Kip1</sup>
cytoplasmic sequestration in (C). (E) Immunofluorescence analysis of the cellular localization of P27<sup>Kip1</sup>
in CACYBP-depleted Huh7 cells. Endogenous P27<sup>Kip1</sup>
and CACYBP were detected by anti-P27<sup>Kip1</sup>
(green staining) or anti-CACYBP (red staining) immunostaining, respectively. Nuclear was stained by DAPI (blue staining). Scale bar: 10 μm. (F) Quantification of the percentage of cells with predominantly nuclear localization of P27<sup>Kip1</sup>
in (E). (G) Representative images of the cell cycle distributions of control or CACYBP-depleted SK-Hep-1 and Huh7 cells. (H) Quantification of the percentage of cells in different cell cycle phases in (G). *P < 0.05; **P < 0.01.</p>
</caption>
<graphic xlink:href="thnov09p8392g005"></graphic>
</fig>
<fig id="F6" position="float"><label>Figure 6</label>
<caption><p><bold> Ser10 phosphorylation of P27<sup>Kip1</sup>
mediates the effect of CACYBP on HCC cells.</bold>
(A) Western blotting analysis of cell cycle proteins after reconstitution with P27<sup>Kip1</sup>
phosphomimetic mutants in CACYBP-depleted SK-Hep-1 cells. Cells were transfected with the indicated plasmids and incubated for 24 h. Cell lysates were subjected to immunoblotting analysis with the indicated antibodies. (B) P27<sup>Kip1</sup>
-S10D overexpression rescued the apoptotic phenotype after CACYBP depletion in SK-Hep-1 cells. Cells were transfected with the indicated plasmids and incubated for 24 h. Detection of apoptosis was performed by concurrent staining with Annexin V-FITC and PI. (C) Quantification of the percentage of apoptotic cells in (B). (D) Schematic diagram of CACYBP-mediated HCC progression. *P < 0.05; **P < 0.01; NS, not significant.</p>
</caption>
<graphic xlink:href="thnov09p8392g006"></graphic>
</fig>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p>Association between CACYBP expression and clinicopathological parameters in 136 HCC specimens.</p>
</caption>
<table frame="hsides" rules="groups"><thead valign="top"><tr><th rowspan="1" colspan="1">Variable</th>
<th rowspan="1" colspan="1">n</th>
<th rowspan="1" colspan="1">CACYBP low</th>
<th rowspan="1" colspan="1">CACYBP high</th>
<th rowspan="1" colspan="1">P</th>
</tr>
</thead>
<tbody valign="top"><tr><td rowspan="1" colspan="1">Age (years)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">≤ 45</td>
<td rowspan="1" colspan="1">63</td>
<td rowspan="1" colspan="1">33</td>
<td rowspan="1" colspan="1">30</td>
<td rowspan="1" colspan="1">0.430</td>
</tr>
<tr><td rowspan="1" colspan="1">> 45</td>
<td rowspan="1" colspan="1">73</td>
<td rowspan="1" colspan="1">38</td>
<td rowspan="1" colspan="1">35</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Gender</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Male</td>
<td rowspan="1" colspan="1">118</td>
<td rowspan="1" colspan="1">64</td>
<td rowspan="1" colspan="1">54</td>
<td rowspan="1" colspan="1">0.225</td>
</tr>
<tr><td rowspan="1" colspan="1">Female</td>
<td rowspan="1" colspan="1">18</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1">11</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Tumor size (cm)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">≤ 5</td>
<td rowspan="1" colspan="1">45</td>
<td rowspan="1" colspan="1">26</td>
<td rowspan="1" colspan="1">19</td>
<td rowspan="1" colspan="1">0.246</td>
</tr>
<tr><td rowspan="1" colspan="1">> 5</td>
<td rowspan="1" colspan="1">87</td>
<td rowspan="1" colspan="1">41</td>
<td rowspan="1" colspan="1">46</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Capsular formation</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Negative</td>
<td rowspan="1" colspan="1">33</td>
<td rowspan="1" colspan="1">17</td>
<td rowspan="1" colspan="1">16</td>
<td rowspan="1" colspan="1">0.920</td>
</tr>
<tr><td rowspan="1" colspan="1">Positive</td>
<td rowspan="1" colspan="1">99</td>
<td rowspan="1" colspan="1">50</td>
<td rowspan="1" colspan="1">49</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Tumor thrombus</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Negative</td>
<td rowspan="1" colspan="1">123</td>
<td rowspan="1" colspan="1">65</td>
<td rowspan="1" colspan="1">58</td>
<td rowspan="1" colspan="1">0.646</td>
</tr>
<tr><td rowspan="1" colspan="1">Positive</td>
<td rowspan="1" colspan="1">13</td>
<td rowspan="1" colspan="1">6</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Tumor nodes</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Single</td>
<td rowspan="1" colspan="1">108</td>
<td rowspan="1" colspan="1">55</td>
<td rowspan="1" colspan="1">53</td>
<td rowspan="1" colspan="1">0.935</td>
</tr>
<tr><td rowspan="1" colspan="1">Multiple</td>
<td rowspan="1" colspan="1">24</td>
<td rowspan="1" colspan="1">12</td>
<td rowspan="1" colspan="1">12</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Ascites</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Negative</td>
<td rowspan="1" colspan="1">124</td>
<td rowspan="1" colspan="1">67</td>
<td rowspan="1" colspan="1">57</td>
<td rowspan="1" colspan="1">0.285</td>
</tr>
<tr><td rowspan="1" colspan="1">Positive</td>
<td rowspan="1" colspan="1">12</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1">8</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Metastasis</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Negative</td>
<td rowspan="1" colspan="1">121</td>
<td rowspan="1" colspan="1">63</td>
<td rowspan="1" colspan="1">58</td>
<td rowspan="1" colspan="1">0.884</td>
</tr>
<tr><td rowspan="1" colspan="1">Positive</td>
<td rowspan="1" colspan="1">14</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">1</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">TMN stage</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">I-II</td>
<td rowspan="1" colspan="1">103</td>
<td rowspan="1" colspan="1">56</td>
<td rowspan="1" colspan="1">47</td>
<td rowspan="1" colspan="1">0.372</td>
</tr>
<tr><td rowspan="1" colspan="1">III-IV</td>
<td rowspan="1" colspan="1">33</td>
<td rowspan="1" colspan="1">15</td>
<td rowspan="1" colspan="1">18</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">AFP (ng/mL)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">≤ 400</td>
<td rowspan="1" colspan="1">71</td>
<td rowspan="1" colspan="1">44</td>
<td rowspan="1" colspan="1">27</td>
<td rowspan="1" colspan="1">0.007*</td>
</tr>
<tr><td rowspan="1" colspan="1">> 400</td>
<td rowspan="1" colspan="1">60</td>
<td rowspan="1" colspan="1">23</td>
<td rowspan="1" colspan="1">37</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">HBsAg</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Positive</td>
<td rowspan="1" colspan="1">114</td>
<td rowspan="1" colspan="1">58</td>
<td rowspan="1" colspan="1">56</td>
<td rowspan="1" colspan="1">0.769</td>
</tr>
<tr><td rowspan="1" colspan="1">Negative</td>
<td rowspan="1" colspan="1">17</td>
<td rowspan="1" colspan="1">8</td>
<td rowspan="1" colspan="1">9</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">5</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">HBeAg</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Positive</td>
<td rowspan="1" colspan="1">123</td>
<td rowspan="1" colspan="1">62</td>
<td rowspan="1" colspan="1">61</td>
<td rowspan="1" colspan="1">0.982</td>
</tr>
<tr><td rowspan="1" colspan="1">Negative</td>
<td rowspan="1" colspan="1">8</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">5</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Cirrhosis</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Negative</td>
<td rowspan="1" colspan="1">29</td>
<td rowspan="1" colspan="1">19</td>
<td rowspan="1" colspan="1">10</td>
<td rowspan="1" colspan="1">0.072</td>
</tr>
<tr><td rowspan="1" colspan="1">Positive</td>
<td rowspan="1" colspan="1">103</td>
<td rowspan="1" colspan="1">48</td>
<td rowspan="1" colspan="1">55</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">ALT (U)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">≤ 40</td>
<td rowspan="1" colspan="1">66</td>
<td rowspan="1" colspan="1">33</td>
<td rowspan="1" colspan="1">33</td>
<td rowspan="1" colspan="1">0.862</td>
</tr>
<tr><td rowspan="1" colspan="1">> 40</td>
<td rowspan="1" colspan="1">66</td>
<td rowspan="1" colspan="1">34</td>
<td rowspan="1" colspan="1">32</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">AST (U)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">≤ 40</td>
<td rowspan="1" colspan="1">59</td>
<td rowspan="1" colspan="1">39</td>
<td rowspan="1" colspan="1">20</td>
<td rowspan="1" colspan="1">0.002*</td>
</tr>
<tr><td rowspan="1" colspan="1">> 40</td>
<td rowspan="1" colspan="1">73</td>
<td rowspan="1" colspan="1">28</td>
<td rowspan="1" colspan="1">45</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">ALB (g/L)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">≤ 35</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1">0</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1">0.018*</td>
</tr>
<tr><td rowspan="1" colspan="1">> 35</td>
<td rowspan="1" colspan="1">125</td>
<td rowspan="1" colspan="1">67</td>
<td rowspan="1" colspan="1">58</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">PT (s)</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">≤ 14</td>
<td rowspan="1" colspan="1">100</td>
<td rowspan="1" colspan="1">51</td>
<td rowspan="1" colspan="1">49</td>
<td rowspan="1" colspan="1">0.952</td>
</tr>
<tr><td rowspan="1" colspan="1">> 14</td>
<td rowspan="1" colspan="1">31</td>
<td rowspan="1" colspan="1">16</td>
<td rowspan="1" colspan="1">15</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">5</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Survival</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">74</td>
<td rowspan="1" colspan="1">48</td>
<td rowspan="1" colspan="1">26</td>
<td rowspan="1" colspan="1">0.001*</td>
</tr>
<tr><td rowspan="1" colspan="1">No</td>
<td rowspan="1" colspan="1">62</td>
<td rowspan="1" colspan="1">23</td>
<td rowspan="1" colspan="1">39</td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Recurrence</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">83</td>
<td rowspan="1" colspan="1">35</td>
<td rowspan="1" colspan="1">48</td>
<td rowspan="1" colspan="1">0.003*</td>
</tr>
<tr><td rowspan="1" colspan="1">No</td>
<td rowspan="1" colspan="1">53</td>
<td rowspan="1" colspan="1">36</td>
<td rowspan="1" colspan="1">17</td>
<td rowspan="1" colspan="1"></td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>*P < 0.05</p>
<p>Abbreviations: AFP, alpha-fetoprotein; ALT, Alanine aminotransferase; ALB: albumin; AST, Aspartate transaminase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; NA, not available; PT, prothrombin time.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>
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