Upregulated expression of Nucleostemin/GNL3 is associated with poor prognosis and Sorafenib Resistance in Hepatocellular Carcinoma
Nucleostemin (NS)/GNL3 protein has been recently documented to be a nucleolar protein that was abundantly expressed in stem cells and cancer cells. Herein, we showed that NS was upregulated in HCC tissues and the expression of NS was inversely correlated with that of p53. Overexpression of NS predic...
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| Veröffentlicht in: | Pathology, research and practice research and practice, 2017-06, Vol.213 (6), p.688-697 |
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| creator | Hua, Lu Hu, Baoying Yan, Daliang Liu, Jinxia Shen, Yifen Zhao, Fengbo Shen, Chaoyan Chen, Buyou Cui, Xiaopeng |
| description | Nucleostemin (NS)/GNL3 protein has been recently documented to be a nucleolar protein that was abundantly expressed in stem cells and cancer cells. Herein, we showed that NS was upregulated in HCC tissues and the expression of NS was inversely correlated with that of p53. Overexpression of NS predicted significantly worsened prognosis in HCC patients, suggesting that NS might serve as a prognostic marker of HCC. In addition, we found that depletion of NS sensitized HCC cells to sorafenib-induced apoptosis. Moreover, we found that the mechanism underlying NS-mediated sorafenib resistance involved dysregulated expression of p53, and downstream Bax and Bcl-2 proteins. NS interacted with p53 in HCC cells. Depletion of NS increased the expression of p53 and Bax, whereas impaired the level of cellular Bcl-2. Interference of NS enhanced the cytotoxic effects of sorafenib in HCC cells. Furthermore, ectopic expression of NS impaired the apoptosis of HCC cells following sorafenib exposure. Therefore, NS may contribute to sorafenib resistance in HCC cells through the modulation of p53 pathway and Bcl-2 proteins. These findings indicated that the combination of silencing NS expression and sorafenib treatment is a promising therapeutic strategy in treatment of HCC. |
| doi_str_mv | 10.1016/j.prp.2016.11.014 |
| format | Article |
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Herein, we showed that NS was upregulated in HCC tissues and the expression of NS was inversely correlated with that of p53. Overexpression of NS predicted significantly worsened prognosis in HCC patients, suggesting that NS might serve as a prognostic marker of HCC. In addition, we found that depletion of NS sensitized HCC cells to sorafenib-induced apoptosis. Moreover, we found that the mechanism underlying NS-mediated sorafenib resistance involved dysregulated expression of p53, and downstream Bax and Bcl-2 proteins. NS interacted with p53 in HCC cells. Depletion of NS increased the expression of p53 and Bax, whereas impaired the level of cellular Bcl-2. Interference of NS enhanced the cytotoxic effects of sorafenib in HCC cells. Furthermore, ectopic expression of NS impaired the apoptosis of HCC cells following sorafenib exposure. Therefore, NS may contribute to sorafenib resistance in HCC cells through the modulation of p53 pathway and Bcl-2 proteins. These findings indicated that the combination of silencing NS expression and sorafenib treatment is a promising therapeutic strategy in treatment of HCC.</description><identifier>ISSN: 0344-0338</identifier><identifier>EISSN: 1618-0631</identifier><identifier>DOI: 10.1016/j.prp.2016.11.014</identifier><identifier>PMID: 28476378</identifier><language>eng</language><publisher>Germany: Elsevier GmbH</publisher><subject>Adult ; Aged ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis - drug effects ; bcl-2-Associated X Protein - metabolism ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - mortality ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm - physiology ; Female ; GTP-Binding Proteins - metabolism ; Hepatocellular carcinoma ; Humans ; Liver Neoplasms - drug therapy ; Liver Neoplasms - metabolism ; Liver Neoplasms - mortality ; Liver Neoplasms - pathology ; Male ; Middle Aged ; Niacinamide - analogs & derivatives ; Niacinamide - pharmacology ; Niacinamide - therapeutic use ; Nuclear Proteins - metabolism ; Nucleostemin/GNL3 ; p53 ; Phenylurea Compounds - pharmacology ; Phenylurea Compounds - therapeutic use ; Prognosis ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Sorafenib resistance ; Survival Rate ; Up-Regulation ; Young Adult</subject><ispartof>Pathology, research and practice, 2017-06, Vol.213 (6), p.688-697</ispartof><rights>2016 Elsevier GmbH</rights><rights>Copyright © 2016 Elsevier GmbH. 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Herein, we showed that NS was upregulated in HCC tissues and the expression of NS was inversely correlated with that of p53. Overexpression of NS predicted significantly worsened prognosis in HCC patients, suggesting that NS might serve as a prognostic marker of HCC. In addition, we found that depletion of NS sensitized HCC cells to sorafenib-induced apoptosis. Moreover, we found that the mechanism underlying NS-mediated sorafenib resistance involved dysregulated expression of p53, and downstream Bax and Bcl-2 proteins. NS interacted with p53 in HCC cells. Depletion of NS increased the expression of p53 and Bax, whereas impaired the level of cellular Bcl-2. Interference of NS enhanced the cytotoxic effects of sorafenib in HCC cells. Furthermore, ectopic expression of NS impaired the apoptosis of HCC cells following sorafenib exposure. Therefore, NS may contribute to sorafenib resistance in HCC cells through the modulation of p53 pathway and Bcl-2 proteins. These findings indicated that the combination of silencing NS expression and sorafenib treatment is a promising therapeutic strategy in treatment of HCC.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - mortality</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Drug Resistance, Neoplasm - physiology</subject><subject>Female</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - mortality</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - pharmacology</subject><subject>Niacinamide - therapeutic use</subject><subject>Nuclear Proteins - metabolism</subject><subject>Nucleostemin/GNL3</subject><subject>p53</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Phenylurea Compounds - therapeutic use</subject><subject>Prognosis</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Sorafenib resistance</subject><subject>Survival Rate</subject><subject>Up-Regulation</subject><subject>Young Adult</subject><issn>0344-0338</issn><issn>1618-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAQhi1ERZfCA3BBPnJJ6olTxxEntKIt0qqVgJ6tiTMpXiV2sJNSrjw5XrZw5GR7_M3v8cfYGxAlCFDn-3KOc1nlbQlQCqifsQ0o0IVQEp6zjZB1XQgp9Sl7mdJeCNGIGl6w00rXjZKN3rBfd3Ok-3XEhXpOj_mQkgueh4HfrHakkBaanD-_utlJ7hLHlIJ1f-gfbvnG5xAin2O49yEdrn3Pv4SIA3nX8c-Uawt6S9x5fk0zLsHSOObnIt9itM6HCV-xkwHHRK-f1jN2d_nx6_a62N1efdp-2BVWXsil0L2yLWpJYC0QdlpXFqBDe0HYVNg03dB2UleDkEK2HWGlWuo7bOu6l4MCecbeHXPzuN9XSouZXDqMg57CmgzoVgnZKGgyCkfUxpBSpMHM0U0YfxoQ5qDe7HNlNgf1BsBk9bnn7VP82k3U_-v46zoD748A5U8-OIomWUdZTu8i2cX0wf0n_jdWsZez</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Hua, Lu</creator><creator>Hu, Baoying</creator><creator>Yan, Daliang</creator><creator>Liu, Jinxia</creator><creator>Shen, Yifen</creator><creator>Zhao, Fengbo</creator><creator>Shen, Chaoyan</creator><creator>Chen, Buyou</creator><creator>Cui, Xiaopeng</creator><general>Elsevier GmbH</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20170601</creationdate><title>Upregulated expression of Nucleostemin/GNL3 is associated with poor prognosis and Sorafenib Resistance in Hepatocellular Carcinoma</title><author>Hua, Lu ; Hu, Baoying ; Yan, Daliang ; Liu, Jinxia ; Shen, Yifen ; Zhao, Fengbo ; Shen, Chaoyan ; Chen, Buyou ; Cui, Xiaopeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-8d6c9a83e1cc1eab882c11bac5ea72a77bf9b382f03039bea269edba944d3f613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis - drug effects</topic><topic>bcl-2-Associated X Protein - metabolism</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - mortality</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Drug Resistance, Neoplasm - physiology</topic><topic>Female</topic><topic>GTP-Binding Proteins - metabolism</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - mortality</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - pharmacology</topic><topic>Niacinamide - therapeutic use</topic><topic>Nuclear Proteins - metabolism</topic><topic>Nucleostemin/GNL3</topic><topic>p53</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>Phenylurea Compounds - therapeutic use</topic><topic>Prognosis</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Sorafenib resistance</topic><topic>Survival Rate</topic><topic>Up-Regulation</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hua, Lu</creatorcontrib><creatorcontrib>Hu, Baoying</creatorcontrib><creatorcontrib>Yan, Daliang</creatorcontrib><creatorcontrib>Liu, Jinxia</creatorcontrib><creatorcontrib>Shen, Yifen</creatorcontrib><creatorcontrib>Zhao, Fengbo</creatorcontrib><creatorcontrib>Shen, Chaoyan</creatorcontrib><creatorcontrib>Chen, Buyou</creatorcontrib><creatorcontrib>Cui, Xiaopeng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Pathology, research and practice</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hua, Lu</au><au>Hu, Baoying</au><au>Yan, Daliang</au><au>Liu, Jinxia</au><au>Shen, Yifen</au><au>Zhao, Fengbo</au><au>Shen, Chaoyan</au><au>Chen, Buyou</au><au>Cui, Xiaopeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Upregulated expression of Nucleostemin/GNL3 is associated with poor prognosis and Sorafenib Resistance in Hepatocellular Carcinoma</atitle><jtitle>Pathology, research and practice</jtitle><addtitle>Pathol Res Pract</addtitle><date>2017-06-01</date><risdate>2017</risdate><volume>213</volume><issue>6</issue><spage>688</spage><epage>697</epage><pages>688-697</pages><issn>0344-0338</issn><eissn>1618-0631</eissn><abstract>Nucleostemin (NS)/GNL3 protein has been recently documented to be a nucleolar protein that was abundantly expressed in stem cells and cancer cells. Herein, we showed that NS was upregulated in HCC tissues and the expression of NS was inversely correlated with that of p53. Overexpression of NS predicted significantly worsened prognosis in HCC patients, suggesting that NS might serve as a prognostic marker of HCC. In addition, we found that depletion of NS sensitized HCC cells to sorafenib-induced apoptosis. Moreover, we found that the mechanism underlying NS-mediated sorafenib resistance involved dysregulated expression of p53, and downstream Bax and Bcl-2 proteins. NS interacted with p53 in HCC cells. Depletion of NS increased the expression of p53 and Bax, whereas impaired the level of cellular Bcl-2. Interference of NS enhanced the cytotoxic effects of sorafenib in HCC cells. Furthermore, ectopic expression of NS impaired the apoptosis of HCC cells following sorafenib exposure. Therefore, NS may contribute to sorafenib resistance in HCC cells through the modulation of p53 pathway and Bcl-2 proteins. These findings indicated that the combination of silencing NS expression and sorafenib treatment is a promising therapeutic strategy in treatment of HCC.</abstract><cop>Germany</cop><pub>Elsevier GmbH</pub><pmid>28476378</pmid><doi>10.1016/j.prp.2016.11.014</doi><tpages>10</tpages></addata></record> |
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| ispartof | Pathology, research and practice, 2017-06, Vol.213 (6), p.688-697 |
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| subjects | Adult Aged Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis - drug effects bcl-2-Associated X Protein - metabolism Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - mortality Carcinoma, Hepatocellular - pathology Cell Line, Tumor Drug Resistance, Neoplasm - physiology Female GTP-Binding Proteins - metabolism Hepatocellular carcinoma Humans Liver Neoplasms - drug therapy Liver Neoplasms - metabolism Liver Neoplasms - mortality Liver Neoplasms - pathology Male Middle Aged Niacinamide - analogs & derivatives Niacinamide - pharmacology Niacinamide - therapeutic use Nuclear Proteins - metabolism Nucleostemin/GNL3 p53 Phenylurea Compounds - pharmacology Phenylurea Compounds - therapeutic use Prognosis Proto-Oncogene Proteins c-bcl-2 - metabolism Sorafenib resistance Survival Rate Up-Regulation Young Adult |
| title | Upregulated expression of Nucleostemin/GNL3 is associated with poor prognosis and Sorafenib Resistance in Hepatocellular Carcinoma |
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