Ubiquitin B in cervical cancer: critical for the maintenance of cancer stem-like cell characters
Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark...
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description | Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells. |
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Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0084457</identifier><identifier>PMID: 24367661</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Apoptosis ; Biodegradation ; Biology ; Biomarkers ; Breast cancer ; Cancer ; Cancer therapies ; Cell cycle ; Cell proliferation ; Cell Transformation, Neoplastic - drug effects ; Cervical cancer ; Cervix ; Chemoresistance ; Chemotherapy ; Cosmetics industry ; Degradation ; Disease ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Silencing ; Genes ; HeLa Cells ; Histone deacetylase ; Histone Deacetylase Inhibitors - pharmacology ; Hospitals ; Humans ; Hydroxamic Acids - pharmacology ; Hypotheses ; Malignancy ; Mice ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Oct-4 protein ; Pathology ; Proteasomes ; Proteins ; Proteolysis ; RNA, Small Interfering - genetics ; Science ; Selectivity ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - pathology ; Squamous cell carcinoma ; Stem cells ; Trichostatin A ; Tumors ; Turnover rate ; Ubiquitin ; Ubiquitin - deficiency ; Ubiquitin - genetics ; Ubiquitin - metabolism ; Up-Regulation - drug effects ; Uterine Cervical Neoplasms - drug therapy ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - pathology ; Vaccines ; Western blotting ; Xenografts</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e84457</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Tian et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Tian et al 2013 Tian et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-65cdc1d0b928b728ccb7c0af40ef169d85430833416898832484263a62190b8b3</citedby><cites>FETCH-LOGICAL-c758t-65cdc1d0b928b728ccb7c0af40ef169d85430833416898832484263a62190b8b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867485/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867485/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24367661$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ahmad, Aamir</contributor><creatorcontrib>Tian, Yuan</creatorcontrib><creatorcontrib>Ding, Wencheng</creatorcontrib><creatorcontrib>Wang, Yingying</creatorcontrib><creatorcontrib>Ji, Teng</creatorcontrib><creatorcontrib>Sun, Shujuan</creatorcontrib><creatorcontrib>Mo, Qingqing</creatorcontrib><creatorcontrib>Chen, Pingbo</creatorcontrib><creatorcontrib>Fang, Yong</creatorcontrib><creatorcontrib>Liu, Jia</creatorcontrib><creatorcontrib>Wang, Beibei</creatorcontrib><creatorcontrib>Zhou, Jianfeng</creatorcontrib><creatorcontrib>Ma, Ding</creatorcontrib><creatorcontrib>Wu, Peng</creatorcontrib><title>Ubiquitin B in cervical cancer: critical for the maintenance of cancer stem-like cell characters</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biodegradation</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell proliferation</subject><subject>Cell Transformation, Neoplastic - drug effects</subject><subject>Cervical cancer</subject><subject>Cervix</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Cosmetics industry</subject><subject>Degradation</subject><subject>Disease</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Silencing</subject><subject>Genes</subject><subject>HeLa Cells</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Hypotheses</subject><subject>Malignancy</subject><subject>Mice</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Oct-4 protein</subject><subject>Pathology</subject><subject>Proteasomes</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>RNA, Small Interfering - genetics</subject><subject>Science</subject><subject>Selectivity</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - pathology</subject><subject>Squamous cell carcinoma</subject><subject>Stem cells</subject><subject>Trichostatin A</subject><subject>Tumors</subject><subject>Turnover rate</subject><subject>Ubiquitin</subject><subject>Ubiquitin - deficiency</subject><subject>Ubiquitin - genetics</subject><subject>Ubiquitin - metabolism</subject><subject>Up-Regulation - drug effects</subject><subject>Uterine Cervical Neoplasms - drug therapy</subject><subject>Uterine Cervical Neoplasms - genetics</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>Vaccines</subject><subject>Western blotting</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkmuL1DAUhoso7kX_gWhBWPBDx9yaix-EdfEysLCgrl9jmqbTjG0zm6SL_ntTp7tMQUEKaTjned-kp2-WPYNgBTGDr7du9IPqVjs3mBUAnJCSPciOocCooAjghwf7o-wkhC0AJeaUPs6OEMGUUQqPs-_Xlb0ZbbRD_i5Pizb-1mrV5VoNaf8m1z41p0LjfB5bk_fKDtEMUzt3zczlIZq-6OwPkxy6pG6VVzoaH55kjxrVBfN0fp9m1x_ef734VFxefVxfnF8WmpU8FrTUtYY1qATiFUNc64ppoBoCTAOpqHlJMOAYE0i54BwjwgmiWFEEBah4hU-zF3vfXeeCnIcTJCRUYECSayLWe6J2ait33vbK_5JOWfmn4PxGKp--tTOyxiWHtWBYGEKM0KqBrG5EjSvGSYVY8no7nzZWvam1GaJX3cJ02RlsKzfuVqYfwAgvk8HL2cC7m9GE-I8rz9RGpVvZoXHJTPc2aHlOGEdIMDB5rf5Cpac2vdUpHo1N9YXg1UKQmGh-xo0aQ5DrL5__n736tmTPDtjWqC62wXVjtG4IS5DsQe1dCN4095ODQE7pvpuGnNIt53Qn2fPDqd-L7uKMfwOtjfO_</recordid><startdate>20131218</startdate><enddate>20131218</enddate><creator>Tian, Yuan</creator><creator>Ding, Wencheng</creator><creator>Wang, Yingying</creator><creator>Ji, Teng</creator><creator>Sun, Shujuan</creator><creator>Mo, Qingqing</creator><creator>Chen, Pingbo</creator><creator>Fang, Yong</creator><creator>Liu, Jia</creator><creator>Wang, Beibei</creator><creator>Zhou, Jianfeng</creator><creator>Ma, Ding</creator><creator>Wu, Peng</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131218</creationdate><title>Ubiquitin B in cervical cancer: critical for the maintenance of cancer stem-like cell characters</title><author>Tian, Yuan ; Ding, Wencheng ; Wang, Yingying ; Ji, Teng ; Sun, Shujuan ; Mo, Qingqing ; Chen, Pingbo ; Fang, Yong ; Liu, Jia ; Wang, Beibei ; Zhou, Jianfeng ; Ma, Ding ; Wu, Peng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-65cdc1d0b928b728ccb7c0af40ef169d85430833416898832484263a62190b8b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Biodegradation</topic><topic>Biology</topic><topic>Biomarkers</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Cell proliferation</topic><topic>Cell Transformation, Neoplastic - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tian, Yuan</au><au>Ding, Wencheng</au><au>Wang, Yingying</au><au>Ji, Teng</au><au>Sun, Shujuan</au><au>Mo, Qingqing</au><au>Chen, Pingbo</au><au>Fang, Yong</au><au>Liu, Jia</au><au>Wang, Beibei</au><au>Zhou, Jianfeng</au><au>Ma, Ding</au><au>Wu, Peng</au><au>Ahmad, Aamir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ubiquitin B in cervical cancer: critical for the maintenance of cancer stem-like cell characters</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-12-18</date><risdate>2013</risdate><volume>8</volume><issue>12</issue><spage>e84457</spage><pages>e84457-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24367661</pmid><doi>10.1371/journal.pone.0084457</doi><tpages>e84457</tpages><oa>free_for_read</oa></addata></record> |
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identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2013-12, Vol.8 (12), p.e84457 |
issn | 1932-6203 1932-6203 |
language | eng |
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source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Animals Apoptosis Biodegradation Biology Biomarkers Breast cancer Cancer Cancer therapies Cell cycle Cell proliferation Cell Transformation, Neoplastic - drug effects Cervical cancer Cervix Chemoresistance Chemotherapy Cosmetics industry Degradation Disease Drug resistance Drug Resistance, Neoplasm - drug effects Female Gene Expression Regulation, Neoplastic - drug effects Gene Silencing Genes HeLa Cells Histone deacetylase Histone Deacetylase Inhibitors - pharmacology Hospitals Humans Hydroxamic Acids - pharmacology Hypotheses Malignancy Mice Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Oct-4 protein Pathology Proteasomes Proteins Proteolysis RNA, Small Interfering - genetics Science Selectivity Spheroids, Cellular - drug effects Spheroids, Cellular - pathology Squamous cell carcinoma Stem cells Trichostatin A Tumors Turnover rate Ubiquitin Ubiquitin - deficiency Ubiquitin - genetics Ubiquitin - metabolism Up-Regulation - drug effects Uterine Cervical Neoplasms - drug therapy Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - pathology Vaccines Western blotting Xenografts |
title | Ubiquitin B in cervical cancer: critical for the maintenance of cancer stem-like cell characters |
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