Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells
Wnt/β‐catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRN...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2016-12, Vol.64 (6), p.2062-2076 |
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| creator | Chai, Stella Ng, Kai‐Yu Tong, Man Lau, Eunice Y. Lee, Terence K. Chan, Kwok Wah Yuan, Yun‐Fei Cheung, Tan‐To Cheung, Siu‐Tim Wang, Xiao‐Qi Wong, Nathalie Lo, Chung‐Mau Man, Kwan Guan, Xin‐Yuan Ma, Stephanie |
| description | Wnt/β‐catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR‐1246, promotes cancer stemness, including self‐renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β‐catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β‐catenin destruction complex. Clinically, high endogenous and circulating miR‐1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR‐1246, which cooperatively drive β‐catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β‐catenin in liver CSCs by the Oct4/miR‐1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062‐2076). |
| doi_str_mv | 10.1002/hep.28821 |
| format | Article |
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However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR‐1246, promotes cancer stemness, including self‐renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β‐catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β‐catenin destruction complex. Clinically, high endogenous and circulating miR‐1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR‐1246, which cooperatively drive β‐catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β‐catenin in liver CSCs by the Oct4/miR‐1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062‐2076).</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.28821</identifier><identifier>PMID: 27639189</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; beta Catenin - physiology ; Carcinoma, Hepatocellular - physiopathology ; Humans ; Liver Neoplasms - physiopathology ; Male ; Mice ; Mice, Inbred BALB C ; MicroRNAs - physiology ; Neoplastic Stem Cells ; Octamer Transcription Factor-3 - physiology ; Wnt Signaling Pathway - physiology</subject><ispartof>Hepatology (Baltimore, Md.), 2016-12, Vol.64 (6), p.2062-2076</ispartof><rights>2016 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3931-6312e9ddbd5acb0c819be911081f16adf91db789474a9dc2569d80a460cbb6da3</citedby><cites>FETCH-LOGICAL-c3931-6312e9ddbd5acb0c819be911081f16adf91db789474a9dc2569d80a460cbb6da3</cites><orcidid>0000-0002-4485-6017</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.28821$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.28821$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27639189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chai, Stella</creatorcontrib><creatorcontrib>Ng, Kai‐Yu</creatorcontrib><creatorcontrib>Tong, Man</creatorcontrib><creatorcontrib>Lau, Eunice Y.</creatorcontrib><creatorcontrib>Lee, Terence K.</creatorcontrib><creatorcontrib>Chan, Kwok Wah</creatorcontrib><creatorcontrib>Yuan, Yun‐Fei</creatorcontrib><creatorcontrib>Cheung, Tan‐To</creatorcontrib><creatorcontrib>Cheung, Siu‐Tim</creatorcontrib><creatorcontrib>Wang, Xiao‐Qi</creatorcontrib><creatorcontrib>Wong, Nathalie</creatorcontrib><creatorcontrib>Lo, Chung‐Mau</creatorcontrib><creatorcontrib>Man, Kwan</creatorcontrib><creatorcontrib>Guan, Xin‐Yuan</creatorcontrib><creatorcontrib>Ma, Stephanie</creatorcontrib><title>Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Wnt/β‐catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR‐1246, promotes cancer stemness, including self‐renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β‐catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β‐catenin destruction complex. Clinically, high endogenous and circulating miR‐1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR‐1246, which cooperatively drive β‐catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β‐catenin in liver CSCs by the Oct4/miR‐1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062‐2076).</description><subject>Animals</subject><subject>beta Catenin - physiology</subject><subject>Carcinoma, Hepatocellular - physiopathology</subject><subject>Humans</subject><subject>Liver Neoplasms - physiopathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>MicroRNAs - physiology</subject><subject>Neoplastic Stem Cells</subject><subject>Octamer Transcription Factor-3 - physiology</subject><subject>Wnt Signaling Pathway - physiology</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0UFKAzEUBuAgitbqwgtIlrqYNi-ZySRLKdUKoiKKyyGTZGpkZlon02p3HsGzeBAP4UlMbXUnuHo8-Ph5vB-hAyA9IIT2H-y0R4WgsIE6kNA0Yiwhm6hDaEoiCUzuoF3vHwkhMqZiG-3QlDMJQnZQcaVbVdkGx_3K6WZyc3ny-foGNObYu3GtSlePsXpxHpvGza3H93Xb_3gPRqvW1q7GSrdurlo3qXHYyoAarFWtw_CtrbC2Zen30FahSm_317OL7k6Ht4NRdHF1dj44uYg0kwwizoBaaUxuEqVzogXI3EoAIqAArkwhweSpkHEaK2k0Tbg0gqiYE53n3CjWRUer3GkzeZpZ32aV88sLVG0nM5-BSEgqUsrhH5QlXEgqkkCPVzQ8yPvGFtm0cZVqFhmQbNlAFhrIvhsI9nAdO8sra37lz8sD6K_Asyvt4u-kbDS8XkV-AQpFkck</recordid><startdate>201612</startdate><enddate>201612</enddate><creator>Chai, Stella</creator><creator>Ng, Kai‐Yu</creator><creator>Tong, Man</creator><creator>Lau, Eunice Y.</creator><creator>Lee, Terence K.</creator><creator>Chan, Kwok Wah</creator><creator>Yuan, Yun‐Fei</creator><creator>Cheung, Tan‐To</creator><creator>Cheung, Siu‐Tim</creator><creator>Wang, Xiao‐Qi</creator><creator>Wong, Nathalie</creator><creator>Lo, Chung‐Mau</creator><creator>Man, Kwan</creator><creator>Guan, Xin‐Yuan</creator><creator>Ma, Stephanie</creator><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><scope>7T5</scope><scope>H94</scope><orcidid>https://orcid.org/0000-0002-4485-6017</orcidid></search><sort><creationdate>201612</creationdate><title>Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells</title><author>Chai, Stella ; Ng, Kai‐Yu ; Tong, Man ; Lau, Eunice Y. ; Lee, Terence K. ; Chan, Kwok Wah ; Yuan, Yun‐Fei ; Cheung, Tan‐To ; Cheung, Siu‐Tim ; Wang, Xiao‐Qi ; Wong, Nathalie ; Lo, Chung‐Mau ; Man, Kwan ; Guan, Xin‐Yuan ; Ma, Stephanie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3931-6312e9ddbd5acb0c819be911081f16adf91db789474a9dc2569d80a460cbb6da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>beta Catenin - physiology</topic><topic>Carcinoma, Hepatocellular - physiopathology</topic><topic>Humans</topic><topic>Liver Neoplasms - physiopathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>MicroRNAs - physiology</topic><topic>Neoplastic Stem Cells</topic><topic>Octamer Transcription Factor-3 - physiology</topic><topic>Wnt Signaling Pathway - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chai, Stella</creatorcontrib><creatorcontrib>Ng, Kai‐Yu</creatorcontrib><creatorcontrib>Tong, Man</creatorcontrib><creatorcontrib>Lau, Eunice Y.</creatorcontrib><creatorcontrib>Lee, Terence K.</creatorcontrib><creatorcontrib>Chan, Kwok Wah</creatorcontrib><creatorcontrib>Yuan, Yun‐Fei</creatorcontrib><creatorcontrib>Cheung, Tan‐To</creatorcontrib><creatorcontrib>Cheung, Siu‐Tim</creatorcontrib><creatorcontrib>Wang, Xiao‐Qi</creatorcontrib><creatorcontrib>Wong, Nathalie</creatorcontrib><creatorcontrib>Lo, Chung‐Mau</creatorcontrib><creatorcontrib>Man, Kwan</creatorcontrib><creatorcontrib>Guan, Xin‐Yuan</creatorcontrib><creatorcontrib>Ma, Stephanie</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><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chai, Stella</au><au>Ng, Kai‐Yu</au><au>Tong, Man</au><au>Lau, Eunice Y.</au><au>Lee, Terence K.</au><au>Chan, Kwok Wah</au><au>Yuan, Yun‐Fei</au><au>Cheung, Tan‐To</au><au>Cheung, Siu‐Tim</au><au>Wang, Xiao‐Qi</au><au>Wong, Nathalie</au><au>Lo, Chung‐Mau</au><au>Man, Kwan</au><au>Guan, Xin‐Yuan</au><au>Ma, Stephanie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2016-12</date><risdate>2016</risdate><volume>64</volume><issue>6</issue><spage>2062</spage><epage>2076</epage><pages>2062-2076</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><abstract>Wnt/β‐catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR‐1246, promotes cancer stemness, including self‐renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β‐catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β‐catenin destruction complex. Clinically, high endogenous and circulating miR‐1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR‐1246, which cooperatively drive β‐catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β‐catenin in liver CSCs by the Oct4/miR‐1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062‐2076).</abstract><cop>United States</cop><pmid>27639189</pmid><doi>10.1002/hep.28821</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-4485-6017</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals beta Catenin - physiology Carcinoma, Hepatocellular - physiopathology Humans Liver Neoplasms - physiopathology Male Mice Mice, Inbred BALB C MicroRNAs - physiology Neoplastic Stem Cells Octamer Transcription Factor-3 - physiology Wnt Signaling Pathway - physiology |
| title | Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells |
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