Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2....
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| Veröffentlicht in: | Clinical and Translational Medicine 2021-09, Vol.11 (9), p.e536-n/a, Article 536 |
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| creator | Yang, Tianfeng Huo, Jian Xu, Rui Su, Qi Tang, Wenjuan Zhang, Dongdong Zhu, Man Zhan, Yingzhuan Dai, Bingling Zhang, Yanmin |
| description | Background
Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates.
Methods
The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor.
Results
PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo.
Conclusions
Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.
The C‐MET/STAT3 signaling axis as a novel downstream target of pleomorphic adenoma gene like‐2 (PLAGL2) contributed to PLAGL2‐induced mitochondrial apoptosis resistance in HCC. Selenium sulfide (SeS2) induced cell proliferation inhibition and apoptosis on HCC cells by inhibiting the activity of PLAGL2 and restraining the novel PLAGL2/C‐MET/STAT3, AKT/mTOR and MAPK signaling pathways. |
| doi_str_mv | 10.1002/ctm2.536 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_wiley</sourceid><recordid>TN_cdi_wiley_primary_10_1002_ctm2_536_CTM2536</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A693325694</galeid><doaj_id>oai_doaj_org_article_769b517ae0a34af99893265a8d4ff97b</doaj_id><sourcerecordid>A693325694</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5016-2722da5d86ce1870594632e92c65c869fdc310802dfdbbc71eaa2bef9d8582d63</originalsourceid><addsrcrecordid>eNqNkt1qFDEUxwdRbKkFn0AGvBFk23zM5ONGWJZaC1sUul6HTHJmN2UmWZOM0jvBF_AZfRKzbq2tIJhc5JD8zj_nHP5V9RyjE4wQOTV5JCctZY-qQ4IQnmFK2ON78UF1nNI1Kks0UnLytDqgTSsYJ-yw-nYFA3g3jXWaht5ZqK1LcdrmVOcN1B-W8_MlOV38-Pr98mx1erWar2iJnbeTAVtHSC5l7Q3Ueq2dT7keXQ5mE7yNTg-13oZtDgWqna83sNXlEYZhGnSsjY7G-TDqZ9WTXg8Jjm_Po-rj27PV4t1s-f78YjFfzkyLMJsRTojVrRXMABYctbJhlIAkhrVGMNlbQzESiNjedp3hGLQmHfTSilYQy-hRdbHXtUFfq210o443Kminfl2EuFY6ZmcGUJzJrsVcA9K00b2UQpZJtlrYpu8l74rWm73WdupGsAZ8jnp4IPrwxbuNWofPSjQNxlQWgVe3AjF8miBlNbq0m432EKakSMs5p62kTUFf_oVehyn6MipFOEMCS9TwQp3sqbUuDTjfh_KvKdvC6Ezw0LtyP2eSUtIy2fypwMSQUoT-rnqM1M5ZaucsVZxV0Bf3u70Df_uoAK_3wBfoQp-Mg-KJO6xYjyMkEaIlIqTQ4v_phcs6u-AXYfK5pM5uU0s3N_-sWC1Wl2RX-U8y2vqV</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2760819047</pqid></control><display><type>article</type><title>Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma</title><source>Wiley Online Library - AutoHoldings Journals</source><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library (Open Access Collection)</source><source>PubMed Central</source><creator>Yang, Tianfeng ; Huo, Jian ; Xu, Rui ; Su, Qi ; Tang, Wenjuan ; Zhang, Dongdong ; Zhu, Man ; Zhan, Yingzhuan ; Dai, Bingling ; Zhang, Yanmin</creator><creatorcontrib>Yang, Tianfeng ; Huo, Jian ; Xu, Rui ; Su, Qi ; Tang, Wenjuan ; Zhang, Dongdong ; Zhu, Man ; Zhan, Yingzhuan ; Dai, Bingling ; Zhang, Yanmin</creatorcontrib><description>Background
Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates.
Methods
The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor.
Results
PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo.
Conclusions
Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.
The C‐MET/STAT3 signaling axis as a novel downstream target of pleomorphic adenoma gene like‐2 (PLAGL2) contributed to PLAGL2‐induced mitochondrial apoptosis resistance in HCC. Selenium sulfide (SeS2) induced cell proliferation inhibition and apoptosis on HCC cells by inhibiting the activity of PLAGL2 and restraining the novel PLAGL2/C‐MET/STAT3, AKT/mTOR and MAPK signaling pathways.</description><identifier>ISSN: 2001-1326</identifier><identifier>EISSN: 2001-1326</identifier><identifier>DOI: 10.1002/ctm2.536</identifier><identifier>PMID: 34586726</identifier><language>eng</language><publisher>CHICHESTER: Wiley</publisher><subject>Adapter proteins ; Analysis ; Animals ; Antibodies ; Apoptosis ; Apoptosis - drug effects ; Cancer therapies ; Carcinoma, Hepatocellular - metabolism ; Cell cycle ; Cell Line, Tumor ; Clinical medicine ; C‐MET/STAT3 ; DNA-Binding Proteins - metabolism ; Drugs ; Genetic aspects ; HCC ; Health aspects ; Hepatoma ; Humans ; Kinases ; Life Sciences & Biomedicine ; Liver - chemistry ; Liver cancer ; Liver Neoplasms - metabolism ; Lung cancer ; Male ; Medicine, Research & Experimental ; Mice ; Mice, Nude ; Mitochondria - metabolism ; Mycoses ; Oncology ; PLAGL2 ; Plasmids ; Proto-Oncogene Proteins c-met - metabolism ; Research & Experimental Medicine ; RNA-Binding Proteins - metabolism ; Science & Technology ; Selenium Compounds - pharmacology ; Selenium sulfide ; Signal Transduction - drug effects ; STAT3 Transcription Factor - metabolism ; Transcription Factors - metabolism</subject><ispartof>Clinical and Translational Medicine, 2021-09, Vol.11 (9), p.e536-n/a, Article 536</ispartof><rights>2021 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics</rights><rights>2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.</rights><rights>COPYRIGHT 2021 John Wiley & Sons, Inc.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>13</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000700900300022</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c5016-2722da5d86ce1870594632e92c65c869fdc310802dfdbbc71eaa2bef9d8582d63</citedby><cites>FETCH-LOGICAL-c5016-2722da5d86ce1870594632e92c65c869fdc310802dfdbbc71eaa2bef9d8582d63</cites><orcidid>0000-0001-7307-9408</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441139/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441139/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,1418,2103,2115,11567,27929,27930,39263,45579,45580,46057,46481,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34586726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Tianfeng</creatorcontrib><creatorcontrib>Huo, Jian</creatorcontrib><creatorcontrib>Xu, Rui</creatorcontrib><creatorcontrib>Su, Qi</creatorcontrib><creatorcontrib>Tang, Wenjuan</creatorcontrib><creatorcontrib>Zhang, Dongdong</creatorcontrib><creatorcontrib>Zhu, Man</creatorcontrib><creatorcontrib>Zhan, Yingzhuan</creatorcontrib><creatorcontrib>Dai, Bingling</creatorcontrib><creatorcontrib>Zhang, Yanmin</creatorcontrib><title>Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma</title><title>Clinical and Translational Medicine</title><addtitle>CLIN TRANSL MED</addtitle><addtitle>Clin Transl Med</addtitle><description>Background
Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates.
Methods
The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor.
Results
PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo.
Conclusions
Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.
The C‐MET/STAT3 signaling axis as a novel downstream target of pleomorphic adenoma gene like‐2 (PLAGL2) contributed to PLAGL2‐induced mitochondrial apoptosis resistance in HCC. Selenium sulfide (SeS2) induced cell proliferation inhibition and apoptosis on HCC cells by inhibiting the activity of PLAGL2 and restraining the novel PLAGL2/C‐MET/STAT3, AKT/mTOR and MAPK signaling pathways.</description><subject>Adapter proteins</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Cancer therapies</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Clinical medicine</subject><subject>C‐MET/STAT3</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drugs</subject><subject>Genetic aspects</subject><subject>HCC</subject><subject>Health aspects</subject><subject>Hepatoma</subject><subject>Humans</subject><subject>Kinases</subject><subject>Life Sciences & Biomedicine</subject><subject>Liver - chemistry</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - metabolism</subject><subject>Lung cancer</subject><subject>Male</subject><subject>Medicine, Research & Experimental</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mitochondria - metabolism</subject><subject>Mycoses</subject><subject>Oncology</subject><subject>PLAGL2</subject><subject>Plasmids</subject><subject>Proto-Oncogene Proteins c-met - metabolism</subject><subject>Research & Experimental Medicine</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Science & Technology</subject><subject>Selenium Compounds - pharmacology</subject><subject>Selenium sulfide</subject><subject>Signal Transduction - drug effects</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Transcription Factors - metabolism</subject><issn>2001-1326</issn><issn>2001-1326</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqNkt1qFDEUxwdRbKkFn0AGvBFk23zM5ONGWJZaC1sUul6HTHJmN2UmWZOM0jvBF_AZfRKzbq2tIJhc5JD8zj_nHP5V9RyjE4wQOTV5JCctZY-qQ4IQnmFK2ON78UF1nNI1Kks0UnLytDqgTSsYJ-yw-nYFA3g3jXWaht5ZqK1LcdrmVOcN1B-W8_MlOV38-Pr98mx1erWar2iJnbeTAVtHSC5l7Q3Ueq2dT7keXQ5mE7yNTg-13oZtDgWqna83sNXlEYZhGnSsjY7G-TDqZ9WTXg8Jjm_Po-rj27PV4t1s-f78YjFfzkyLMJsRTojVrRXMABYctbJhlIAkhrVGMNlbQzESiNjedp3hGLQmHfTSilYQy-hRdbHXtUFfq210o443Kminfl2EuFY6ZmcGUJzJrsVcA9K00b2UQpZJtlrYpu8l74rWm73WdupGsAZ8jnp4IPrwxbuNWofPSjQNxlQWgVe3AjF8miBlNbq0m432EKakSMs5p62kTUFf_oVehyn6MipFOEMCS9TwQp3sqbUuDTjfh_KvKdvC6Ezw0LtyP2eSUtIy2fypwMSQUoT-rnqM1M5ZaucsVZxV0Bf3u70Df_uoAK_3wBfoQp-Mg-KJO6xYjyMkEaIlIqTQ4v_phcs6u-AXYfK5pM5uU0s3N_-sWC1Wl2RX-U8y2vqV</recordid><startdate>202109</startdate><enddate>202109</enddate><creator>Yang, Tianfeng</creator><creator>Huo, Jian</creator><creator>Xu, Rui</creator><creator>Su, Qi</creator><creator>Tang, Wenjuan</creator><creator>Zhang, Dongdong</creator><creator>Zhu, Man</creator><creator>Zhan, Yingzhuan</creator><creator>Dai, Bingling</creator><creator>Zhang, Yanmin</creator><general>Wiley</general><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><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>IAO</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-7307-9408</orcidid></search><sort><creationdate>202109</creationdate><title>Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma</title><author>Yang, Tianfeng ; Huo, Jian ; Xu, Rui ; Su, Qi ; Tang, Wenjuan ; Zhang, Dongdong ; Zhu, Man ; Zhan, Yingzhuan ; Dai, Bingling ; Zhang, Yanmin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5016-2722da5d86ce1870594632e92c65c869fdc310802dfdbbc71eaa2bef9d8582d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adapter proteins</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Cancer therapies</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Clinical medicine</topic><topic>C‐MET/STAT3</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drugs</topic><topic>Genetic aspects</topic><topic>HCC</topic><topic>Health aspects</topic><topic>Hepatoma</topic><topic>Humans</topic><topic>Kinases</topic><topic>Life Sciences & Biomedicine</topic><topic>Liver - chemistry</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - metabolism</topic><topic>Lung cancer</topic><topic>Male</topic><topic>Medicine, Research & Experimental</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mitochondria - metabolism</topic><topic>Mycoses</topic><topic>Oncology</topic><topic>PLAGL2</topic><topic>Plasmids</topic><topic>Proto-Oncogene Proteins c-met - metabolism</topic><topic>Research & Experimental Medicine</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Science & Technology</topic><topic>Selenium Compounds - pharmacology</topic><topic>Selenium sulfide</topic><topic>Signal Transduction - drug effects</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Tianfeng</creatorcontrib><creatorcontrib>Huo, Jian</creatorcontrib><creatorcontrib>Xu, Rui</creatorcontrib><creatorcontrib>Su, Qi</creatorcontrib><creatorcontrib>Tang, Wenjuan</creatorcontrib><creatorcontrib>Zhang, Dongdong</creatorcontrib><creatorcontrib>Zhu, Man</creatorcontrib><creatorcontrib>Zhan, Yingzhuan</creatorcontrib><creatorcontrib>Dai, Bingling</creatorcontrib><creatorcontrib>Zhang, Yanmin</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale Academic OneFile</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Proquest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Clinical and Translational Medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Tianfeng</au><au>Huo, Jian</au><au>Xu, Rui</au><au>Su, Qi</au><au>Tang, Wenjuan</au><au>Zhang, Dongdong</au><au>Zhu, Man</au><au>Zhan, Yingzhuan</au><au>Dai, Bingling</au><au>Zhang, Yanmin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma</atitle><jtitle>Clinical and Translational Medicine</jtitle><stitle>CLIN TRANSL MED</stitle><addtitle>Clin Transl Med</addtitle><date>2021-09</date><risdate>2021</risdate><volume>11</volume><issue>9</issue><spage>e536</spage><epage>n/a</epage><pages>e536-n/a</pages><artnum>536</artnum><issn>2001-1326</issn><eissn>2001-1326</eissn><abstract>Background
Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates.
Methods
The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor.
Results
PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo.
Conclusions
Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.
The C‐MET/STAT3 signaling axis as a novel downstream target of pleomorphic adenoma gene like‐2 (PLAGL2) contributed to PLAGL2‐induced mitochondrial apoptosis resistance in HCC. Selenium sulfide (SeS2) induced cell proliferation inhibition and apoptosis on HCC cells by inhibiting the activity of PLAGL2 and restraining the novel PLAGL2/C‐MET/STAT3, AKT/mTOR and MAPK signaling pathways.</abstract><cop>CHICHESTER</cop><pub>Wiley</pub><pmid>34586726</pmid><doi>10.1002/ctm2.536</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-7307-9408</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 2001-1326 |
| ispartof | Clinical and Translational Medicine, 2021-09, Vol.11 (9), p.e536-n/a, Article 536 |
| issn | 2001-1326 2001-1326 |
| language | eng |
| recordid | cdi_wiley_primary_10_1002_ctm2_536_CTM2536 |
| source | Wiley Online Library - AutoHoldings Journals; MEDLINE; DOAJ Directory of Open Access Journals; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; EZB-FREE-00999 freely available EZB journals; Wiley Online Library (Open Access Collection); PubMed Central |
| subjects | Adapter proteins Analysis Animals Antibodies Apoptosis Apoptosis - drug effects Cancer therapies Carcinoma, Hepatocellular - metabolism Cell cycle Cell Line, Tumor Clinical medicine C‐MET/STAT3 DNA-Binding Proteins - metabolism Drugs Genetic aspects HCC Health aspects Hepatoma Humans Kinases Life Sciences & Biomedicine Liver - chemistry Liver cancer Liver Neoplasms - metabolism Lung cancer Male Medicine, Research & Experimental Mice Mice, Nude Mitochondria - metabolism Mycoses Oncology PLAGL2 Plasmids Proto-Oncogene Proteins c-met - metabolism Research & Experimental Medicine RNA-Binding Proteins - metabolism Science & Technology Selenium Compounds - pharmacology Selenium sulfide Signal Transduction - drug effects STAT3 Transcription Factor - metabolism Transcription Factors - metabolism |
| title | Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-12T04%3A28%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_wiley&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Selenium%20sulfide%20disrupts%20the%20PLAGL2/C%E2%80%90MET/STAT3%E2%80%90induced%20resistance%20against%20mitochondrial%20apoptosis%20in%20hepatocellular%20carcinoma&rft.jtitle=Clinical%20and%20Translational%20Medicine&rft.au=Yang,%20Tianfeng&rft.date=2021-09&rft.volume=11&rft.issue=9&rft.spage=e536&rft.epage=n/a&rft.pages=e536-n/a&rft.artnum=536&rft.issn=2001-1326&rft.eissn=2001-1326&rft_id=info:doi/10.1002/ctm2.536&rft_dat=%3Cgale_wiley%3EA693325694%3C/gale_wiley%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2760819047&rft_id=info:pmid/34586726&rft_galeid=A693325694&rft_doaj_id=oai_doaj_org_article_769b517ae0a34af99893265a8d4ff97b&rfr_iscdi=true |