MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer
Trastuzumab resistance has been becoming a major obstacle for treatment of HER-2-positive breast cancer patients. Increasing evidence suggests that mesenchymal stem cells (MSCs) play critical roles during the formation of drug resistance, however, the underlying mechanism is not well known. In this...
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| Veröffentlicht in: | Oncogene 2021-01, Vol.40 (4), p.833 |
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| creator | Han, Jing Qu, Hongbo Han, Mingli Ding, Yichao Xie, Mingwei Hu, Jianguo Chen, Yuanwen Dong, Huaying |
| description | Trastuzumab resistance has been becoming a major obstacle for treatment of HER-2-positive breast cancer patients. Increasing evidence suggests that mesenchymal stem cells (MSCs) play critical roles during the formation of drug resistance, however, the underlying mechanism is not well known. In this study, mass spectrometry, RNA pulldown and RNA immunoprecipitation assays were performed to verify the direct interactions among AGAP2-AS1 and other associated targets, such as human antigen R (HuR), miR-15a-5p, and carnitine palmitoyl transferase 1 (CPT1). In vitro and in vivo experimental assays were done to clarify the functional role of AGAP2-AS1 in trastuzumab resistance, stemness, and fatty acid oxidation (FAO). The results showed that MSC co-culture induced trastuzumab resistance. AGAP2-AS1 was upregulated in MSC-cultured cells, and knockdown of AGAP2-AS1 reversed the MSC-mediated trastuzumab resistance. Furthermore, MSC culture-induced AGAP2-AS1 regulates stemness and trastuzumab resistance via activating FAO. Mechanistically, AGAP2-AS1 is associated with HuR, and the AGAP2-AS1-HuR complex could directly bind to the CPT1, increasing its expression via improving RNA stability. In addition, AGAP2-AS1 could serve as ceRNA via sponging miR-15a-5p and releasing CPT1 mRNA. Clinically, increased expression of serum AGAP2-AS1 predicts poor response to trastuzumab treatment in breast cancer patients. In conclusion, MSC culture-induced AGAP2-AS1 caused stemness and trastuzumab resistance via promoting CPT1 expression and inducing FAO. Our results provide new insight of the role of MSCs in trastuzumab resistance and AGAP2-AS1 could be promising predictive biomarker and therapeutic target for HER-2+ breast cancer patients. |
| doi_str_mv | 10.1038/s41388-020-01574-8 |
| format | Article |
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Increasing evidence suggests that mesenchymal stem cells (MSCs) play critical roles during the formation of drug resistance, however, the underlying mechanism is not well known. In this study, mass spectrometry, RNA pulldown and RNA immunoprecipitation assays were performed to verify the direct interactions among AGAP2-AS1 and other associated targets, such as human antigen R (HuR), miR-15a-5p, and carnitine palmitoyl transferase 1 (CPT1). In vitro and in vivo experimental assays were done to clarify the functional role of AGAP2-AS1 in trastuzumab resistance, stemness, and fatty acid oxidation (FAO). The results showed that MSC co-culture induced trastuzumab resistance. AGAP2-AS1 was upregulated in MSC-cultured cells, and knockdown of AGAP2-AS1 reversed the MSC-mediated trastuzumab resistance. Furthermore, MSC culture-induced AGAP2-AS1 regulates stemness and trastuzumab resistance via activating FAO. Mechanistically, AGAP2-AS1 is associated with HuR, and the AGAP2-AS1-HuR complex could directly bind to the CPT1, increasing its expression via improving RNA stability. In addition, AGAP2-AS1 could serve as ceRNA via sponging miR-15a-5p and releasing CPT1 mRNA. Clinically, increased expression of serum AGAP2-AS1 predicts poor response to trastuzumab treatment in breast cancer patients. In conclusion, MSC culture-induced AGAP2-AS1 caused stemness and trastuzumab resistance via promoting CPT1 expression and inducing FAO. Our results provide new insight of the role of MSCs in trastuzumab resistance and AGAP2-AS1 could be promising predictive biomarker and therapeutic target for HER-2+ breast cancer patients.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-020-01574-8</identifier><identifier>PMID: 33273726</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Cancer cells ; Care and treatment ; Carnitine O-Palmitoyltransferase - genetics ; Carnitine O-Palmitoyltransferase - physiology ; Cell Line, Tumor ; Development and progression ; Drug Resistance, Neoplasm ; ELAV-Like Protein 1 - physiology ; Fatty Acids - metabolism ; Female ; Gene expression ; Genetic aspects ; Health aspects ; Humans ; Mesenchymal Stem Cells - physiology ; MicroRNAs - physiology ; Oxidation-Reduction ; RNA ; RNA, Long Noncoding - physiology ; Stem cells ; Trastuzumab - therapeutic use</subject><ispartof>Oncogene, 2021-01, Vol.40 (4), p.833</ispartof><rights>COPYRIGHT 2021 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-4905-6940</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33273726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Jing</creatorcontrib><creatorcontrib>Qu, Hongbo</creatorcontrib><creatorcontrib>Han, Mingli</creatorcontrib><creatorcontrib>Ding, Yichao</creatorcontrib><creatorcontrib>Xie, Mingwei</creatorcontrib><creatorcontrib>Hu, Jianguo</creatorcontrib><creatorcontrib>Chen, Yuanwen</creatorcontrib><creatorcontrib>Dong, Huaying</creatorcontrib><title>MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer</title><title>Oncogene</title><addtitle>Oncogene</addtitle><description>Trastuzumab resistance has been becoming a major obstacle for treatment of HER-2-positive breast cancer patients. Increasing evidence suggests that mesenchymal stem cells (MSCs) play critical roles during the formation of drug resistance, however, the underlying mechanism is not well known. In this study, mass spectrometry, RNA pulldown and RNA immunoprecipitation assays were performed to verify the direct interactions among AGAP2-AS1 and other associated targets, such as human antigen R (HuR), miR-15a-5p, and carnitine palmitoyl transferase 1 (CPT1). In vitro and in vivo experimental assays were done to clarify the functional role of AGAP2-AS1 in trastuzumab resistance, stemness, and fatty acid oxidation (FAO). The results showed that MSC co-culture induced trastuzumab resistance. AGAP2-AS1 was upregulated in MSC-cultured cells, and knockdown of AGAP2-AS1 reversed the MSC-mediated trastuzumab resistance. Furthermore, MSC culture-induced AGAP2-AS1 regulates stemness and trastuzumab resistance via activating FAO. Mechanistically, AGAP2-AS1 is associated with HuR, and the AGAP2-AS1-HuR complex could directly bind to the CPT1, increasing its expression via improving RNA stability. In addition, AGAP2-AS1 could serve as ceRNA via sponging miR-15a-5p and releasing CPT1 mRNA. Clinically, increased expression of serum AGAP2-AS1 predicts poor response to trastuzumab treatment in breast cancer patients. In conclusion, MSC culture-induced AGAP2-AS1 caused stemness and trastuzumab resistance via promoting CPT1 expression and inducing FAO. Our results provide new insight of the role of MSCs in trastuzumab resistance and AGAP2-AS1 could be promising predictive biomarker and therapeutic target for HER-2+ breast cancer patients.</description><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cancer cells</subject><subject>Care and treatment</subject><subject>Carnitine O-Palmitoyltransferase - genetics</subject><subject>Carnitine O-Palmitoyltransferase - physiology</subject><subject>Cell Line, Tumor</subject><subject>Development and progression</subject><subject>Drug Resistance, Neoplasm</subject><subject>ELAV-Like Protein 1 - physiology</subject><subject>Fatty Acids - metabolism</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Mesenchymal Stem Cells - physiology</subject><subject>MicroRNAs - physiology</subject><subject>Oxidation-Reduction</subject><subject>RNA</subject><subject>RNA, Long Noncoding - physiology</subject><subject>Stem cells</subject><subject>Trastuzumab - therapeutic use</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkElLxTAUhYMo-hz-gAsJuI5maJpmWR5O4ITD-pEmtzXymj6aFNQf4u81TgtB7uLCud85cC5C-4weMSqq41gwUVWEckook6og1RqasUKVREpdrKMZ1ZISzQXfQtsxPlNKlaZ8E20JwZVQvJyh96v7OfHBTRYcXgZ7d13j-qy-5aS-Z3g1Dv2QIOKYoA8QIzbB4TSamKa3qTcNHiH6mEywgNPTOEzdU5a6aWmSDx2e3z4wDC-rTEU_hC93a1J6xcZ6h4cX7zKYDz7gZoQci-1n1riLNlqzjLD3s3fQ4-nJw_ycXN6cXczrS9JxVSXS2KKAlloFpWukBsGUa5yVlInScsVd1TCrAZgxVSvaUkuhqWxabbh0RpViBx1-53ZmCQsf2iGXs72PdlGXUiomdFVk6ugfKo-D3tshQOuz_sdw8G1YTU0PbrEafW_G18Xv38UHkK-GjQ</recordid><startdate>20210128</startdate><enddate>20210128</enddate><creator>Han, Jing</creator><creator>Qu, Hongbo</creator><creator>Han, Mingli</creator><creator>Ding, Yichao</creator><creator>Xie, Mingwei</creator><creator>Hu, Jianguo</creator><creator>Chen, Yuanwen</creator><creator>Dong, Huaying</creator><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-4905-6940</orcidid></search><sort><creationdate>20210128</creationdate><title>MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer</title><author>Han, Jing ; Qu, Hongbo ; Han, Mingli ; Ding, Yichao ; Xie, Mingwei ; Hu, Jianguo ; Chen, Yuanwen ; Dong, Huaying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g278t-bc44ef0c7e6db59e317dbdc50136c272d8b1c9ee1aa8f3f6953905bf9a25da763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cancer cells</topic><topic>Care and treatment</topic><topic>Carnitine O-Palmitoyltransferase - genetics</topic><topic>Carnitine O-Palmitoyltransferase - physiology</topic><topic>Cell Line, Tumor</topic><topic>Development and progression</topic><topic>Drug Resistance, Neoplasm</topic><topic>ELAV-Like Protein 1 - physiology</topic><topic>Fatty Acids - metabolism</topic><topic>Female</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Mesenchymal Stem Cells - physiology</topic><topic>MicroRNAs - physiology</topic><topic>Oxidation-Reduction</topic><topic>RNA</topic><topic>RNA, Long Noncoding - physiology</topic><topic>Stem cells</topic><topic>Trastuzumab - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Jing</creatorcontrib><creatorcontrib>Qu, Hongbo</creatorcontrib><creatorcontrib>Han, Mingli</creatorcontrib><creatorcontrib>Ding, Yichao</creatorcontrib><creatorcontrib>Xie, Mingwei</creatorcontrib><creatorcontrib>Hu, Jianguo</creatorcontrib><creatorcontrib>Chen, Yuanwen</creatorcontrib><creatorcontrib>Dong, Huaying</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Jing</au><au>Qu, Hongbo</au><au>Han, Mingli</au><au>Ding, Yichao</au><au>Xie, Mingwei</au><au>Hu, Jianguo</au><au>Chen, Yuanwen</au><au>Dong, Huaying</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer</atitle><jtitle>Oncogene</jtitle><addtitle>Oncogene</addtitle><date>2021-01-28</date><risdate>2021</risdate><volume>40</volume><issue>4</issue><spage>833</spage><pages>833-</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Trastuzumab resistance has been becoming a major obstacle for treatment of HER-2-positive breast cancer patients. Increasing evidence suggests that mesenchymal stem cells (MSCs) play critical roles during the formation of drug resistance, however, the underlying mechanism is not well known. In this study, mass spectrometry, RNA pulldown and RNA immunoprecipitation assays were performed to verify the direct interactions among AGAP2-AS1 and other associated targets, such as human antigen R (HuR), miR-15a-5p, and carnitine palmitoyl transferase 1 (CPT1). In vitro and in vivo experimental assays were done to clarify the functional role of AGAP2-AS1 in trastuzumab resistance, stemness, and fatty acid oxidation (FAO). The results showed that MSC co-culture induced trastuzumab resistance. AGAP2-AS1 was upregulated in MSC-cultured cells, and knockdown of AGAP2-AS1 reversed the MSC-mediated trastuzumab resistance. Furthermore, MSC culture-induced AGAP2-AS1 regulates stemness and trastuzumab resistance via activating FAO. Mechanistically, AGAP2-AS1 is associated with HuR, and the AGAP2-AS1-HuR complex could directly bind to the CPT1, increasing its expression via improving RNA stability. In addition, AGAP2-AS1 could serve as ceRNA via sponging miR-15a-5p and releasing CPT1 mRNA. Clinically, increased expression of serum AGAP2-AS1 predicts poor response to trastuzumab treatment in breast cancer patients. In conclusion, MSC culture-induced AGAP2-AS1 caused stemness and trastuzumab resistance via promoting CPT1 expression and inducing FAO. Our results provide new insight of the role of MSCs in trastuzumab resistance and AGAP2-AS1 could be promising predictive biomarker and therapeutic target for HER-2+ breast cancer patients.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>33273726</pmid><doi>10.1038/s41388-020-01574-8</doi><orcidid>https://orcid.org/0000-0002-4905-6940</orcidid></addata></record> |
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| subjects | Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Cancer cells Care and treatment Carnitine O-Palmitoyltransferase - genetics Carnitine O-Palmitoyltransferase - physiology Cell Line, Tumor Development and progression Drug Resistance, Neoplasm ELAV-Like Protein 1 - physiology Fatty Acids - metabolism Female Gene expression Genetic aspects Health aspects Humans Mesenchymal Stem Cells - physiology MicroRNAs - physiology Oxidation-Reduction RNA RNA, Long Noncoding - physiology Stem cells Trastuzumab - therapeutic use |
| title | MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer |
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