Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity
Purpose Neuroblastoma arises from developmental block of embryonic neural crest cells and is one of the most common and deadly pediatric tumors. However, the mechanism underlying this block is still unclear. Here, we show that targeting Rho guanine nucleotide exchange factor 12 (ARHGEF12, also named...
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| Veröffentlicht in: | Cellular oncology (Dordrecht) 2023-02, Vol.46 (1), p.133-143 |
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| creator | Yang, Yi Wang, Siqi Cai, Jiaoyang Liang, Jianwei Zhang, Yingwen Xie, Yangyang Luo, Fei Tang, Jingyan Gao, Yijin Shen, Shuhong Feng, Haizhong Li, Yanxin |
| description | Purpose
Neuroblastoma arises from developmental block of embryonic neural crest cells and is one of the most common and deadly pediatric tumors. However, the mechanism underlying this block is still unclear. Here, we show that targeting Rho guanine nucleotide exchange factor 12 (ARHGEF12, also named LARG) promotes MYCN degradation and neuroblastoma differentiation, leading to reduced neuroblastoma malignancy.
Methods
The neuroblastoma TARGET dataset was downloaded to assess ARHGEF12 expression. Cell differentiation, proliferation, colony formation and cell migration analyses were performed to investigate the effects of ARHGEF12 knockdown on neuroblastoma cells. Western blotting and immunohistochemistry were employed to determine protein expression. Animal xenograft models were used to investigate antitumor effects after ARHGEF12 knockdown or treatment with the ARHGEF12 inhibitor Y16 in vivo.
Results
We found that the expression level of ARHGEF12 was higher in neuroblastoma than in better-differentiated ganglioneuroblastoma. Knockdown of ARHGEF12 promoted neuroblastoma differentiation, decreased stemness-related gene expression, and increased differentiation-related gene expression. ARHGEF12 knockdown reduced tumor growth, and the resulting tumors showed bigger tumor cells compared to those in control neuroblastoma xenografts. In addition, it was found that ARHGEF12 knockdown promoted MYCN ubiquitination and degradation in MYCN-amplified tumors through RhoA/ROCK/GSK3β signaling. Targeting ARHGEF12 with the small molecular inhibitor Y16 induced cell differentiation and attenuated neuroblastoma tumorigenicity.
Conclusion
Our findings provide new insight into the mechanism by which ARHGEF12 regulates neuroblastoma tumorigenicity and suggest a translatable therapeutic approach by targeting ARHGEF12 with a small molecular inhibitor. |
| doi_str_mv | 10.1007/s13402-022-00739-9 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2754859445</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2779140750</sourcerecordid><originalsourceid>FETCH-LOGICAL-c375t-412a3c85325d4a614c43b8d62e567499b7d3f9a6e155696fc9096b2e6dd1fead3</originalsourceid><addsrcrecordid>eNp9kUtLBSEYhiWKiuoPtIiBNi2a8j7HZRy6QReIWrQSZ_xmMM5oqbPo32edU0GLBP1En_f18iK0T_AJwbg5TYRxTGtMS8cNU7VaQ9uUElIzzuT6z5zOttBeSi-4NC6JFHITbTEpKC7DNhoeTRwgOz9UZw9Xl-cXhFavMYwhQ6o8TDG0C5NyGE1lXd9DBJ-dyS744-r2eX5XWRiisasV420VwU5dEedpDNEN4F3n8vsu2ujNIsHequ6gp4vzx_lVfXN_eT0_u6k71ohcc0IN62aCUWG5kYR3nLUzKykI2XCl2sayXhkJRAipZN8prGRLQVpLejCW7aCjpW95xNsEKevRpQ4WC-MhTEnTRvCZUJyLgh7-QV_CFH25XaEaRThuBC4UXVJdDClF6PVrdKOJ75pg_ZmEXiahSxL6KwmtiuhgZT21I9gfyfe_F4AtgVS2_ADx9-x_bD8AhzeS4g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2779140750</pqid></control><display><type>article</type><title>Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Yang, Yi ; Wang, Siqi ; Cai, Jiaoyang ; Liang, Jianwei ; Zhang, Yingwen ; Xie, Yangyang ; Luo, Fei ; Tang, Jingyan ; Gao, Yijin ; Shen, Shuhong ; Feng, Haizhong ; Li, Yanxin</creator><creatorcontrib>Yang, Yi ; Wang, Siqi ; Cai, Jiaoyang ; Liang, Jianwei ; Zhang, Yingwen ; Xie, Yangyang ; Luo, Fei ; Tang, Jingyan ; Gao, Yijin ; Shen, Shuhong ; Feng, Haizhong ; Li, Yanxin</creatorcontrib><description>Purpose
Neuroblastoma arises from developmental block of embryonic neural crest cells and is one of the most common and deadly pediatric tumors. However, the mechanism underlying this block is still unclear. Here, we show that targeting Rho guanine nucleotide exchange factor 12 (ARHGEF12, also named LARG) promotes MYCN degradation and neuroblastoma differentiation, leading to reduced neuroblastoma malignancy.
Methods
The neuroblastoma TARGET dataset was downloaded to assess ARHGEF12 expression. Cell differentiation, proliferation, colony formation and cell migration analyses were performed to investigate the effects of ARHGEF12 knockdown on neuroblastoma cells. Western blotting and immunohistochemistry were employed to determine protein expression. Animal xenograft models were used to investigate antitumor effects after ARHGEF12 knockdown or treatment with the ARHGEF12 inhibitor Y16 in vivo.
Results
We found that the expression level of ARHGEF12 was higher in neuroblastoma than in better-differentiated ganglioneuroblastoma. Knockdown of ARHGEF12 promoted neuroblastoma differentiation, decreased stemness-related gene expression, and increased differentiation-related gene expression. ARHGEF12 knockdown reduced tumor growth, and the resulting tumors showed bigger tumor cells compared to those in control neuroblastoma xenografts. In addition, it was found that ARHGEF12 knockdown promoted MYCN ubiquitination and degradation in MYCN-amplified tumors through RhoA/ROCK/GSK3β signaling. Targeting ARHGEF12 with the small molecular inhibitor Y16 induced cell differentiation and attenuated neuroblastoma tumorigenicity.
Conclusion
Our findings provide new insight into the mechanism by which ARHGEF12 regulates neuroblastoma tumorigenicity and suggest a translatable therapeutic approach by targeting ARHGEF12 with a small molecular inhibitor.</description><identifier>ISSN: 2211-3428</identifier><identifier>EISSN: 2211-3436</identifier><identifier>DOI: 10.1007/s13402-022-00739-9</identifier><identifier>PMID: 36520365</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Animal models ; Animals ; Antitumor activity ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell Differentiation ; Cell Line, Tumor ; Cell migration ; Cell Proliferation ; Degradation ; Gene expression ; Gene Expression Regulation, Neoplastic ; Guanine nucleotide exchange factor ; Humans ; Immunohistochemistry ; Malignancy ; N-Myc Proto-Oncogene Protein - genetics ; N-Myc Proto-Oncogene Protein - metabolism ; Neural crest ; Neuroblastoma ; Neuroblastoma - metabolism ; Neuroblastoma - pathology ; Neuroblasts ; Oncology ; Original Article ; Pathology ; Pediatrics ; Rho Guanine Nucleotide Exchange Factors - metabolism ; Rho-associated kinase ; RhoA protein ; Signal Transduction ; Tumor cells ; Tumorigenicity ; Tumors ; Ubiquitination ; Western blotting ; Xenografts</subject><ispartof>Cellular oncology (Dordrecht), 2023-02, Vol.46 (1), p.133-143</ispartof><rights>Springer Nature Switzerland AG 2022. corrected publication 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2022. Springer Nature Switzerland AG.</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-412a3c85325d4a614c43b8d62e567499b7d3f9a6e155696fc9096b2e6dd1fead3</citedby><cites>FETCH-LOGICAL-c375t-412a3c85325d4a614c43b8d62e567499b7d3f9a6e155696fc9096b2e6dd1fead3</cites><orcidid>0000-0003-1055-5029</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s13402-022-00739-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s13402-022-00739-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36520365$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Yi</creatorcontrib><creatorcontrib>Wang, Siqi</creatorcontrib><creatorcontrib>Cai, Jiaoyang</creatorcontrib><creatorcontrib>Liang, Jianwei</creatorcontrib><creatorcontrib>Zhang, Yingwen</creatorcontrib><creatorcontrib>Xie, Yangyang</creatorcontrib><creatorcontrib>Luo, Fei</creatorcontrib><creatorcontrib>Tang, Jingyan</creatorcontrib><creatorcontrib>Gao, Yijin</creatorcontrib><creatorcontrib>Shen, Shuhong</creatorcontrib><creatorcontrib>Feng, Haizhong</creatorcontrib><creatorcontrib>Li, Yanxin</creatorcontrib><title>Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity</title><title>Cellular oncology (Dordrecht)</title><addtitle>Cell Oncol</addtitle><addtitle>Cell Oncol (Dordr)</addtitle><description>Purpose
Neuroblastoma arises from developmental block of embryonic neural crest cells and is one of the most common and deadly pediatric tumors. However, the mechanism underlying this block is still unclear. Here, we show that targeting Rho guanine nucleotide exchange factor 12 (ARHGEF12, also named LARG) promotes MYCN degradation and neuroblastoma differentiation, leading to reduced neuroblastoma malignancy.
Methods
The neuroblastoma TARGET dataset was downloaded to assess ARHGEF12 expression. Cell differentiation, proliferation, colony formation and cell migration analyses were performed to investigate the effects of ARHGEF12 knockdown on neuroblastoma cells. Western blotting and immunohistochemistry were employed to determine protein expression. Animal xenograft models were used to investigate antitumor effects after ARHGEF12 knockdown or treatment with the ARHGEF12 inhibitor Y16 in vivo.
Results
We found that the expression level of ARHGEF12 was higher in neuroblastoma than in better-differentiated ganglioneuroblastoma. Knockdown of ARHGEF12 promoted neuroblastoma differentiation, decreased stemness-related gene expression, and increased differentiation-related gene expression. ARHGEF12 knockdown reduced tumor growth, and the resulting tumors showed bigger tumor cells compared to those in control neuroblastoma xenografts. In addition, it was found that ARHGEF12 knockdown promoted MYCN ubiquitination and degradation in MYCN-amplified tumors through RhoA/ROCK/GSK3β signaling. Targeting ARHGEF12 with the small molecular inhibitor Y16 induced cell differentiation and attenuated neuroblastoma tumorigenicity.
Conclusion
Our findings provide new insight into the mechanism by which ARHGEF12 regulates neuroblastoma tumorigenicity and suggest a translatable therapeutic approach by targeting ARHGEF12 with a small molecular inhibitor.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antitumor activity</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell Differentiation</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Proliferation</subject><subject>Degradation</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Guanine nucleotide exchange factor</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Malignancy</subject><subject>N-Myc Proto-Oncogene Protein - genetics</subject><subject>N-Myc Proto-Oncogene Protein - metabolism</subject><subject>Neural crest</subject><subject>Neuroblastoma</subject><subject>Neuroblastoma - metabolism</subject><subject>Neuroblastoma - pathology</subject><subject>Neuroblasts</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pathology</subject><subject>Pediatrics</subject><subject>Rho Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Rho-associated kinase</subject><subject>RhoA protein</subject><subject>Signal Transduction</subject><subject>Tumor cells</subject><subject>Tumorigenicity</subject><subject>Tumors</subject><subject>Ubiquitination</subject><subject>Western blotting</subject><subject>Xenografts</subject><issn>2211-3428</issn><issn>2211-3436</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtLBSEYhiWKiuoPtIiBNi2a8j7HZRy6QReIWrQSZ_xmMM5oqbPo32edU0GLBP1En_f18iK0T_AJwbg5TYRxTGtMS8cNU7VaQ9uUElIzzuT6z5zOttBeSi-4NC6JFHITbTEpKC7DNhoeTRwgOz9UZw9Xl-cXhFavMYwhQ6o8TDG0C5NyGE1lXd9DBJ-dyS744-r2eX5XWRiisasV420VwU5dEedpDNEN4F3n8vsu2ujNIsHequ6gp4vzx_lVfXN_eT0_u6k71ohcc0IN62aCUWG5kYR3nLUzKykI2XCl2sayXhkJRAipZN8prGRLQVpLejCW7aCjpW95xNsEKevRpQ4WC-MhTEnTRvCZUJyLgh7-QV_CFH25XaEaRThuBC4UXVJdDClF6PVrdKOJ75pg_ZmEXiahSxL6KwmtiuhgZT21I9gfyfe_F4AtgVS2_ADx9-x_bD8AhzeS4g</recordid><startdate>20230201</startdate><enddate>20230201</enddate><creator>Yang, Yi</creator><creator>Wang, Siqi</creator><creator>Cai, Jiaoyang</creator><creator>Liang, Jianwei</creator><creator>Zhang, Yingwen</creator><creator>Xie, Yangyang</creator><creator>Luo, Fei</creator><creator>Tang, Jingyan</creator><creator>Gao, Yijin</creator><creator>Shen, Shuhong</creator><creator>Feng, Haizhong</creator><creator>Li, Yanxin</creator><general>Springer Netherlands</general><general>Springer Nature B.V</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><orcidid>https://orcid.org/0000-0003-1055-5029</orcidid></search><sort><creationdate>20230201</creationdate><title>Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity</title><author>Yang, Yi ; Wang, Siqi ; Cai, Jiaoyang ; Liang, Jianwei ; Zhang, Yingwen ; Xie, Yangyang ; Luo, Fei ; Tang, Jingyan ; Gao, Yijin ; Shen, Shuhong ; Feng, Haizhong ; Li, Yanxin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-412a3c85325d4a614c43b8d62e567499b7d3f9a6e155696fc9096b2e6dd1fead3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Antitumor activity</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Cell Differentiation</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Proliferation</topic><topic>Degradation</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Guanine nucleotide exchange factor</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Malignancy</topic><topic>N-Myc Proto-Oncogene Protein - genetics</topic><topic>N-Myc Proto-Oncogene Protein - metabolism</topic><topic>Neural crest</topic><topic>Neuroblastoma</topic><topic>Neuroblastoma - metabolism</topic><topic>Neuroblastoma - pathology</topic><topic>Neuroblasts</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pathology</topic><topic>Pediatrics</topic><topic>Rho Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Rho-associated kinase</topic><topic>RhoA protein</topic><topic>Signal Transduction</topic><topic>Tumor cells</topic><topic>Tumorigenicity</topic><topic>Tumors</topic><topic>Ubiquitination</topic><topic>Western blotting</topic><topic>Xenografts</topic><toplevel>online_resources</toplevel><creatorcontrib>Yang, Yi</creatorcontrib><creatorcontrib>Wang, Siqi</creatorcontrib><creatorcontrib>Cai, Jiaoyang</creatorcontrib><creatorcontrib>Liang, Jianwei</creatorcontrib><creatorcontrib>Zhang, Yingwen</creatorcontrib><creatorcontrib>Xie, Yangyang</creatorcontrib><creatorcontrib>Luo, Fei</creatorcontrib><creatorcontrib>Tang, Jingyan</creatorcontrib><creatorcontrib>Gao, Yijin</creatorcontrib><creatorcontrib>Shen, Shuhong</creatorcontrib><creatorcontrib>Feng, Haizhong</creatorcontrib><creatorcontrib>Li, Yanxin</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>Cellular oncology (Dordrecht)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Yi</au><au>Wang, Siqi</au><au>Cai, Jiaoyang</au><au>Liang, Jianwei</au><au>Zhang, Yingwen</au><au>Xie, Yangyang</au><au>Luo, Fei</au><au>Tang, Jingyan</au><au>Gao, Yijin</au><au>Shen, Shuhong</au><au>Feng, Haizhong</au><au>Li, Yanxin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity</atitle><jtitle>Cellular oncology (Dordrecht)</jtitle><stitle>Cell Oncol</stitle><addtitle>Cell Oncol (Dordr)</addtitle><date>2023-02-01</date><risdate>2023</risdate><volume>46</volume><issue>1</issue><spage>133</spage><epage>143</epage><pages>133-143</pages><issn>2211-3428</issn><eissn>2211-3436</eissn><abstract>Purpose
Neuroblastoma arises from developmental block of embryonic neural crest cells and is one of the most common and deadly pediatric tumors. However, the mechanism underlying this block is still unclear. Here, we show that targeting Rho guanine nucleotide exchange factor 12 (ARHGEF12, also named LARG) promotes MYCN degradation and neuroblastoma differentiation, leading to reduced neuroblastoma malignancy.
Methods
The neuroblastoma TARGET dataset was downloaded to assess ARHGEF12 expression. Cell differentiation, proliferation, colony formation and cell migration analyses were performed to investigate the effects of ARHGEF12 knockdown on neuroblastoma cells. Western blotting and immunohistochemistry were employed to determine protein expression. Animal xenograft models were used to investigate antitumor effects after ARHGEF12 knockdown or treatment with the ARHGEF12 inhibitor Y16 in vivo.
Results
We found that the expression level of ARHGEF12 was higher in neuroblastoma than in better-differentiated ganglioneuroblastoma. Knockdown of ARHGEF12 promoted neuroblastoma differentiation, decreased stemness-related gene expression, and increased differentiation-related gene expression. ARHGEF12 knockdown reduced tumor growth, and the resulting tumors showed bigger tumor cells compared to those in control neuroblastoma xenografts. In addition, it was found that ARHGEF12 knockdown promoted MYCN ubiquitination and degradation in MYCN-amplified tumors through RhoA/ROCK/GSK3β signaling. Targeting ARHGEF12 with the small molecular inhibitor Y16 induced cell differentiation and attenuated neuroblastoma tumorigenicity.
Conclusion
Our findings provide new insight into the mechanism by which ARHGEF12 regulates neuroblastoma tumorigenicity and suggest a translatable therapeutic approach by targeting ARHGEF12 with a small molecular inhibitor.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>36520365</pmid><doi>10.1007/s13402-022-00739-9</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-1055-5029</orcidid></addata></record> |
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| subjects | Animal models Animals Antitumor activity Biomedical and Life Sciences Biomedicine Cancer Research Cell Differentiation Cell Line, Tumor Cell migration Cell Proliferation Degradation Gene expression Gene Expression Regulation, Neoplastic Guanine nucleotide exchange factor Humans Immunohistochemistry Malignancy N-Myc Proto-Oncogene Protein - genetics N-Myc Proto-Oncogene Protein - metabolism Neural crest Neuroblastoma Neuroblastoma - metabolism Neuroblastoma - pathology Neuroblasts Oncology Original Article Pathology Pediatrics Rho Guanine Nucleotide Exchange Factors - metabolism Rho-associated kinase RhoA protein Signal Transduction Tumor cells Tumorigenicity Tumors Ubiquitination Western blotting Xenografts |
| title | Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity |
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