Limb expression 1‐like protein promotes epithelial–mesenchymal transition and epidermal growth factor receptor‐tyrosine kinase inhibitor resistance via nucleolin‐mediated ribosomal RNA synthesis in non‐small cell lung cancer
Limb expression 1‐like protein (LIX1L) might be an RNA‐binding protein involved in post‐transcriptional regulation. However, little is known regarding the biological function and mechanism of LIX1L in cancer cells. Here we demonstrate a clear correlation between LIX1L expression and epithelial–mesen...
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| Veröffentlicht in: | Cancer science 2023-04, Vol.114 (4), p.1740-1756 |
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| creator | Li, Minglei Zhang, Jiaxi Meng, Xue Liu, Bei Xie, Shelly M. Liu, Fang Yao, Demin Zhang, Jingguo Shen, Haitao Xing, Lingxiao |
| description | Limb expression 1‐like protein (LIX1L) might be an RNA‐binding protein involved in post‐transcriptional regulation. However, little is known regarding the biological function and mechanism of LIX1L in cancer cells. Here we demonstrate a clear correlation between LIX1L expression and epithelial–mesenchymal transition (EMT) markers in 81 non‐small cell lung cancer (NSCLC) tissues and The Cancer Genome Atlas database, suggesting that LIX1L is a mesenchymal marker. Besides, LIX1L expression is obviously elevated in TGFβ1‐induced EMT NSCLC cells and enhances cell migration, invasion, anoikis resistance, epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) resistance, and proliferation. Interestingly, the increased LIX1L expression prominently localizes to the nucleoli, where it physically interacts with the key ribosome biogenesis regulator NCL protein, inducing ribosomal RNA (rRNA) synthesis in EMT NSCLC cells. NCL knockdown or inhibition of rRNA synthesis reverses the enhanced EMT functions and proliferation ability caused by LIX1L overexpression in NSCLC cells, indicating that NCL expression and rRNA synthesis participates in LIX1L‐mediated biological functions during EMT. Collectively, our findings suggest that the LIX1L–NCL–rRNA synthesis axis is a novel EMT‐activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR‐TKI resistance in NSCLC.
Our results suggest that the LIX1L‐NCL‐rRNA synthesis axis is a novel EMT‐activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR‐TKIs resistance in NSCLC. |
| doi_str_mv | 10.1111/cas.15687 |
| format | Article |
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Our results suggest that the LIX1L‐NCL‐rRNA synthesis axis is a novel EMT‐activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR‐TKIs resistance in NSCLC.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.15687</identifier><identifier>PMID: 36478492</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Anoikis ; Apoptosis ; Autophagy-Related Proteins - metabolism ; Biosynthesis ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - metabolism ; Cell Line, Tumor ; Cell migration ; Cell proliferation ; Cells ; Drug Resistance, Neoplasm ; EMT ; Enzyme inhibitors ; Epidermal growth factor ; Epidermal growth factor receptors ; Epithelial-Mesenchymal Transition - genetics ; ErbB Receptors ; Gene regulation ; Genes ; Genomes ; Humans ; Kinases ; LIX1L ; Lung cancer ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Metastasis ; Non-small cell lung carcinoma ; NSCLC ; Nucleoli ; Nucleolin ; Original ; Post-transcription ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Ribosomal DNA ; ribosomal RNA synthesis ; Ribosomes - metabolism ; RNA polymerase ; RNA, Ribosomal - genetics ; RNA-binding protein ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; rRNA ; Small cell lung carcinoma ; Transforming growth factor-b1 ; Tumors ; Tyrosine Kinase Inhibitors</subject><ispartof>Cancer science, 2023-04, Vol.114 (4), p.1740-1756</ispartof><rights>2022 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2023. This work is published under http://creativecommons.org/licenses/by-nc-nd/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>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4687-63aea86e5bace57aeac2e87ecf340b2524d2950681091a29543b63b7eb1af3ff3</citedby><cites>FETCH-LOGICAL-c4687-63aea86e5bace57aeac2e87ecf340b2524d2950681091a29543b63b7eb1af3ff3</cites><orcidid>0000-0002-0787-7636 ; 0000-0003-3111-0133 ; 0000-0003-1030-2822</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/PMC10067404/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067404/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,1412,11543,27905,27906,45555,45556,46033,46457,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36478492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Minglei</creatorcontrib><creatorcontrib>Zhang, Jiaxi</creatorcontrib><creatorcontrib>Meng, Xue</creatorcontrib><creatorcontrib>Liu, Bei</creatorcontrib><creatorcontrib>Xie, Shelly M.</creatorcontrib><creatorcontrib>Liu, Fang</creatorcontrib><creatorcontrib>Yao, Demin</creatorcontrib><creatorcontrib>Zhang, Jingguo</creatorcontrib><creatorcontrib>Shen, Haitao</creatorcontrib><creatorcontrib>Xing, Lingxiao</creatorcontrib><title>Limb expression 1‐like protein promotes epithelial–mesenchymal transition and epidermal growth factor receptor‐tyrosine kinase inhibitor resistance via nucleolin‐mediated ribosomal RNA synthesis in non‐small cell lung cancer</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Limb expression 1‐like protein (LIX1L) might be an RNA‐binding protein involved in post‐transcriptional regulation. However, little is known regarding the biological function and mechanism of LIX1L in cancer cells. Here we demonstrate a clear correlation between LIX1L expression and epithelial–mesenchymal transition (EMT) markers in 81 non‐small cell lung cancer (NSCLC) tissues and The Cancer Genome Atlas database, suggesting that LIX1L is a mesenchymal marker. Besides, LIX1L expression is obviously elevated in TGFβ1‐induced EMT NSCLC cells and enhances cell migration, invasion, anoikis resistance, epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) resistance, and proliferation. Interestingly, the increased LIX1L expression prominently localizes to the nucleoli, where it physically interacts with the key ribosome biogenesis regulator NCL protein, inducing ribosomal RNA (rRNA) synthesis in EMT NSCLC cells. NCL knockdown or inhibition of rRNA synthesis reverses the enhanced EMT functions and proliferation ability caused by LIX1L overexpression in NSCLC cells, indicating that NCL expression and rRNA synthesis participates in LIX1L‐mediated biological functions during EMT. Collectively, our findings suggest that the LIX1L–NCL–rRNA synthesis axis is a novel EMT‐activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR‐TKI resistance in NSCLC.
Our results suggest that the LIX1L‐NCL‐rRNA synthesis axis is a novel EMT‐activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR‐TKIs resistance in NSCLC.</description><subject>Anoikis</subject><subject>Apoptosis</subject><subject>Autophagy-Related Proteins - metabolism</subject><subject>Biosynthesis</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell proliferation</subject><subject>Cells</subject><subject>Drug Resistance, Neoplasm</subject><subject>EMT</subject><subject>Enzyme inhibitors</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>ErbB Receptors</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genomes</subject><subject>Humans</subject><subject>Kinases</subject><subject>LIX1L</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Metastasis</subject><subject>Non-small cell lung carcinoma</subject><subject>NSCLC</subject><subject>Nucleoli</subject><subject>Nucleolin</subject><subject>Original</subject><subject>Post-transcription</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proteins</subject><subject>Ribosomal DNA</subject><subject>ribosomal RNA synthesis</subject><subject>Ribosomes - metabolism</subject><subject>RNA polymerase</subject><subject>RNA, Ribosomal - genetics</subject><subject>RNA-binding protein</subject><subject>RNA-Binding Proteins - genetics</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>rRNA</subject><subject>Small cell lung carcinoma</subject><subject>Transforming growth factor-b1</subject><subject>Tumors</subject><subject>Tyrosine Kinase Inhibitors</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1ks1u1DAQxyMEoqVw4AWQJS7lkNaJ8-UTWq34klYg8XG2HO9kd1rHDnbSsrc-AhJv2CNPwaRbKkDCB89Y85u_x-NJkqcZP8lonRodT7Kyaup7yWEmCpnWnFf3b_w6lVzkB8mjGM84F1Uhi4fJAdm6KWR-mPxcYd8y-DYEiBG9Y9n11XeL58CG4EdAN9uevMhgwHELFrW9vvrRQwRntrteWzYG7SKOc7Z265lbQ5gDm-Avxy3rtBl9YAEMDOTQBeMu-IgO2Dk6HYGh22KLeyhiHLUzwC5QMzcZC96io6Qe1qhHWLOArY9-vuDj-wWLO0dlURapMOdnMlLMMgO02cltmJn1wuPkQadthCe39ij58vrV5-XbdPXhzbvlYpWaglqYVkKDbiooW22grOlgcmhqMJ0oeJuXebHOZcmrJuMy0-QWoq1EW0Ob6U50nThKXu51h6mlmg04apBVQ8Beh53yGtXfEYdbtfEXKqNfqwtekMLxrULwXyeIo-oxzs_RDvwUVV6XQnApuST0-T_omZ-Co_cRJUXdSCk4US_2lKG-xwDdXTUZV_MIKRohdTNCxD77s_w78vfMEHC6By7Rwu7_Smq5-LSX_AXpx95s</recordid><startdate>202304</startdate><enddate>202304</enddate><creator>Li, Minglei</creator><creator>Zhang, Jiaxi</creator><creator>Meng, Xue</creator><creator>Liu, Bei</creator><creator>Xie, Shelly M.</creator><creator>Liu, Fang</creator><creator>Yao, Demin</creator><creator>Zhang, Jingguo</creator><creator>Shen, Haitao</creator><creator>Xing, Lingxiao</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0787-7636</orcidid><orcidid>https://orcid.org/0000-0003-3111-0133</orcidid><orcidid>https://orcid.org/0000-0003-1030-2822</orcidid></search><sort><creationdate>202304</creationdate><title>Limb expression 1‐like protein promotes epithelial–mesenchymal transition and epidermal growth factor receptor‐tyrosine kinase inhibitor resistance via nucleolin‐mediated ribosomal RNA synthesis in non‐small cell lung cancer</title><author>Li, Minglei ; Zhang, Jiaxi ; Meng, Xue ; Liu, Bei ; Xie, Shelly M. ; Liu, Fang ; Yao, Demin ; Zhang, Jingguo ; Shen, Haitao ; Xing, Lingxiao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4687-63aea86e5bace57aeac2e87ecf340b2524d2950681091a29543b63b7eb1af3ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Anoikis</topic><topic>Apoptosis</topic><topic>Autophagy-Related Proteins - metabolism</topic><topic>Biosynthesis</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell proliferation</topic><topic>Cells</topic><topic>Drug Resistance, Neoplasm</topic><topic>EMT</topic><topic>Enzyme inhibitors</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>Epithelial-Mesenchymal Transition - genetics</topic><topic>ErbB Receptors</topic><topic>Gene regulation</topic><topic>Genes</topic><topic>Genomes</topic><topic>Humans</topic><topic>Kinases</topic><topic>LIX1L</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Metastasis</topic><topic>Non-small cell lung carcinoma</topic><topic>NSCLC</topic><topic>Nucleoli</topic><topic>Nucleolin</topic><topic>Original</topic><topic>Post-transcription</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proteins</topic><topic>Ribosomal DNA</topic><topic>ribosomal RNA synthesis</topic><topic>Ribosomes - metabolism</topic><topic>RNA polymerase</topic><topic>RNA, Ribosomal - genetics</topic><topic>RNA-binding protein</topic><topic>RNA-Binding Proteins - genetics</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>rRNA</topic><topic>Small cell lung carcinoma</topic><topic>Transforming growth factor-b1</topic><topic>Tumors</topic><topic>Tyrosine Kinase Inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Minglei</creatorcontrib><creatorcontrib>Zhang, Jiaxi</creatorcontrib><creatorcontrib>Meng, Xue</creatorcontrib><creatorcontrib>Liu, Bei</creatorcontrib><creatorcontrib>Xie, Shelly M.</creatorcontrib><creatorcontrib>Liu, Fang</creatorcontrib><creatorcontrib>Yao, Demin</creatorcontrib><creatorcontrib>Zhang, Jingguo</creatorcontrib><creatorcontrib>Shen, Haitao</creatorcontrib><creatorcontrib>Xing, Lingxiao</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</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>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Minglei</au><au>Zhang, Jiaxi</au><au>Meng, Xue</au><au>Liu, Bei</au><au>Xie, Shelly M.</au><au>Liu, Fang</au><au>Yao, Demin</au><au>Zhang, Jingguo</au><au>Shen, Haitao</au><au>Xing, Lingxiao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Limb expression 1‐like protein promotes epithelial–mesenchymal transition and epidermal growth factor receptor‐tyrosine kinase inhibitor resistance via nucleolin‐mediated ribosomal RNA synthesis in non‐small cell lung cancer</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2023-04</date><risdate>2023</risdate><volume>114</volume><issue>4</issue><spage>1740</spage><epage>1756</epage><pages>1740-1756</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Limb expression 1‐like protein (LIX1L) might be an RNA‐binding protein involved in post‐transcriptional regulation. However, little is known regarding the biological function and mechanism of LIX1L in cancer cells. Here we demonstrate a clear correlation between LIX1L expression and epithelial–mesenchymal transition (EMT) markers in 81 non‐small cell lung cancer (NSCLC) tissues and The Cancer Genome Atlas database, suggesting that LIX1L is a mesenchymal marker. Besides, LIX1L expression is obviously elevated in TGFβ1‐induced EMT NSCLC cells and enhances cell migration, invasion, anoikis resistance, epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) resistance, and proliferation. Interestingly, the increased LIX1L expression prominently localizes to the nucleoli, where it physically interacts with the key ribosome biogenesis regulator NCL protein, inducing ribosomal RNA (rRNA) synthesis in EMT NSCLC cells. NCL knockdown or inhibition of rRNA synthesis reverses the enhanced EMT functions and proliferation ability caused by LIX1L overexpression in NSCLC cells, indicating that NCL expression and rRNA synthesis participates in LIX1L‐mediated biological functions during EMT. Collectively, our findings suggest that the LIX1L–NCL–rRNA synthesis axis is a novel EMT‐activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR‐TKI resistance in NSCLC.
Our results suggest that the LIX1L‐NCL‐rRNA synthesis axis is a novel EMT‐activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR‐TKIs resistance in NSCLC.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>36478492</pmid><doi>10.1111/cas.15687</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-0787-7636</orcidid><orcidid>https://orcid.org/0000-0003-3111-0133</orcidid><orcidid>https://orcid.org/0000-0003-1030-2822</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer science, 2023-04, Vol.114 (4), p.1740-1756 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Wiley Online Library Open Access; PubMed Central |
| subjects | Anoikis Apoptosis Autophagy-Related Proteins - metabolism Biosynthesis Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Cell Line, Tumor Cell migration Cell proliferation Cells Drug Resistance, Neoplasm EMT Enzyme inhibitors Epidermal growth factor Epidermal growth factor receptors Epithelial-Mesenchymal Transition - genetics ErbB Receptors Gene regulation Genes Genomes Humans Kinases LIX1L Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Metastasis Non-small cell lung carcinoma NSCLC Nucleoli Nucleolin Original Post-transcription Protein Kinase Inhibitors - pharmacology Proteins Ribosomal DNA ribosomal RNA synthesis Ribosomes - metabolism RNA polymerase RNA, Ribosomal - genetics RNA-binding protein RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism rRNA Small cell lung carcinoma Transforming growth factor-b1 Tumors Tyrosine Kinase Inhibitors |
| title | Limb expression 1‐like protein promotes epithelial–mesenchymal transition and epidermal growth factor receptor‐tyrosine kinase inhibitor resistance via nucleolin‐mediated ribosomal RNA synthesis in non‐small cell lung cancer |
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