Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma
Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression...
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| Veröffentlicht in: | Virchows Archiv : an international journal of pathology 2022-04, Vol.480 (4), p.831-841 |
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| creator | Kadonaga, Taichi Sakabe, Tomohiko Kidokoro, Yoshiteru Haruki, Tomohiro Nosaka, Kanae Nakamura, Hiroshige Umekita, Yoshihisa |
| description | Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression profiles of non-invasive lesions (non-ILs) and adjacent histologically normal lung (aNL) tissues within invasive LUAD have not been investigated. Herein, we analyzed differentially expressed genes (DEGs) specific to early-stage carcinogenesis in LUAD. Invasive LUAD tissue samples containing both non-ILs and aNL tissues were obtained from seven patients with pathological stage I LUAD, and each component was subjected to microdissection. Gene expression profiles of each component were determined using targeted RNA-sequencing. In total, 2536 DEGs, including 863 upregulated and 1673 downregulated genes, were identified in non-ILs. In non-ILs, the expression of
SLC44A5
, a choline transporter-like protein-coding gene, was significantly upregulated, and that of
TMEM100
, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein–protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD. |
| doi_str_mv | 10.1007/s00428-021-03250-y |
| format | Article |
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SLC44A5
, a choline transporter-like protein-coding gene, was significantly upregulated, and that of
TMEM100
, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein–protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD.</description><identifier>ISSN: 0945-6317</identifier><identifier>EISSN: 1432-2307</identifier><identifier>DOI: 10.1007/s00428-021-03250-y</identifier><identifier>PMID: 35067776</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adenocarcinoma ; Adenocarcinoma of Lung - genetics ; Adenocarcinoma of Lung - pathology ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cancer ; Carcinogenesis ; Carcinogenesis - genetics ; Carcinogens ; Carcinoma, Non-Small-Cell Lung - genetics ; Cell death ; Choline ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - genetics ; Gene sequencing ; Gene set enrichment analysis ; Genes ; Hepatocellular carcinoma ; Humans ; Immune response ; Immune system ; Lesions ; Lung - pathology ; Lung cancer ; Lung Neoplasms - pathology ; Medicine ; Medicine & Public Health ; Membrane Proteins - genetics ; Network analysis ; Network hubs ; Non-small cell lung carcinoma ; Original Article ; Pathology ; Protein transport ; Proteins ; Ribonucleic acid ; RNA ; Small cell lung carcinoma ; Tumor suppressor genes ; Tumors</subject><ispartof>Virchows Archiv : an international journal of pathology, 2022-04, Vol.480 (4), p.831-841</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c569t-d15128a132f161e11c72611385fe18619531551c94acce51f544f49d479b7f1a3</citedby><cites>FETCH-LOGICAL-c569t-d15128a132f161e11c72611385fe18619531551c94acce51f544f49d479b7f1a3</cites><orcidid>0000-0002-2846-390X</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/s00428-021-03250-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00428-021-03250-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,781,785,27929,27930,41493,42562,51324</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35067776$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kadonaga, Taichi</creatorcontrib><creatorcontrib>Sakabe, Tomohiko</creatorcontrib><creatorcontrib>Kidokoro, Yoshiteru</creatorcontrib><creatorcontrib>Haruki, Tomohiro</creatorcontrib><creatorcontrib>Nosaka, Kanae</creatorcontrib><creatorcontrib>Nakamura, Hiroshige</creatorcontrib><creatorcontrib>Umekita, Yoshihisa</creatorcontrib><title>Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma</title><title>Virchows Archiv : an international journal of pathology</title><addtitle>Virchows Arch</addtitle><addtitle>Virchows Arch</addtitle><description>Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression profiles of non-invasive lesions (non-ILs) and adjacent histologically normal lung (aNL) tissues within invasive LUAD have not been investigated. Herein, we analyzed differentially expressed genes (DEGs) specific to early-stage carcinogenesis in LUAD. Invasive LUAD tissue samples containing both non-ILs and aNL tissues were obtained from seven patients with pathological stage I LUAD, and each component was subjected to microdissection. Gene expression profiles of each component were determined using targeted RNA-sequencing. In total, 2536 DEGs, including 863 upregulated and 1673 downregulated genes, were identified in non-ILs. In non-ILs, the expression of
SLC44A5
, a choline transporter-like protein-coding gene, was significantly upregulated, and that of
TMEM100
, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein–protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD.</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma of Lung - genetics</subject><subject>Adenocarcinoma of Lung - pathology</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogens</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Cell death</subject><subject>Choline</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Gene sequencing</subject><subject>Gene set enrichment analysis</subject><subject>Genes</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Lesions</subject><subject>Lung - pathology</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - pathology</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane Proteins - genetics</subject><subject>Network analysis</subject><subject>Network hubs</subject><subject>Non-small cell lung carcinoma</subject><subject>Original Article</subject><subject>Pathology</subject><subject>Protein transport</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Small cell lung carcinoma</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><issn>0945-6317</issn><issn>1432-2307</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><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>eNp9kc9u1DAQxi0EosvCC3BAlrhwMXj8L8mxqqAgVSAhOEeuM9m6cuzFTqrue_GAON2WShy4zEjj3_eNRx8hr4G_B86bD4VzJVrGBTAuhebs8IRsQEnBhOTNU7LhndLMSGhOyItSrnklWzDPyYnU3DRNYzbk9zlGpHi7z1iKT5Hucxp98HFHl7LW2eYdzjjQ719PWcFfC0Z3N08Uw-L8YGek8xWuwt2DyZjTRK98mVNIO-9sCAcaU55soGFZxb6UBctqElNkPt7Y4m-QBlzlhfpIH2erwA4Yk7O5rk6TfUmejTYUfHXft-Tnp48_zj6zi2_nX85OL5jTppvZABpEa0GKEQwggGuEAZCtHhFaA52WoDW4TlnnUMOolRpVN6imu2xGsHJL3h1962318DL3ky8OQ7AR01J6YYRQLehqtCVv_0Gv05Jj_V2ltORSK8MrJY6Uy6mUjGO_z36y-dAD79dM-2OmfU2qv8u0P1TRm3vr5XLC4a_kIcQKyCNQ6lPcYX7c_R_bP1U4sOU</recordid><startdate>20220401</startdate><enddate>20220401</enddate><creator>Kadonaga, Taichi</creator><creator>Sakabe, Tomohiko</creator><creator>Kidokoro, Yoshiteru</creator><creator>Haruki, Tomohiro</creator><creator>Nosaka, Kanae</creator><creator>Nakamura, Hiroshige</creator><creator>Umekita, Yoshihisa</creator><general>Springer Berlin Heidelberg</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>3V.</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2846-390X</orcidid></search><sort><creationdate>20220401</creationdate><title>Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma</title><author>Kadonaga, Taichi ; Sakabe, Tomohiko ; Kidokoro, Yoshiteru ; Haruki, Tomohiro ; Nosaka, Kanae ; Nakamura, Hiroshige ; Umekita, Yoshihisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c569t-d15128a132f161e11c72611385fe18619531551c94acce51f544f49d479b7f1a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adenocarcinoma</topic><topic>Adenocarcinoma of Lung - genetics</topic><topic>Adenocarcinoma of Lung - pathology</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cancer</topic><topic>Carcinogenesis</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogens</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Cell death</topic><topic>Choline</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Gene sequencing</topic><topic>Gene set enrichment analysis</topic><topic>Genes</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Lesions</topic><topic>Lung - pathology</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - pathology</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Membrane Proteins - genetics</topic><topic>Network analysis</topic><topic>Network hubs</topic><topic>Non-small cell lung carcinoma</topic><topic>Original Article</topic><topic>Pathology</topic><topic>Protein transport</topic><topic>Proteins</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Small cell lung carcinoma</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kadonaga, Taichi</creatorcontrib><creatorcontrib>Sakabe, Tomohiko</creatorcontrib><creatorcontrib>Kidokoro, Yoshiteru</creatorcontrib><creatorcontrib>Haruki, Tomohiro</creatorcontrib><creatorcontrib>Nosaka, Kanae</creatorcontrib><creatorcontrib>Nakamura, Hiroshige</creatorcontrib><creatorcontrib>Umekita, Yoshihisa</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science 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>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><jtitle>Virchows Archiv : an international journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kadonaga, Taichi</au><au>Sakabe, Tomohiko</au><au>Kidokoro, Yoshiteru</au><au>Haruki, Tomohiro</au><au>Nosaka, Kanae</au><au>Nakamura, Hiroshige</au><au>Umekita, Yoshihisa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma</atitle><jtitle>Virchows Archiv : an international journal of pathology</jtitle><stitle>Virchows Arch</stitle><addtitle>Virchows Arch</addtitle><date>2022-04-01</date><risdate>2022</risdate><volume>480</volume><issue>4</issue><spage>831</spage><epage>841</epage><pages>831-841</pages><issn>0945-6317</issn><eissn>1432-2307</eissn><abstract>Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression profiles of non-invasive lesions (non-ILs) and adjacent histologically normal lung (aNL) tissues within invasive LUAD have not been investigated. Herein, we analyzed differentially expressed genes (DEGs) specific to early-stage carcinogenesis in LUAD. Invasive LUAD tissue samples containing both non-ILs and aNL tissues were obtained from seven patients with pathological stage I LUAD, and each component was subjected to microdissection. Gene expression profiles of each component were determined using targeted RNA-sequencing. In total, 2536 DEGs, including 863 upregulated and 1673 downregulated genes, were identified in non-ILs. In non-ILs, the expression of
SLC44A5
, a choline transporter-like protein-coding gene, was significantly upregulated, and that of
TMEM100
, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein–protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>35067776</pmid><doi>10.1007/s00428-021-03250-y</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-2846-390X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenocarcinoma Adenocarcinoma of Lung - genetics Adenocarcinoma of Lung - pathology Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cancer Carcinogenesis Carcinogenesis - genetics Carcinogens Carcinoma, Non-Small-Cell Lung - genetics Cell death Choline Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - genetics Gene sequencing Gene set enrichment analysis Genes Hepatocellular carcinoma Humans Immune response Immune system Lesions Lung - pathology Lung cancer Lung Neoplasms - pathology Medicine Medicine & Public Health Membrane Proteins - genetics Network analysis Network hubs Non-small cell lung carcinoma Original Article Pathology Protein transport Proteins Ribonucleic acid RNA Small cell lung carcinoma Tumor suppressor genes Tumors |
| title | Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma |
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