Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients
Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC...
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| Veröffentlicht in: | International journal of molecular sciences 2024-07, Vol.25 (13), p.6881 |
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| creator | Armesto, María Nemours, Stéphane Arestín, María Bernal, Iraide Solano-Iturri, Jon Danel Manrique, Manuel Basterretxea, Laura Larrinaga, Gorka Angulo, Javier C Lecumberri, David Iturregui, Ane Miren López, José I Lawrie, Charles H |
| description | Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (
,
,
,
) and target genes (
,
and
) in 35 ccRCC patients. High levels of
and low levels of
,
and
were associated with worse overall survival (OS), and combined
+
levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (
) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (
) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect
we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation. |
| doi_str_mv | 10.3390/ijms25136881 |
| format | Article |
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,
,
,
) and target genes (
,
and
) in 35 ccRCC patients. High levels of
and low levels of
,
and
were associated with worse overall survival (OS), and combined
+
levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (
) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (
) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect
we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms25136881</identifier><identifier>PMID: 38999991</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adult ; Aged ; Analysis ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biomarkers, Tumor - genetics ; Cancer ; Carcinoma, Renal cell ; Carcinoma, Renal Cell - drug therapy ; Carcinoma, Renal Cell - genetics ; Carcinoma, Renal Cell - pathology ; Cluster analysis ; Drug Resistance, Neoplasm - genetics ; Female ; Females ; Gene expression ; Gene Expression Profiling - methods ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic aspects ; Humans ; Indoles - pharmacology ; Indoles - therapeutic use ; Inhibitor drugs ; International economic relations ; Kidney cancer ; Kidney Neoplasms - drug therapy ; Kidney Neoplasms - genetics ; Kidney Neoplasms - pathology ; Kinases ; Male ; Metastasis ; MicroRNA ; MicroRNAs ; MicroRNAs - genetics ; Middle Aged ; Protein expression ; Scientific equipment and supplies industry ; Sunitinib - pharmacology ; Sunitinib - therapeutic use ; Targeted cancer therapy ; Vascular endothelial growth factor</subject><ispartof>International journal of molecular sciences, 2024-07, Vol.25 (13), p.6881</ispartof><rights>COPYRIGHT 2024 MDPI AG</rights><rights>2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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><cites>FETCH-LOGICAL-c311t-b3662b106c491bff40641a4b04e7369062fa86c200d78e657fd3eda6742b822e3</cites><orcidid>0000-0002-6527-6951 ; 0000-0003-2449-444X ; 0000-0002-2213-9965 ; 0000-0003-0842-5348 ; 0000-0002-1735-8792 ; 0000-0002-0399-5213 ; 0000-0003-0185-3913 ; 0000-0002-8882-1131 ; 0000-0002-6744-818X ; 0000-0001-8450-713X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38999991$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Armesto, María</creatorcontrib><creatorcontrib>Nemours, Stéphane</creatorcontrib><creatorcontrib>Arestín, María</creatorcontrib><creatorcontrib>Bernal, Iraide</creatorcontrib><creatorcontrib>Solano-Iturri, Jon Danel</creatorcontrib><creatorcontrib>Manrique, Manuel</creatorcontrib><creatorcontrib>Basterretxea, Laura</creatorcontrib><creatorcontrib>Larrinaga, Gorka</creatorcontrib><creatorcontrib>Angulo, Javier C</creatorcontrib><creatorcontrib>Lecumberri, David</creatorcontrib><creatorcontrib>Iturregui, Ane Miren</creatorcontrib><creatorcontrib>López, José I</creatorcontrib><creatorcontrib>Lawrie, Charles H</creatorcontrib><title>Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (
,
,
,
) and target genes (
,
and
) in 35 ccRCC patients. High levels of
and low levels of
,
and
were associated with worse overall survival (OS), and combined
+
levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (
) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (
) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect
we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.</description><subject>Adult</subject><subject>Aged</subject><subject>Analysis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Cancer</subject><subject>Carcinoma, Renal cell</subject><subject>Carcinoma, Renal Cell - drug therapy</subject><subject>Carcinoma, Renal Cell - genetics</subject><subject>Carcinoma, Renal Cell - pathology</subject><subject>Cluster analysis</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Females</subject><subject>Gene expression</subject><subject>Gene Expression Profiling - methods</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Indoles - therapeutic use</subject><subject>Inhibitor drugs</subject><subject>International economic relations</subject><subject>Kidney cancer</subject><subject>Kidney Neoplasms - drug therapy</subject><subject>Kidney Neoplasms - genetics</subject><subject>Kidney Neoplasms - pathology</subject><subject>Kinases</subject><subject>Male</subject><subject>Metastasis</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>Middle Aged</subject><subject>Protein expression</subject><subject>Scientific equipment and supplies industry</subject><subject>Sunitinib - pharmacology</subject><subject>Sunitinib - therapeutic use</subject><subject>Targeted cancer therapy</subject><subject>Vascular endothelial growth factor</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkU1v1DAQhq0K1JaWW8-VpV44sMUfWcc5riIolSpA7XKOHGfcziqxW9tRxY2fjldb0IIYH2ZkP-_MWC8hZ5xdStmwD7iZklhyqbTmB-SYV0IsGFP1q736iLxJacOYkGLZHJIjqZtt8GPy83oAn9GhNRmDp8HRCW-_rBI1fqDrB8BI1ybeQ6ZX4CHRVUrBoskw0GfMD_Ru9pjRY09vIWHKxlug6Gk7gom0hXEsD96Mu7I10aIPk6HfyrwyOZ2S186MCd6-5BPy_dPHdft5cfP16rpd3Sys5DwveqmU6DlTtmp471zFVMVN1bMKaqkapoQzWlnB2FBrUMvaDRIGo-pK9FoIkCfk3a7vYwxPM6TcTZhs2cl4CHPqJKsbrZjUrKAX_6CbMMfyhx0leS3UHnVvRujQu5Cjsdum3UozLuWSN7xQl_-hyhlgQhs8OCz3fwne7wQ2hpQiuO4x4mTij46zbmt4t294wc9fdp37CYY_8G-H5S908aQC</recordid><startdate>20240701</startdate><enddate>20240701</enddate><creator>Armesto, María</creator><creator>Nemours, Stéphane</creator><creator>Arestín, María</creator><creator>Bernal, Iraide</creator><creator>Solano-Iturri, Jon Danel</creator><creator>Manrique, Manuel</creator><creator>Basterretxea, Laura</creator><creator>Larrinaga, Gorka</creator><creator>Angulo, Javier C</creator><creator>Lecumberri, David</creator><creator>Iturregui, Ane Miren</creator><creator>López, José I</creator><creator>Lawrie, Charles H</creator><general>MDPI AG</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>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-6527-6951</orcidid><orcidid>https://orcid.org/0000-0003-2449-444X</orcidid><orcidid>https://orcid.org/0000-0002-2213-9965</orcidid><orcidid>https://orcid.org/0000-0003-0842-5348</orcidid><orcidid>https://orcid.org/0000-0002-1735-8792</orcidid><orcidid>https://orcid.org/0000-0002-0399-5213</orcidid><orcidid>https://orcid.org/0000-0003-0185-3913</orcidid><orcidid>https://orcid.org/0000-0002-8882-1131</orcidid><orcidid>https://orcid.org/0000-0002-6744-818X</orcidid><orcidid>https://orcid.org/0000-0001-8450-713X</orcidid></search><sort><creationdate>20240701</creationdate><title>Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients</title><author>Armesto, María ; Nemours, Stéphane ; Arestín, María ; Bernal, Iraide ; Solano-Iturri, Jon Danel ; Manrique, Manuel ; Basterretxea, Laura ; Larrinaga, Gorka ; Angulo, Javier C ; Lecumberri, David ; Iturregui, Ane Miren ; López, José I ; Lawrie, Charles H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c311t-b3662b106c491bff40641a4b04e7369062fa86c200d78e657fd3eda6742b822e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Analysis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Cancer</topic><topic>Carcinoma, Renal cell</topic><topic>Carcinoma, Renal Cell - drug therapy</topic><topic>Carcinoma, Renal Cell - genetics</topic><topic>Carcinoma, Renal Cell - pathology</topic><topic>Cluster analysis</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Female</topic><topic>Females</topic><topic>Gene expression</topic><topic>Gene Expression Profiling - methods</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Humans</topic><topic>Indoles - pharmacology</topic><topic>Indoles - therapeutic use</topic><topic>Inhibitor drugs</topic><topic>International economic relations</topic><topic>Kidney cancer</topic><topic>Kidney Neoplasms - drug therapy</topic><topic>Kidney Neoplasms - genetics</topic><topic>Kidney Neoplasms - pathology</topic><topic>Kinases</topic><topic>Male</topic><topic>Metastasis</topic><topic>MicroRNA</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>Middle Aged</topic><topic>Protein expression</topic><topic>Scientific equipment and supplies industry</topic><topic>Sunitinib - pharmacology</topic><topic>Sunitinib - therapeutic use</topic><topic>Targeted cancer therapy</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Armesto, María</creatorcontrib><creatorcontrib>Nemours, Stéphane</creatorcontrib><creatorcontrib>Arestín, María</creatorcontrib><creatorcontrib>Bernal, Iraide</creatorcontrib><creatorcontrib>Solano-Iturri, Jon Danel</creatorcontrib><creatorcontrib>Manrique, Manuel</creatorcontrib><creatorcontrib>Basterretxea, Laura</creatorcontrib><creatorcontrib>Larrinaga, Gorka</creatorcontrib><creatorcontrib>Angulo, Javier C</creatorcontrib><creatorcontrib>Lecumberri, David</creatorcontrib><creatorcontrib>Iturregui, Ane Miren</creatorcontrib><creatorcontrib>López, José I</creatorcontrib><creatorcontrib>Lawrie, Charles H</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>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Research Library</collection><collection>Research Library (Corporate)</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>ProQuest Central Basic</collection><collection>MEDLINE - 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However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (
,
,
,
) and target genes (
,
and
) in 35 ccRCC patients. High levels of
and low levels of
,
and
were associated with worse overall survival (OS), and combined
+
levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (
) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (
) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect
we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>38999991</pmid><doi>10.3390/ijms25136881</doi><orcidid>https://orcid.org/0000-0002-6527-6951</orcidid><orcidid>https://orcid.org/0000-0003-2449-444X</orcidid><orcidid>https://orcid.org/0000-0002-2213-9965</orcidid><orcidid>https://orcid.org/0000-0003-0842-5348</orcidid><orcidid>https://orcid.org/0000-0002-1735-8792</orcidid><orcidid>https://orcid.org/0000-0002-0399-5213</orcidid><orcidid>https://orcid.org/0000-0003-0185-3913</orcidid><orcidid>https://orcid.org/0000-0002-8882-1131</orcidid><orcidid>https://orcid.org/0000-0002-6744-818X</orcidid><orcidid>https://orcid.org/0000-0001-8450-713X</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central; EZB Electronic Journals Library |
| subjects | Adult Aged Analysis Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biomarkers, Tumor - genetics Cancer Carcinoma, Renal cell Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - pathology Cluster analysis Drug Resistance, Neoplasm - genetics Female Females Gene expression Gene Expression Profiling - methods Gene Expression Regulation, Neoplastic Genes Genetic aspects Humans Indoles - pharmacology Indoles - therapeutic use Inhibitor drugs International economic relations Kidney cancer Kidney Neoplasms - drug therapy Kidney Neoplasms - genetics Kidney Neoplasms - pathology Kinases Male Metastasis MicroRNA MicroRNAs MicroRNAs - genetics Middle Aged Protein expression Scientific equipment and supplies industry Sunitinib - pharmacology Sunitinib - therapeutic use Targeted cancer therapy Vascular endothelial growth factor |
| title | Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients |
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