Identification of EZH2 as Cancer Stem Cell Marker in Clear Cell Renal Cell Carcinoma and the Anti-Tumor Effect of Epigallocatechin-3-Gallate (EGCG)
The aim of the study was to develop a new therapeutic strategy to target cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC) and to identify typical CSC markers to improve therapy effectiveness. It was found that the corrected-mRNA expression-based stemness index was upregulated in k...
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| Veröffentlicht in: | Cancers 2022-08, Vol.14 (17), p.4200 |
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| creator | Lyu, Chen Wang, Lili Stadlbauer, Birgit Noessner, Elfriede Buchner, Alexander Pohla, Heike |
| description | The aim of the study was to develop a new therapeutic strategy to target cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC) and to identify typical CSC markers to improve therapy effectiveness. It was found that the corrected-mRNA expression-based stemness index was upregulated in kidney renal clear cell carcinoma (KIRC) tissues compared to non-tumor tissue and increased with higher tumor stage and grade. EZH2 was identified as a CSC marker and prognosis factor for KIRC patients. The expression of EZH2 was associated with several activated tumor-infiltrating immune cells. High expression of EZH2 was enriched in immune-related pathways, low expression was related to several metabolic pathways. Epigallocatechin-3-gallate (EGCG) was identified as the most potent suppressor of EZH2, was able to inhibit viability, migration, and invasion, and to increase the apoptosis rate of ccRCC CSCs. KIF11, VEGF, and MMP2 were identified as predictive EGCG target genes, suggesting a potential mechanism of how EZH2 might regulate invasiveness and migration. The percentages of FoxP3+ Treg cells in the peripheral blood mononuclear cells of ccRCC patients decreased significantly when cultured with spheres pretreated with EGCG plus sunitinib compared to spheres without treatment. Our findings provide new insights into the treatment options of ccRCC based on targeting CSCs. |
| doi_str_mv | 10.3390/cancers14174200 |
| format | Article |
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It was found that the corrected-mRNA expression-based stemness index was upregulated in kidney renal clear cell carcinoma (KIRC) tissues compared to non-tumor tissue and increased with higher tumor stage and grade. EZH2 was identified as a CSC marker and prognosis factor for KIRC patients. The expression of EZH2 was associated with several activated tumor-infiltrating immune cells. High expression of EZH2 was enriched in immune-related pathways, low expression was related to several metabolic pathways. Epigallocatechin-3-gallate (EGCG) was identified as the most potent suppressor of EZH2, was able to inhibit viability, migration, and invasion, and to increase the apoptosis rate of ccRCC CSCs. KIF11, VEGF, and MMP2 were identified as predictive EGCG target genes, suggesting a potential mechanism of how EZH2 might regulate invasiveness and migration. The percentages of FoxP3+ Treg cells in the peripheral blood mononuclear cells of ccRCC patients decreased significantly when cultured with spheres pretreated with EGCG plus sunitinib compared to spheres without treatment. Our findings provide new insights into the treatment options of ccRCC based on targeting CSCs.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers14174200</identifier><identifier>PMID: 36077742</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Antimitotic agents ; Antineoplastic agents ; Apoptosis ; Biological markers ; Cancer cells ; Cancer therapies ; Carcinoma, Renal cell ; Care and treatment ; Catechin ; Cell culture ; Cell differentiation ; Cell self-renewal ; Chemotherapy ; Clear cell-type renal cell carcinoma ; Diagnosis ; Enzymes ; Epigallocatechin gallate ; Foxp3 protein ; Gelatinase A ; Gene expression ; Growth factors ; Health aspects ; Invasiveness ; Kidney cancer ; Leukocytes (mononuclear) ; Lymphocytes T ; Medical prognosis ; Metabolic pathways ; Metastasis ; Patients ; Peripheral blood mononuclear cells ; Software ; Stem cells ; Survival analysis ; Testing ; Tumor cells ; Tumor-infiltrating lymphocytes ; Vascular endothelial growth factor</subject><ispartof>Cancers, 2022-08, Vol.14 (17), p.4200</ispartof><rights>COPYRIGHT 2022 MDPI AG</rights><rights>2022 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><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-2b489ec790a95de12086339d061d6e8b83d4698ff1a40ff0753d98b1f3f1c8c63</citedby><cites>FETCH-LOGICAL-c488t-2b489ec790a95de12086339d061d6e8b83d4698ff1a40ff0753d98b1f3f1c8c63</cites><orcidid>0000-0001-7895-7070 ; 0000-0003-4709-9266</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/PMC9454898/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454898/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36077742$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lyu, Chen</creatorcontrib><creatorcontrib>Wang, Lili</creatorcontrib><creatorcontrib>Stadlbauer, Birgit</creatorcontrib><creatorcontrib>Noessner, Elfriede</creatorcontrib><creatorcontrib>Buchner, Alexander</creatorcontrib><creatorcontrib>Pohla, Heike</creatorcontrib><title>Identification of EZH2 as Cancer Stem Cell Marker in Clear Cell Renal Cell Carcinoma and the Anti-Tumor Effect of Epigallocatechin-3-Gallate (EGCG)</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>The aim of the study was to develop a new therapeutic strategy to target cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC) and to identify typical CSC markers to improve therapy effectiveness. It was found that the corrected-mRNA expression-based stemness index was upregulated in kidney renal clear cell carcinoma (KIRC) tissues compared to non-tumor tissue and increased with higher tumor stage and grade. EZH2 was identified as a CSC marker and prognosis factor for KIRC patients. The expression of EZH2 was associated with several activated tumor-infiltrating immune cells. High expression of EZH2 was enriched in immune-related pathways, low expression was related to several metabolic pathways. Epigallocatechin-3-gallate (EGCG) was identified as the most potent suppressor of EZH2, was able to inhibit viability, migration, and invasion, and to increase the apoptosis rate of ccRCC CSCs. KIF11, VEGF, and MMP2 were identified as predictive EGCG target genes, suggesting a potential mechanism of how EZH2 might regulate invasiveness and migration. The percentages of FoxP3+ Treg cells in the peripheral blood mononuclear cells of ccRCC patients decreased significantly when cultured with spheres pretreated with EGCG plus sunitinib compared to spheres without treatment. Our findings provide new insights into the treatment options of ccRCC based on targeting CSCs.</description><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Apoptosis</subject><subject>Biological markers</subject><subject>Cancer cells</subject><subject>Cancer therapies</subject><subject>Carcinoma, Renal cell</subject><subject>Care and treatment</subject><subject>Catechin</subject><subject>Cell culture</subject><subject>Cell differentiation</subject><subject>Cell self-renewal</subject><subject>Chemotherapy</subject><subject>Clear cell-type renal cell carcinoma</subject><subject>Diagnosis</subject><subject>Enzymes</subject><subject>Epigallocatechin gallate</subject><subject>Foxp3 protein</subject><subject>Gelatinase A</subject><subject>Gene expression</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>Invasiveness</subject><subject>Kidney cancer</subject><subject>Leukocytes (mononuclear)</subject><subject>Lymphocytes T</subject><subject>Medical prognosis</subject><subject>Metabolic pathways</subject><subject>Metastasis</subject><subject>Patients</subject><subject>Peripheral blood mononuclear cells</subject><subject>Software</subject><subject>Stem cells</subject><subject>Survival analysis</subject><subject>Testing</subject><subject>Tumor cells</subject><subject>Tumor-infiltrating lymphocytes</subject><subject>Vascular endothelial growth factor</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><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>eNptksFu1DAQhiMEolXpmRuyxKUc0tpxYjsXpFW0bCsVIUG5cLG8zrjrktiLnUXiOfrCnd0tpa2wDx6Pv_lH_jVF8ZbRU85bemZNsJAyq5msK0pfFIcVlVUpRFu_fBQfFMc531BcnDMp5OvigAsqJRYdFrcXPYTJO2_N5GMg0ZH5j_OKmEy6nTz5NsFIOhgG8tmkn5jwgXQDmLRPfoVghn3YmWR9iKMhJvRkWgGZoXR5tRljInPnwE47_bW_NsMQsSPYlQ8lLxd4xxs5mS-6xYc3xStnhgzH9-dR8f3T_Ko7Ly-_LC662WVpa6WmslrWqgUrW2rapgdWUSXQl54K1gtQS8X7WrTKOWZq6hyVDe9btWSOO2aVFfyo-LjXXW-WI_QWjUhm0OvkR5P-6Gi8fvoS_Epfx9-6rRtsrVDg5F4gxV8byJMefbZohQkQN1lXklWqEQ1rEX3_DL2Jm4TW7ShWNVJS8Y9Cg0D74CL2tVtRPZN1syWZROr0PxTuHkZvYwDnMf-k4GxfYFPMOYF7-COjejtK-tkoYcW7x9Y88H8Hh98BU-XCxQ</recordid><startdate>20220830</startdate><enddate>20220830</enddate><creator>Lyu, Chen</creator><creator>Wang, Lili</creator><creator>Stadlbauer, Birgit</creator><creator>Noessner, Elfriede</creator><creator>Buchner, Alexander</creator><creator>Pohla, Heike</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7895-7070</orcidid><orcidid>https://orcid.org/0000-0003-4709-9266</orcidid></search><sort><creationdate>20220830</creationdate><title>Identification of EZH2 as Cancer Stem Cell Marker in Clear Cell Renal Cell Carcinoma and the Anti-Tumor Effect of Epigallocatechin-3-Gallate (EGCG)</title><author>Lyu, Chen ; Wang, Lili ; Stadlbauer, Birgit ; Noessner, Elfriede ; Buchner, Alexander ; Pohla, Heike</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c488t-2b489ec790a95de12086339d061d6e8b83d4698ff1a40ff0753d98b1f3f1c8c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antimitotic agents</topic><topic>Antineoplastic agents</topic><topic>Apoptosis</topic><topic>Biological markers</topic><topic>Cancer cells</topic><topic>Cancer therapies</topic><topic>Carcinoma, Renal cell</topic><topic>Care and treatment</topic><topic>Catechin</topic><topic>Cell culture</topic><topic>Cell differentiation</topic><topic>Cell self-renewal</topic><topic>Chemotherapy</topic><topic>Clear cell-type renal cell carcinoma</topic><topic>Diagnosis</topic><topic>Enzymes</topic><topic>Epigallocatechin gallate</topic><topic>Foxp3 protein</topic><topic>Gelatinase A</topic><topic>Gene expression</topic><topic>Growth factors</topic><topic>Health aspects</topic><topic>Invasiveness</topic><topic>Kidney cancer</topic><topic>Leukocytes (mononuclear)</topic><topic>Lymphocytes T</topic><topic>Medical prognosis</topic><topic>Metabolic pathways</topic><topic>Metastasis</topic><topic>Patients</topic><topic>Peripheral blood mononuclear cells</topic><topic>Software</topic><topic>Stem cells</topic><topic>Survival analysis</topic><topic>Testing</topic><topic>Tumor cells</topic><topic>Tumor-infiltrating lymphocytes</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lyu, Chen</creatorcontrib><creatorcontrib>Wang, Lili</creatorcontrib><creatorcontrib>Stadlbauer, Birgit</creatorcontrib><creatorcontrib>Noessner, Elfriede</creatorcontrib><creatorcontrib>Buchner, Alexander</creatorcontrib><creatorcontrib>Pohla, Heike</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</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>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</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 - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lyu, Chen</au><au>Wang, Lili</au><au>Stadlbauer, Birgit</au><au>Noessner, Elfriede</au><au>Buchner, Alexander</au><au>Pohla, Heike</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of EZH2 as Cancer Stem Cell Marker in Clear Cell Renal Cell Carcinoma and the Anti-Tumor Effect of Epigallocatechin-3-Gallate (EGCG)</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2022-08-30</date><risdate>2022</risdate><volume>14</volume><issue>17</issue><spage>4200</spage><pages>4200-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>The aim of the study was to develop a new therapeutic strategy to target cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC) and to identify typical CSC markers to improve therapy effectiveness. It was found that the corrected-mRNA expression-based stemness index was upregulated in kidney renal clear cell carcinoma (KIRC) tissues compared to non-tumor tissue and increased with higher tumor stage and grade. EZH2 was identified as a CSC marker and prognosis factor for KIRC patients. The expression of EZH2 was associated with several activated tumor-infiltrating immune cells. High expression of EZH2 was enriched in immune-related pathways, low expression was related to several metabolic pathways. Epigallocatechin-3-gallate (EGCG) was identified as the most potent suppressor of EZH2, was able to inhibit viability, migration, and invasion, and to increase the apoptosis rate of ccRCC CSCs. KIF11, VEGF, and MMP2 were identified as predictive EGCG target genes, suggesting a potential mechanism of how EZH2 might regulate invasiveness and migration. The percentages of FoxP3+ Treg cells in the peripheral blood mononuclear cells of ccRCC patients decreased significantly when cultured with spheres pretreated with EGCG plus sunitinib compared to spheres without treatment. Our findings provide new insights into the treatment options of ccRCC based on targeting CSCs.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36077742</pmid><doi>10.3390/cancers14174200</doi><orcidid>https://orcid.org/0000-0001-7895-7070</orcidid><orcidid>https://orcid.org/0000-0003-4709-9266</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antimitotic agents Antineoplastic agents Apoptosis Biological markers Cancer cells Cancer therapies Carcinoma, Renal cell Care and treatment Catechin Cell culture Cell differentiation Cell self-renewal Chemotherapy Clear cell-type renal cell carcinoma Diagnosis Enzymes Epigallocatechin gallate Foxp3 protein Gelatinase A Gene expression Growth factors Health aspects Invasiveness Kidney cancer Leukocytes (mononuclear) Lymphocytes T Medical prognosis Metabolic pathways Metastasis Patients Peripheral blood mononuclear cells Software Stem cells Survival analysis Testing Tumor cells Tumor-infiltrating lymphocytes Vascular endothelial growth factor |
| title | Identification of EZH2 as Cancer Stem Cell Marker in Clear Cell Renal Cell Carcinoma and the Anti-Tumor Effect of Epigallocatechin-3-Gallate (EGCG) |
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