Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer
Aim Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo‐response against anti‐cancer drugs and prognosis of epithelial ovarian cancer. Methods HE4‐depleted cells and HE4‐overexpressing cells were generated....
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| Veröffentlicht in: | The journal of obstetrics and gynaecology research 2017-01, Vol.43 (1), p.220-227 |
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| container_title | The journal of obstetrics and gynaecology research |
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| creator | Lee, Seungho Choi, Seowon Lee, Yookyung Chung, Donghae Hong, Suntaek Park, Nohhyun |
| description | Aim
Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo‐response against anti‐cancer drugs and prognosis of epithelial ovarian cancer.
Methods
HE4‐depleted cells and HE4‐overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H‐score.
Results
Knockdown of HE4 in OVCAR‐3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell‐growth‐related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti‐tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4‐overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H‐score > 4.
Conclusion
HE4 induces chemoresistance against anti‐cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients. |
| doi_str_mv | 10.1111/jog.13181 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1868316991</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1841797389</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4101-992839ad3cfc0bf91df0e0d067757095e974a0a7b6cefb9dedeb3fb8b58542e23</originalsourceid><addsrcrecordid>eNqNkU1r3DAQhkVpaD7aQ_9AMPTSHJzVWLI-jiWkSUogENKzK0vjXS22tZXWCfvvq81ueggEMgeNEM_7MqOXkK9AzyHXbBnm58BAwQdyBJzLkspafMx3xqFUVIpDcpzSklKQGtQnclhJJSoh6iPy5z70WISuWEyDGQtceefdZvCpWMWwRj8WvMiHXeAQIiaf1ma0WJjRbYH5GPLTVp6F6wX23vRFeDTRZy-7JeNnctCZPuGXfT8hv39ePlxcl7d3VzcXP25Ly4FCqXWlmDaO2c7SttPgOorUUSFlLamuUUtuqJGtsNi12qHDlnWtamtV8wordkK-73zzWH8nTOsmL2Gx782IYUoNKKEYCK3hHSjPHyWZ0hn99gpdhimOeZEGdEVryjTnmTrbUTaGlCJ2zSr6wcRNA7TZJpRV8-Y5ocye7h2ndkD3n3yJJAOzHfDke9y87dT8urvaWf4D27iaSw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1920503944</pqid></control><display><type>article</type><title>Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><creator>Lee, Seungho ; Choi, Seowon ; Lee, Yookyung ; Chung, Donghae ; Hong, Suntaek ; Park, Nohhyun</creator><creatorcontrib>Lee, Seungho ; Choi, Seowon ; Lee, Yookyung ; Chung, Donghae ; Hong, Suntaek ; Park, Nohhyun</creatorcontrib><description>Aim
Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo‐response against anti‐cancer drugs and prognosis of epithelial ovarian cancer.
Methods
HE4‐depleted cells and HE4‐overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H‐score.
Results
Knockdown of HE4 in OVCAR‐3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell‐growth‐related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti‐tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4‐overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H‐score > 4.
Conclusion
HE4 induces chemoresistance against anti‐cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients.</description><identifier>ISSN: 1341-8076</identifier><identifier>EISSN: 1447-0756</identifier><identifier>DOI: 10.1111/jog.13181</identifier><identifier>PMID: 27862665</identifier><language>eng</language><publisher>Australia: Wiley Subscription Services, Inc</publisher><subject>AKT protein ; Antineoplastic Agents - pharmacology ; Biomarkers, Tumor - metabolism ; Carcinoma, Ovarian Epithelial ; Cell activation ; Cell growth ; Cell Line, Tumor ; Cell Survival - drug effects ; Chemoresistance ; Chemotherapy ; Cisplatin ; Drug Resistance, Neoplasm ; Epidermal growth factor ; Epididymis ; Female ; Gene silencing ; human epididymis protein 4 ; Humans ; MAP Kinase Signaling System - drug effects ; Medical prognosis ; Metabolic pathways ; Middle Aged ; Multivariate analysis ; Neoplasm Staging ; Neoplasms, Glandular and Epithelial - diagnosis ; Neoplasms, Glandular and Epithelial - drug therapy ; Neoplasms, Glandular and Epithelial - metabolism ; Neoplasms, Glandular and Epithelial - pathology ; Ovarian cancer ; Ovarian Neoplasms - diagnosis ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Paclitaxel ; Prognosis ; Proteins - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; RNA, Messenger - metabolism ; Signal transduction ; Survival Analysis</subject><ispartof>The journal of obstetrics and gynaecology research, 2017-01, Vol.43 (1), p.220-227</ispartof><rights>2016 Japan Society of Obstetrics and Gynecology</rights><rights>2016 Japan Society of Obstetrics and Gynecology.</rights><rights>2017 Japan Society of Obstetrics and Gynecology</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4101-992839ad3cfc0bf91df0e0d067757095e974a0a7b6cefb9dedeb3fb8b58542e23</citedby><cites>FETCH-LOGICAL-c4101-992839ad3cfc0bf91df0e0d067757095e974a0a7b6cefb9dedeb3fb8b58542e23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjog.13181$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjog.13181$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27862665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Seungho</creatorcontrib><creatorcontrib>Choi, Seowon</creatorcontrib><creatorcontrib>Lee, Yookyung</creatorcontrib><creatorcontrib>Chung, Donghae</creatorcontrib><creatorcontrib>Hong, Suntaek</creatorcontrib><creatorcontrib>Park, Nohhyun</creatorcontrib><title>Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer</title><title>The journal of obstetrics and gynaecology research</title><addtitle>J Obstet Gynaecol Res</addtitle><description>Aim
Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo‐response against anti‐cancer drugs and prognosis of epithelial ovarian cancer.
Methods
HE4‐depleted cells and HE4‐overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H‐score.
Results
Knockdown of HE4 in OVCAR‐3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell‐growth‐related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti‐tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4‐overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H‐score > 4.
Conclusion
HE4 induces chemoresistance against anti‐cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients.</description><subject>AKT protein</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Carcinoma, Ovarian Epithelial</subject><subject>Cell activation</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Drug Resistance, Neoplasm</subject><subject>Epidermal growth factor</subject><subject>Epididymis</subject><subject>Female</subject><subject>Gene silencing</subject><subject>human epididymis protein 4</subject><subject>Humans</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Medical prognosis</subject><subject>Metabolic pathways</subject><subject>Middle Aged</subject><subject>Multivariate analysis</subject><subject>Neoplasm Staging</subject><subject>Neoplasms, Glandular and Epithelial - diagnosis</subject><subject>Neoplasms, Glandular and Epithelial - drug therapy</subject><subject>Neoplasms, Glandular and Epithelial - metabolism</subject><subject>Neoplasms, Glandular and Epithelial - pathology</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - diagnosis</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Paclitaxel</subject><subject>Prognosis</subject><subject>Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal transduction</subject><subject>Survival Analysis</subject><issn>1341-8076</issn><issn>1447-0756</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1r3DAQhkVpaD7aQ_9AMPTSHJzVWLI-jiWkSUogENKzK0vjXS22tZXWCfvvq81ueggEMgeNEM_7MqOXkK9AzyHXbBnm58BAwQdyBJzLkspafMx3xqFUVIpDcpzSklKQGtQnclhJJSoh6iPy5z70WISuWEyDGQtceefdZvCpWMWwRj8WvMiHXeAQIiaf1ma0WJjRbYH5GPLTVp6F6wX23vRFeDTRZy-7JeNnctCZPuGXfT8hv39ePlxcl7d3VzcXP25Ly4FCqXWlmDaO2c7SttPgOorUUSFlLamuUUtuqJGtsNi12qHDlnWtamtV8wordkK-73zzWH8nTOsmL2Gx782IYUoNKKEYCK3hHSjPHyWZ0hn99gpdhimOeZEGdEVryjTnmTrbUTaGlCJ2zSr6wcRNA7TZJpRV8-Y5ocye7h2ndkD3n3yJJAOzHfDke9y87dT8urvaWf4D27iaSw</recordid><startdate>201701</startdate><enddate>201701</enddate><creator>Lee, Seungho</creator><creator>Choi, Seowon</creator><creator>Lee, Yookyung</creator><creator>Chung, Donghae</creator><creator>Hong, Suntaek</creator><creator>Park, Nohhyun</creator><general>Wiley Subscription Services, Inc</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>7T5</scope><scope>7TO</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201701</creationdate><title>Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer</title><author>Lee, Seungho ; Choi, Seowon ; Lee, Yookyung ; Chung, Donghae ; Hong, Suntaek ; Park, Nohhyun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4101-992839ad3cfc0bf91df0e0d067757095e974a0a7b6cefb9dedeb3fb8b58542e23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>AKT protein</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Carcinoma, Ovarian Epithelial</topic><topic>Cell activation</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chemoresistance</topic><topic>Chemotherapy</topic><topic>Cisplatin</topic><topic>Drug Resistance, Neoplasm</topic><topic>Epidermal growth factor</topic><topic>Epididymis</topic><topic>Female</topic><topic>Gene silencing</topic><topic>human epididymis protein 4</topic><topic>Humans</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Medical prognosis</topic><topic>Metabolic pathways</topic><topic>Middle Aged</topic><topic>Multivariate analysis</topic><topic>Neoplasm Staging</topic><topic>Neoplasms, Glandular and Epithelial - diagnosis</topic><topic>Neoplasms, Glandular and Epithelial - drug therapy</topic><topic>Neoplasms, Glandular and Epithelial - metabolism</topic><topic>Neoplasms, Glandular and Epithelial - pathology</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - diagnosis</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Paclitaxel</topic><topic>Prognosis</topic><topic>Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal transduction</topic><topic>Survival Analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Seungho</creatorcontrib><creatorcontrib>Choi, Seowon</creatorcontrib><creatorcontrib>Lee, Yookyung</creatorcontrib><creatorcontrib>Chung, Donghae</creatorcontrib><creatorcontrib>Hong, Suntaek</creatorcontrib><creatorcontrib>Park, Nohhyun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>The journal of obstetrics and gynaecology research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Seungho</au><au>Choi, Seowon</au><au>Lee, Yookyung</au><au>Chung, Donghae</au><au>Hong, Suntaek</au><au>Park, Nohhyun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer</atitle><jtitle>The journal of obstetrics and gynaecology research</jtitle><addtitle>J Obstet Gynaecol Res</addtitle><date>2017-01</date><risdate>2017</risdate><volume>43</volume><issue>1</issue><spage>220</spage><epage>227</epage><pages>220-227</pages><issn>1341-8076</issn><eissn>1447-0756</eissn><abstract>Aim
Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo‐response against anti‐cancer drugs and prognosis of epithelial ovarian cancer.
Methods
HE4‐depleted cells and HE4‐overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H‐score.
Results
Knockdown of HE4 in OVCAR‐3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell‐growth‐related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti‐tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4‐overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H‐score > 4.
Conclusion
HE4 induces chemoresistance against anti‐cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients.</abstract><cop>Australia</cop><pub>Wiley Subscription Services, Inc</pub><pmid>27862665</pmid><doi>10.1111/jog.13181</doi><tpages>8</tpages></addata></record> |
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| subjects | AKT protein Antineoplastic Agents - pharmacology Biomarkers, Tumor - metabolism Carcinoma, Ovarian Epithelial Cell activation Cell growth Cell Line, Tumor Cell Survival - drug effects Chemoresistance Chemotherapy Cisplatin Drug Resistance, Neoplasm Epidermal growth factor Epididymis Female Gene silencing human epididymis protein 4 Humans MAP Kinase Signaling System - drug effects Medical prognosis Metabolic pathways Middle Aged Multivariate analysis Neoplasm Staging Neoplasms, Glandular and Epithelial - diagnosis Neoplasms, Glandular and Epithelial - drug therapy Neoplasms, Glandular and Epithelial - metabolism Neoplasms, Glandular and Epithelial - pathology Ovarian cancer Ovarian Neoplasms - diagnosis Ovarian Neoplasms - drug therapy Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Paclitaxel Prognosis Proteins - metabolism Proto-Oncogene Proteins c-akt - metabolism RNA, Messenger - metabolism Signal transduction Survival Analysis |
| title | Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer |
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