A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas
Abstract Context Despite progesterone’s key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood. Objective The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiom...
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| Veröffentlicht in: | The journal of clinical endocrinology and metabolism 2017-09, Vol.102 (9), p.3316-3326 |
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| creator | Delaney, Meaghan A Wan, Ying-Wooi Kim, Gyoung-Eun Creighton, Chad J Taylor, Margaret G Masand, Ramya Park, Andrew Valdes, Cecilia Gibbons, William Liu, Zhandong Anderson, Matthew L |
| description | Abstract
Context
Despite progesterone’s key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood.
Objective
The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas.
Design
Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro.
Methods
Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein–protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation—quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines.
Results
Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma.
Conclusions
Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone’s ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis.
Studying patterns of gene expression that vary by menstrual phase, we found that overexpression of sFRP4 is a progesterone-regulated feature of leiomyomas that regulates smooth muscle proliferation. |
| doi_str_mv | 10.1210/jc.2016-4014 |
| format | Article |
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Context
Despite progesterone’s key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood.
Objective
The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas.
Design
Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro.
Methods
Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein–protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation—quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines.
Results
Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma.
Conclusions
Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone’s ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis.
Studying patterns of gene expression that vary by menstrual phase, we found that overexpression of sFRP4 is a progesterone-regulated feature of leiomyomas that regulates smooth muscle proliferation.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/jc.2016-4014</identifier><identifier>PMID: 28637297</identifier><language>eng</language><publisher>Washington, DC: Endocrine Society</publisher><subject>17β-Estradiol ; Apoptosis ; Biopsy, Needle ; Blotting, Western ; Cell Proliferation - genetics ; Chromatin ; Clinical s ; Disease Progression ; Female ; Fibroids ; Frizzled protein ; Frizzled-related protein ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Immunoprecipitation ; Leiomyoma - genetics ; Leiomyoma - pathology ; Menstrual cycle ; Menstruation ; Muscles ; Myocytes, Smooth Muscle - physiology ; Myometrium ; Polymerase chain reaction ; Progesterone ; Progesterone - metabolism ; Promoter Regions, Genetic - genetics ; Protein interaction ; Proteins ; Proto-Oncogene Proteins - genetics ; Real-Time Polymerase Chain Reaction - methods ; RNA, Messenger - metabolism ; Role ; siRNA ; Smooth muscle ; Tumorigenesis ; Uterine Neoplasms - genetics ; Uterine Neoplasms - pathology ; Uterus</subject><ispartof>The journal of clinical endocrinology and metabolism, 2017-09, Vol.102 (9), p.3316-3326</ispartof><rights>Copyright © Oxford University Press 2015</rights><rights>Copyright © 2017 Endocrine Society</rights><rights>Copyright © Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5304-245a0711b21b56540ee223719fbee17892dd2a3b01baf85255196e19b0c8f1633</citedby><cites>FETCH-LOGICAL-c5304-245a0711b21b56540ee223719fbee17892dd2a3b01baf85255196e19b0c8f1633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1970003669?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,780,784,885,21388,21389,27924,27925,33530,33531,33744,33745,43659,43805,64385,64387,64389,72469,73123,73128,73129,73131</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28637297$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Delaney, Meaghan A</creatorcontrib><creatorcontrib>Wan, Ying-Wooi</creatorcontrib><creatorcontrib>Kim, Gyoung-Eun</creatorcontrib><creatorcontrib>Creighton, Chad J</creatorcontrib><creatorcontrib>Taylor, Margaret G</creatorcontrib><creatorcontrib>Masand, Ramya</creatorcontrib><creatorcontrib>Park, Andrew</creatorcontrib><creatorcontrib>Valdes, Cecilia</creatorcontrib><creatorcontrib>Gibbons, William</creatorcontrib><creatorcontrib>Liu, Zhandong</creatorcontrib><creatorcontrib>Anderson, Matthew L</creatorcontrib><title>A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas</title><title>The journal of clinical endocrinology and metabolism</title><addtitle>J Clin Endocrinol Metab</addtitle><description>Abstract
Context
Despite progesterone’s key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood.
Objective
The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas.
Design
Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro.
Methods
Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein–protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation—quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines.
Results
Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma.
Conclusions
Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone’s ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis.
Studying patterns of gene expression that vary by menstrual phase, we found that overexpression of sFRP4 is a progesterone-regulated feature of leiomyomas that regulates smooth muscle proliferation.</description><subject>17β-Estradiol</subject><subject>Apoptosis</subject><subject>Biopsy, Needle</subject><subject>Blotting, Western</subject><subject>Cell Proliferation - genetics</subject><subject>Chromatin</subject><subject>Clinical s</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Fibroids</subject><subject>Frizzled protein</subject><subject>Frizzled-related protein</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Immunoprecipitation</subject><subject>Leiomyoma - genetics</subject><subject>Leiomyoma - pathology</subject><subject>Menstrual cycle</subject><subject>Menstruation</subject><subject>Muscles</subject><subject>Myocytes, Smooth Muscle - physiology</subject><subject>Myometrium</subject><subject>Polymerase chain reaction</subject><subject>Progesterone</subject><subject>Progesterone - metabolism</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Protein interaction</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Real-Time Polymerase Chain Reaction - methods</subject><subject>RNA, Messenger - metabolism</subject><subject>Role</subject><subject>siRNA</subject><subject>Smooth muscle</subject><subject>Tumorigenesis</subject><subject>Uterine Neoplasms - genetics</subject><subject>Uterine Neoplasms - pathology</subject><subject>Uterus</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kcFrFDEUxoModlu9eZYBD3ow9b1MMplchFJaKyxYFgveQmb2ze6sM5M12bH2v2-WWYsW9BBCyO99-b58jL1COEWB8GFTnwrAgktA-YTN0EjFNRr9lM0ABHKjxbcjdhzjBhIhVf6cHYmyyLUwesauzrKF7yhrfMiug19R3FHwA_EFrcbO7WiZxcvFtcwufm0Dxdj6IWuH7CZR7UDZnFrf3_nexRfsWeO6SC8P-wm7ubz4en7F518-fT4_m_Na5SC5kMqBRqwEVqpQEoiEyJPfpiJCXRqxXAqXV4CVa0ollEJTEJoK6rLBIs9P2MdJdztWPS1rGnbBdXYb2t6FO-tda_--Gdq1XfmfVqlSg9JJ4N1BIPgfY8pr-zbW1HVuID9GiwZFAdooldA3j9CNH8OQ4iVKA0BeFCZR7yeqDj7GQM2DGQS7r8huaruvyO4rSvjrPwM8wL87SQBMwK3v0jfH7914S8GuyXW79WNNftCU_xlJRkEWuuRpQINJJ56W2Od7O435cfsv09MD99BLtfM</recordid><startdate>201709</startdate><enddate>201709</enddate><creator>Delaney, Meaghan A</creator><creator>Wan, Ying-Wooi</creator><creator>Kim, Gyoung-Eun</creator><creator>Creighton, Chad J</creator><creator>Taylor, Margaret G</creator><creator>Masand, Ramya</creator><creator>Park, Andrew</creator><creator>Valdes, Cecilia</creator><creator>Gibbons, William</creator><creator>Liu, Zhandong</creator><creator>Anderson, Matthew L</creator><general>Endocrine Society</general><general>Copyright Oxford University Press</general><general>Oxford University Press</general><scope>TOX</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>3V.</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201709</creationdate><title>A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas</title><author>Delaney, Meaghan A ; Wan, Ying-Wooi ; Kim, Gyoung-Eun ; Creighton, Chad J ; Taylor, Margaret G ; Masand, Ramya ; Park, Andrew ; Valdes, Cecilia ; Gibbons, William ; Liu, Zhandong ; Anderson, Matthew L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5304-245a0711b21b56540ee223719fbee17892dd2a3b01baf85255196e19b0c8f1633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>17β-Estradiol</topic><topic>Apoptosis</topic><topic>Biopsy, Needle</topic><topic>Blotting, Western</topic><topic>Cell Proliferation - genetics</topic><topic>Chromatin</topic><topic>Clinical s</topic><topic>Disease Progression</topic><topic>Female</topic><topic>Fibroids</topic><topic>Frizzled protein</topic><topic>Frizzled-related protein</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Immunoprecipitation</topic><topic>Leiomyoma - genetics</topic><topic>Leiomyoma - pathology</topic><topic>Menstrual cycle</topic><topic>Menstruation</topic><topic>Muscles</topic><topic>Myocytes, Smooth Muscle - physiology</topic><topic>Myometrium</topic><topic>Polymerase chain reaction</topic><topic>Progesterone</topic><topic>Progesterone - metabolism</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Protein interaction</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Real-Time Polymerase Chain Reaction - methods</topic><topic>RNA, Messenger - metabolism</topic><topic>Role</topic><topic>siRNA</topic><topic>Smooth muscle</topic><topic>Tumorigenesis</topic><topic>Uterine Neoplasms - genetics</topic><topic>Uterine Neoplasms - pathology</topic><topic>Uterus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Delaney, Meaghan A</creatorcontrib><creatorcontrib>Wan, Ying-Wooi</creatorcontrib><creatorcontrib>Kim, Gyoung-Eun</creatorcontrib><creatorcontrib>Creighton, Chad J</creatorcontrib><creatorcontrib>Taylor, Margaret G</creatorcontrib><creatorcontrib>Masand, Ramya</creatorcontrib><creatorcontrib>Park, Andrew</creatorcontrib><creatorcontrib>Valdes, Cecilia</creatorcontrib><creatorcontrib>Gibbons, William</creatorcontrib><creatorcontrib>Liu, Zhandong</creatorcontrib><creatorcontrib>Anderson, Matthew L</creatorcontrib><collection>Oxford Journals Open Access Collection</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 Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical 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>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Delaney, Meaghan A</au><au>Wan, Ying-Wooi</au><au>Kim, Gyoung-Eun</au><au>Creighton, Chad J</au><au>Taylor, Margaret G</au><au>Masand, Ramya</au><au>Park, Andrew</au><au>Valdes, Cecilia</au><au>Gibbons, William</au><au>Liu, Zhandong</au><au>Anderson, Matthew L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2017-09</date><risdate>2017</risdate><volume>102</volume><issue>9</issue><spage>3316</spage><epage>3326</epage><pages>3316-3326</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><abstract>Abstract
Context
Despite progesterone’s key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood.
Objective
The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas.
Design
Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro.
Methods
Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein–protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation—quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines.
Results
Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma.
Conclusions
Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone’s ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis.
Studying patterns of gene expression that vary by menstrual phase, we found that overexpression of sFRP4 is a progesterone-regulated feature of leiomyomas that regulates smooth muscle proliferation.</abstract><cop>Washington, DC</cop><pub>Endocrine Society</pub><pmid>28637297</pmid><doi>10.1210/jc.2016-4014</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 17β-Estradiol Apoptosis Biopsy, Needle Blotting, Western Cell Proliferation - genetics Chromatin Clinical s Disease Progression Female Fibroids Frizzled protein Frizzled-related protein Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Immunohistochemistry Immunoprecipitation Leiomyoma - genetics Leiomyoma - pathology Menstrual cycle Menstruation Muscles Myocytes, Smooth Muscle - physiology Myometrium Polymerase chain reaction Progesterone Progesterone - metabolism Promoter Regions, Genetic - genetics Protein interaction Proteins Proto-Oncogene Proteins - genetics Real-Time Polymerase Chain Reaction - methods RNA, Messenger - metabolism Role siRNA Smooth muscle Tumorigenesis Uterine Neoplasms - genetics Uterine Neoplasms - pathology Uterus |
| title | A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas |
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