Leptin stimulates the epithelial‑mesenchymal transition and pro‑angiogenic capability of cholangiocarcinoma cells through the miR‑122/PKM2 axis
Leptin is an adipokine minimally known for its activities or underlying mechanisms in cholangiocarcinoma. The present study explored the effects of leptin on the epithelial‑mesenchymal transition (EMT) and pro‑angiogenic capability of cholangiocarcinoma cells, and investigated the underlying mechani...
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| Veröffentlicht in: | International journal of oncology 2019-07, Vol.55 (1), p.298-308 |
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| creator | Peng, Chuang Sun, Zengpeng Li, Ou Guo, Chao Yi, Weimin Tan, Zhaoxia Jiang, Bo |
| description | Leptin is an adipokine minimally known for its activities or underlying mechanisms in cholangiocarcinoma. The present study explored the effects of leptin on the epithelial‑mesenchymal transition (EMT) and pro‑angiogenic capability of cholangiocarcinoma cells, and investigated the underlying mechanisms. Cholangiocarcinoma cells were treated with leptin, and their migration and invasion rates were investigated using Transwell assays. Furthermore, conditioned medium was collected from cholangiocarcinoma cells following leptin treatment and applied to human umbilical vein endothelial cells to assess tube formation. The expression of EMT and pro‑angiogenic factors was examined by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses. Mechanistically, the function of pyruvate kinase muscle isozyme M2 (PKM2) was assessed in leptin‑induced phenotypes using siRNA targeting PKM2 (si‑PKM2). Bioinformatics screening and luciferase reporter assays were used to reveal microRNA (miR)‑122 as the potential mediator between leptin and PKM2. Finally, the associations between leptin and miR‑122 or PKM2 levels in patients with cholangiocarcinoma were assessed by ELISA and RT‑qPCR. Leptin significantly increased the EMT and pro‑angiogenic capability of cholangiocarcinoma cells, visibly inhibited endogenous miR‑122 expression, and upregulated PKM2. Furthermore, si‑PKM2 inhibited leptin‑induced migration, invasion, EMT‑associated marker expression levels and the pro‑angiogenic capability in cholangiocarcinoma cells. In addition, miR‑122 negatively regulated the expression of PKM2. When applied together with leptin, miR‑122 was sufficient to reverse the multiple malignancy‑promoting effects of leptin. Consistently, the serum leptin level positively correlated with that of PKM2, but negatively with that of miR‑122 in patients with cholangiocarcinoma. Leptin, by downregulating miR‑122 and elevating PKM2 expression, acts as a pleiotropic pro‑malignancy cytokine for cholangiocarcinoma. Therefore, increasing miR‑122 expression and inhibiting PKM2 may be future approaches for cholangiocarcinoma treatment. |
| doi_str_mv | 10.3892/ijo.2019.4807 |
| format | Article |
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The present study explored the effects of leptin on the epithelial‑mesenchymal transition (EMT) and pro‑angiogenic capability of cholangiocarcinoma cells, and investigated the underlying mechanisms. Cholangiocarcinoma cells were treated with leptin, and their migration and invasion rates were investigated using Transwell assays. Furthermore, conditioned medium was collected from cholangiocarcinoma cells following leptin treatment and applied to human umbilical vein endothelial cells to assess tube formation. The expression of EMT and pro‑angiogenic factors was examined by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses. Mechanistically, the function of pyruvate kinase muscle isozyme M2 (PKM2) was assessed in leptin‑induced phenotypes using siRNA targeting PKM2 (si‑PKM2). Bioinformatics screening and luciferase reporter assays were used to reveal microRNA (miR)‑122 as the potential mediator between leptin and PKM2. Finally, the associations between leptin and miR‑122 or PKM2 levels in patients with cholangiocarcinoma were assessed by ELISA and RT‑qPCR. Leptin significantly increased the EMT and pro‑angiogenic capability of cholangiocarcinoma cells, visibly inhibited endogenous miR‑122 expression, and upregulated PKM2. Furthermore, si‑PKM2 inhibited leptin‑induced migration, invasion, EMT‑associated marker expression levels and the pro‑angiogenic capability in cholangiocarcinoma cells. In addition, miR‑122 negatively regulated the expression of PKM2. When applied together with leptin, miR‑122 was sufficient to reverse the multiple malignancy‑promoting effects of leptin. Consistently, the serum leptin level positively correlated with that of PKM2, but negatively with that of miR‑122 in patients with cholangiocarcinoma. Leptin, by downregulating miR‑122 and elevating PKM2 expression, acts as a pleiotropic pro‑malignancy cytokine for cholangiocarcinoma. Therefore, increasing miR‑122 expression and inhibiting PKM2 may be future approaches for cholangiocarcinoma treatment.</description><identifier>ISSN: 1019-6439</identifier><identifier>EISSN: 1791-2423</identifier><identifier>DOI: 10.3892/ijo.2019.4807</identifier><identifier>PMID: 31115511</identifier><language>eng</language><publisher>Greece: Spandidos Publications</publisher><subject>Angiogenesis ; Bile Duct Neoplasms - genetics ; Bile Duct Neoplasms - metabolism ; Bile Duct Neoplasms - pathology ; Biliary tract cancer ; Breast cancer ; Cancer therapies ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell growth ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Cholangiocarcinoma ; Cholangiocarcinoma - genetics ; Cholangiocarcinoma - metabolism ; Cholangiocarcinoma - pathology ; Computational biology ; Culture Media, Conditioned - chemistry ; Endothelium ; Enzyme-linked immunosorbent assay ; Epithelial-Mesenchymal Transition ; Gene Expression Regulation, Neoplastic ; Human Umbilical Vein Endothelial Cells ; Humans ; Kinases ; Leptin ; Leptin - blood ; Leptin - metabolism ; Luciferase ; Medical prognosis ; Medical research ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Metastasis ; MicroRNA ; MicroRNAs - genetics ; Phenotypes ; Polymerase chain reaction ; Proteins ; Scientific equipment industry ; Signal transduction ; Stem cells ; Studies ; Thyroid Hormone-Binding Proteins ; Thyroid Hormones - genetics ; Thyroid Hormones - metabolism ; Vascular endothelial growth factor</subject><ispartof>International journal of oncology, 2019-07, Vol.55 (1), p.298-308</ispartof><rights>COPYRIGHT 2019 Spandidos Publications</rights><rights>Copyright Spandidos Publications UK Ltd. 2019</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c458t-20f6a1d7b0207617b494d78cd77913bf4cea0023267f2092277a39f39bd5bbd13</citedby><cites>FETCH-LOGICAL-c458t-20f6a1d7b0207617b494d78cd77913bf4cea0023267f2092277a39f39bd5bbd13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31115511$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Peng, Chuang</creatorcontrib><creatorcontrib>Sun, Zengpeng</creatorcontrib><creatorcontrib>Li, Ou</creatorcontrib><creatorcontrib>Guo, Chao</creatorcontrib><creatorcontrib>Yi, Weimin</creatorcontrib><creatorcontrib>Tan, Zhaoxia</creatorcontrib><creatorcontrib>Jiang, Bo</creatorcontrib><title>Leptin stimulates the epithelial‑mesenchymal transition and pro‑angiogenic capability of cholangiocarcinoma cells through the miR‑122/PKM2 axis</title><title>International journal of oncology</title><addtitle>Int J Oncol</addtitle><description>Leptin is an adipokine minimally known for its activities or underlying mechanisms in cholangiocarcinoma. The present study explored the effects of leptin on the epithelial‑mesenchymal transition (EMT) and pro‑angiogenic capability of cholangiocarcinoma cells, and investigated the underlying mechanisms. Cholangiocarcinoma cells were treated with leptin, and their migration and invasion rates were investigated using Transwell assays. Furthermore, conditioned medium was collected from cholangiocarcinoma cells following leptin treatment and applied to human umbilical vein endothelial cells to assess tube formation. The expression of EMT and pro‑angiogenic factors was examined by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses. Mechanistically, the function of pyruvate kinase muscle isozyme M2 (PKM2) was assessed in leptin‑induced phenotypes using siRNA targeting PKM2 (si‑PKM2). Bioinformatics screening and luciferase reporter assays were used to reveal microRNA (miR)‑122 as the potential mediator between leptin and PKM2. Finally, the associations between leptin and miR‑122 or PKM2 levels in patients with cholangiocarcinoma were assessed by ELISA and RT‑qPCR. Leptin significantly increased the EMT and pro‑angiogenic capability of cholangiocarcinoma cells, visibly inhibited endogenous miR‑122 expression, and upregulated PKM2. Furthermore, si‑PKM2 inhibited leptin‑induced migration, invasion, EMT‑associated marker expression levels and the pro‑angiogenic capability in cholangiocarcinoma cells. In addition, miR‑122 negatively regulated the expression of PKM2. When applied together with leptin, miR‑122 was sufficient to reverse the multiple malignancy‑promoting effects of leptin. Consistently, the serum leptin level positively correlated with that of PKM2, but negatively with that of miR‑122 in patients with cholangiocarcinoma. Leptin, by downregulating miR‑122 and elevating PKM2 expression, acts as a pleiotropic pro‑malignancy cytokine for cholangiocarcinoma. Therefore, increasing miR‑122 expression and inhibiting PKM2 may be future approaches for cholangiocarcinoma treatment.</description><subject>Angiogenesis</subject><subject>Bile Duct Neoplasms - genetics</subject><subject>Bile Duct Neoplasms - metabolism</subject><subject>Bile Duct Neoplasms - pathology</subject><subject>Biliary tract cancer</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Cholangiocarcinoma</subject><subject>Cholangiocarcinoma - genetics</subject><subject>Cholangiocarcinoma - metabolism</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Computational biology</subject><subject>Culture Media, Conditioned - chemistry</subject><subject>Endothelium</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Kinases</subject><subject>Leptin</subject><subject>Leptin - blood</subject><subject>Leptin - metabolism</subject><subject>Luciferase</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Metastasis</subject><subject>MicroRNA</subject><subject>MicroRNAs - genetics</subject><subject>Phenotypes</subject><subject>Polymerase chain reaction</subject><subject>Proteins</subject><subject>Scientific equipment industry</subject><subject>Signal transduction</subject><subject>Stem cells</subject><subject>Studies</subject><subject>Thyroid Hormone-Binding Proteins</subject><subject>Thyroid Hormones - genetics</subject><subject>Thyroid Hormones - metabolism</subject><subject>Vascular endothelial growth factor</subject><issn>1019-6439</issn><issn>1791-2423</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNptkstu1TAQhi1ERUthyRZZQmKXU1-SOF5WVbmIUxUhWFuO45zMkWOH2JE4O16BBS_Ik-C0pVAJeTHW-Jv5NeMfoReUbHgj2Rnsw4YRKjdlQ8QjdEKFpAUrGX-c7zlf1CWXx-hpjHtCWFUR-gQdc0ppVVF6gn5u7ZTA45hgXJxONuI0WGwnyMGBdr--_xhttN4Mh1E7nGbtIyQIHmvf4WkOGdB-B2FnPRhs9KRbcJAOOPTYDMHdPBo9G_Bh1NhY51aNOSy74UZrhE-5B2Xs7OOHK4b1N4jP0FGvXbTP7-Ip-vLm8vPFu2J7_fb9xfm2MGXVpIKRvta0Ey1hRNRUtKUsO9GYTuQl8LYvjdV5aM5q0TMiGRNCc9lz2XZV23aUn6JXt33zHF8XG5Pah2X2WVIxxptGlLSRf6mddlaB70PeghkhGnVeZSFWElJnavMfKp_OjmCCtz3k_IOC1_8UDFa7NMTglnW58SFY3IJmDjHOtlfTDKOeD4oStZpAZROo1QRqNUHmX95NtbSj7e7pP7_OfwMzQ69w</recordid><startdate>20190701</startdate><enddate>20190701</enddate><creator>Peng, Chuang</creator><creator>Sun, Zengpeng</creator><creator>Li, Ou</creator><creator>Guo, Chao</creator><creator>Yi, Weimin</creator><creator>Tan, Zhaoxia</creator><creator>Jiang, Bo</creator><general>Spandidos Publications</general><general>Spandidos Publications UK Ltd</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>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20190701</creationdate><title>Leptin stimulates the epithelial‑mesenchymal transition and pro‑angiogenic capability of cholangiocarcinoma cells through the miR‑122/PKM2 axis</title><author>Peng, Chuang ; Sun, Zengpeng ; Li, Ou ; Guo, Chao ; Yi, Weimin ; Tan, Zhaoxia ; Jiang, Bo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c458t-20f6a1d7b0207617b494d78cd77913bf4cea0023267f2092277a39f39bd5bbd13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Angiogenesis</topic><topic>Bile Duct Neoplasms - genetics</topic><topic>Bile Duct Neoplasms - metabolism</topic><topic>Bile Duct Neoplasms - pathology</topic><topic>Biliary tract cancer</topic><topic>Breast cancer</topic><topic>Cancer therapies</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Cell Proliferation</topic><topic>Cholangiocarcinoma</topic><topic>Cholangiocarcinoma - genetics</topic><topic>Cholangiocarcinoma - metabolism</topic><topic>Cholangiocarcinoma - pathology</topic><topic>Computational biology</topic><topic>Culture Media, Conditioned - chemistry</topic><topic>Endothelium</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Kinases</topic><topic>Leptin</topic><topic>Leptin - blood</topic><topic>Leptin - metabolism</topic><topic>Luciferase</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Metastasis</topic><topic>MicroRNA</topic><topic>MicroRNAs - genetics</topic><topic>Phenotypes</topic><topic>Polymerase chain reaction</topic><topic>Proteins</topic><topic>Scientific equipment industry</topic><topic>Signal transduction</topic><topic>Stem cells</topic><topic>Studies</topic><topic>Thyroid Hormone-Binding Proteins</topic><topic>Thyroid Hormones - genetics</topic><topic>Thyroid Hormones - metabolism</topic><topic>Vascular endothelial growth factor</topic><toplevel>online_resources</toplevel><creatorcontrib>Peng, Chuang</creatorcontrib><creatorcontrib>Sun, Zengpeng</creatorcontrib><creatorcontrib>Li, Ou</creatorcontrib><creatorcontrib>Guo, Chao</creatorcontrib><creatorcontrib>Yi, Weimin</creatorcontrib><creatorcontrib>Tan, Zhaoxia</creatorcontrib><creatorcontrib>Jiang, Bo</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 Nursing & Allied Health Source</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>British Nursing Database</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>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</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><jtitle>International journal of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Peng, Chuang</au><au>Sun, Zengpeng</au><au>Li, Ou</au><au>Guo, Chao</au><au>Yi, Weimin</au><au>Tan, Zhaoxia</au><au>Jiang, Bo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leptin stimulates the epithelial‑mesenchymal transition and pro‑angiogenic capability of cholangiocarcinoma cells through the miR‑122/PKM2 axis</atitle><jtitle>International journal of oncology</jtitle><addtitle>Int J Oncol</addtitle><date>2019-07-01</date><risdate>2019</risdate><volume>55</volume><issue>1</issue><spage>298</spage><epage>308</epage><pages>298-308</pages><issn>1019-6439</issn><eissn>1791-2423</eissn><abstract>Leptin is an adipokine minimally known for its activities or underlying mechanisms in cholangiocarcinoma. The present study explored the effects of leptin on the epithelial‑mesenchymal transition (EMT) and pro‑angiogenic capability of cholangiocarcinoma cells, and investigated the underlying mechanisms. Cholangiocarcinoma cells were treated with leptin, and their migration and invasion rates were investigated using Transwell assays. Furthermore, conditioned medium was collected from cholangiocarcinoma cells following leptin treatment and applied to human umbilical vein endothelial cells to assess tube formation. The expression of EMT and pro‑angiogenic factors was examined by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses. Mechanistically, the function of pyruvate kinase muscle isozyme M2 (PKM2) was assessed in leptin‑induced phenotypes using siRNA targeting PKM2 (si‑PKM2). Bioinformatics screening and luciferase reporter assays were used to reveal microRNA (miR)‑122 as the potential mediator between leptin and PKM2. Finally, the associations between leptin and miR‑122 or PKM2 levels in patients with cholangiocarcinoma were assessed by ELISA and RT‑qPCR. Leptin significantly increased the EMT and pro‑angiogenic capability of cholangiocarcinoma cells, visibly inhibited endogenous miR‑122 expression, and upregulated PKM2. Furthermore, si‑PKM2 inhibited leptin‑induced migration, invasion, EMT‑associated marker expression levels and the pro‑angiogenic capability in cholangiocarcinoma cells. In addition, miR‑122 negatively regulated the expression of PKM2. When applied together with leptin, miR‑122 was sufficient to reverse the multiple malignancy‑promoting effects of leptin. Consistently, the serum leptin level positively correlated with that of PKM2, but negatively with that of miR‑122 in patients with cholangiocarcinoma. Leptin, by downregulating miR‑122 and elevating PKM2 expression, acts as a pleiotropic pro‑malignancy cytokine for cholangiocarcinoma. Therefore, increasing miR‑122 expression and inhibiting PKM2 may be future approaches for cholangiocarcinoma treatment.</abstract><cop>Greece</cop><pub>Spandidos Publications</pub><pmid>31115511</pmid><doi>10.3892/ijo.2019.4807</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | Spandidos Publications Journals; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Angiogenesis Bile Duct Neoplasms - genetics Bile Duct Neoplasms - metabolism Bile Duct Neoplasms - pathology Biliary tract cancer Breast cancer Cancer therapies Carrier Proteins - genetics Carrier Proteins - metabolism Cell growth Cell Line, Tumor Cell Movement Cell Proliferation Cholangiocarcinoma Cholangiocarcinoma - genetics Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology Computational biology Culture Media, Conditioned - chemistry Endothelium Enzyme-linked immunosorbent assay Epithelial-Mesenchymal Transition Gene Expression Regulation, Neoplastic Human Umbilical Vein Endothelial Cells Humans Kinases Leptin Leptin - blood Leptin - metabolism Luciferase Medical prognosis Medical research Membrane Proteins - genetics Membrane Proteins - metabolism Metastasis MicroRNA MicroRNAs - genetics Phenotypes Polymerase chain reaction Proteins Scientific equipment industry Signal transduction Stem cells Studies Thyroid Hormone-Binding Proteins Thyroid Hormones - genetics Thyroid Hormones - metabolism Vascular endothelial growth factor |
| title | Leptin stimulates the epithelial‑mesenchymal transition and pro‑angiogenic capability of cholangiocarcinoma cells through the miR‑122/PKM2 axis |
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