Pancreatic Tumor Progression Associated With CD133 Overexpression: Involvement of Increased TERT Expression and Epidermal Growth Factor Receptor-Dependent Akt Activation
The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling. The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated i...
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| Veröffentlicht in: | Pancreas 2016-03, Vol.45 (3), p.443-457 |
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| creator | Weng, Ching-Chieh Kuo, Kung-Kai Su, Huei-Ting Hsiao, Pi-Jung Chen, Yu-Wen Wu, Deng-Chyang Hung, Wen-Chun Cheng, Kuang-Hung |
| description | The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling.
The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo.
AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGF expression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133-induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion.
Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance. |
| doi_str_mv | 10.1097/MPA.0000000000000460 |
| format | Article |
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The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo.
AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGF expression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133-induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion.
Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance.</description><identifier>ISSN: 0885-3177</identifier><identifier>EISSN: 1536-4828</identifier><identifier>DOI: 10.1097/MPA.0000000000000460</identifier><identifier>PMID: 26646272</identifier><language>eng</language><publisher>United States</publisher><subject>AC133 Antigen - genetics ; AC133 Antigen - metabolism ; Animals ; Antineoplastic Agents - pharmacology ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Cell Survival - drug effects ; Cell Survival - genetics ; Disease Progression ; Drug Resistance, Neoplasm - genetics ; Female ; Fluorouracil - pharmacology ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Mice, SCID ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Phosphorylation ; Proto-Oncogene Proteins c-akt - metabolism ; Quinazolines - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - genetics ; Receptor, Epidermal Growth Factor - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; Telomerase - genetics ; Telomerase - metabolism ; Transplantation, Heterologous</subject><ispartof>Pancreas, 2016-03, Vol.45 (3), p.443-457</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c326t-8f04bb12c4a4989075f4c9fc4feaa88c589a66ff9ab98688efeab6f525264e1b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26646272$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weng, Ching-Chieh</creatorcontrib><creatorcontrib>Kuo, Kung-Kai</creatorcontrib><creatorcontrib>Su, Huei-Ting</creatorcontrib><creatorcontrib>Hsiao, Pi-Jung</creatorcontrib><creatorcontrib>Chen, Yu-Wen</creatorcontrib><creatorcontrib>Wu, Deng-Chyang</creatorcontrib><creatorcontrib>Hung, Wen-Chun</creatorcontrib><creatorcontrib>Cheng, Kuang-Hung</creatorcontrib><title>Pancreatic Tumor Progression Associated With CD133 Overexpression: Involvement of Increased TERT Expression and Epidermal Growth Factor Receptor-Dependent Akt Activation</title><title>Pancreas</title><addtitle>Pancreas</addtitle><description>The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling.
The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo.
AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGF expression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133-induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion.
Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance.</description><subject>AC133 Antigen - genetics</subject><subject>AC133 Antigen - metabolism</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Blotting, Western</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - genetics</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - genetics</subject><subject>Disease Progression</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Fluorouracil - pharmacology</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice, SCID</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Quinazolines - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Receptor, Epidermal Growth Factor - genetics</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>Telomerase - genetics</subject><subject>Telomerase - metabolism</subject><subject>Transplantation, Heterologous</subject><issn>0885-3177</issn><issn>1536-4828</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUV1LwzAUDaLo_PgHInn0pZo0aZr6NrY5B4pDJj6WNL3RatvUpJv6k_yXZjhFvHC5H5xz7oWD0DElZ5Rk6fnNfHhG_gYXZAsNaMJExGUst9GASJlEjKbpHtr3_pkQmrIk20V7sRBcxGk8QJ9z1WoHqq80Xiwb6_Dc2UcH3le2xUPvra5UDyV-qPonPBpTxvDtChy8dxvQBZ61K1uvoIG2x9aEcS3oA2cxuVvgyS8Sq7bEk64qwTWqxlNn34LmpdJ9OHsHGrrQRGPooC3XWsOXkLqvVuE72x6iHaNqD0ebeoDuLyeL0VV0fTudjYbXkWax6CNpCC8KGmuueCYzkiaG68xobkApKXUiMyWEMZkqMimkhLAvhEniJBYcaMEO0Om3bufs6xJ8nzeV11DXqgW79DlNRUIpk5IEKP-Game9d2DyzlWNch85JfnapDyYlP83KdBONheWRQPlL-nHFfYFoNuQHw</recordid><startdate>20160301</startdate><enddate>20160301</enddate><creator>Weng, Ching-Chieh</creator><creator>Kuo, Kung-Kai</creator><creator>Su, Huei-Ting</creator><creator>Hsiao, Pi-Jung</creator><creator>Chen, Yu-Wen</creator><creator>Wu, Deng-Chyang</creator><creator>Hung, Wen-Chun</creator><creator>Cheng, Kuang-Hung</creator><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>7X8</scope></search><sort><creationdate>20160301</creationdate><title>Pancreatic Tumor Progression Associated With CD133 Overexpression: Involvement of Increased TERT Expression and Epidermal Growth Factor Receptor-Dependent Akt Activation</title><author>Weng, Ching-Chieh ; Kuo, Kung-Kai ; Su, Huei-Ting ; Hsiao, Pi-Jung ; Chen, Yu-Wen ; Wu, Deng-Chyang ; Hung, Wen-Chun ; Cheng, Kuang-Hung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c326t-8f04bb12c4a4989075f4c9fc4feaa88c589a66ff9ab98688efeab6f525264e1b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>AC133 Antigen - genetics</topic><topic>AC133 Antigen - metabolism</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Blotting, Western</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Proliferation - genetics</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - genetics</topic><topic>Disease Progression</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Female</topic><topic>Fluorouracil - pharmacology</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice, SCID</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Phosphorylation</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Quinazolines - pharmacology</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><topic>Receptor, Epidermal Growth Factor - genetics</topic><topic>Receptor, Epidermal Growth Factor - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>Telomerase - genetics</topic><topic>Telomerase - metabolism</topic><topic>Transplantation, Heterologous</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weng, Ching-Chieh</creatorcontrib><creatorcontrib>Kuo, Kung-Kai</creatorcontrib><creatorcontrib>Su, Huei-Ting</creatorcontrib><creatorcontrib>Hsiao, Pi-Jung</creatorcontrib><creatorcontrib>Chen, Yu-Wen</creatorcontrib><creatorcontrib>Wu, Deng-Chyang</creatorcontrib><creatorcontrib>Hung, Wen-Chun</creatorcontrib><creatorcontrib>Cheng, Kuang-Hung</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Pancreas</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weng, Ching-Chieh</au><au>Kuo, Kung-Kai</au><au>Su, Huei-Ting</au><au>Hsiao, Pi-Jung</au><au>Chen, Yu-Wen</au><au>Wu, Deng-Chyang</au><au>Hung, Wen-Chun</au><au>Cheng, Kuang-Hung</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pancreatic Tumor Progression Associated With CD133 Overexpression: Involvement of Increased TERT Expression and Epidermal Growth Factor Receptor-Dependent Akt Activation</atitle><jtitle>Pancreas</jtitle><addtitle>Pancreas</addtitle><date>2016-03-01</date><risdate>2016</risdate><volume>45</volume><issue>3</issue><spage>443</spage><epage>457</epage><pages>443-457</pages><issn>0885-3177</issn><eissn>1536-4828</eissn><abstract>The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling.
The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo.
AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGF expression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133-induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion.
Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance.</abstract><cop>United States</cop><pmid>26646272</pmid><doi>10.1097/MPA.0000000000000460</doi><tpages>15</tpages></addata></record> |
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| subjects | AC133 Antigen - genetics AC133 Antigen - metabolism Animals Antineoplastic Agents - pharmacology Blotting, Western Cell Line, Tumor Cell Proliferation - drug effects Cell Proliferation - genetics Cell Survival - drug effects Cell Survival - genetics Disease Progression Drug Resistance, Neoplasm - genetics Female Fluorouracil - pharmacology Gene Expression Regulation, Neoplastic HEK293 Cells Humans Mice, SCID Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Quinazolines - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA Interference Telomerase - genetics Telomerase - metabolism Transplantation, Heterologous |
| title | Pancreatic Tumor Progression Associated With CD133 Overexpression: Involvement of Increased TERT Expression and Epidermal Growth Factor Receptor-Dependent Akt Activation |
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