Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells
Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological ta...
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| Veröffentlicht in: | The Journal of experimental medicine 2015-07, Vol.212 (8), p.1219-1237 |
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| creator | Kang, Dong Woo Choi, Chi Yeol Cho, Yong-Hee Tian, Huasong Di Paolo, Gilbert Choi, Kang-Yell Min, Do Sik |
| description | Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1-miR-4496-β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis. |
| doi_str_mv | 10.1084/jem.20141254 |
| format | Article |
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However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1-miR-4496-β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20141254</identifier><identifier>PMID: 26122663</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Animals ; Apoptosis - physiology ; Azoxymethane ; beta Catenin - genetics ; beta Catenin - metabolism ; Blotting, Western ; Carcinogenesis - metabolism ; Dextran Sulfate ; DNA Primers - genetics ; Flow Cytometry ; HEK293 Cells ; Humans ; Immunohistochemistry ; Immunoprecipitation ; In Situ Nick-End Labeling ; Intestinal Neoplasms - metabolism ; Intestinal Neoplasms - physiopathology ; Mice ; MicroRNAs - metabolism ; Mutagenesis, Site-Directed ; Phospholipase D - metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction - physiology ; Tissue Array Analysis</subject><ispartof>The Journal of experimental medicine, 2015-07, Vol.212 (8), p.1219-1237</ispartof><rights>2015 Kang et al.</rights><rights>2015 Kang et al. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-bd1d86eafee81b483e05d2515dd56d4926be030c2787facb016e11f4b103c6683</citedby><cites>FETCH-LOGICAL-c417t-bd1d86eafee81b483e05d2515dd56d4926be030c2787facb016e11f4b103c6683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26122663$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kang, Dong Woo</creatorcontrib><creatorcontrib>Choi, Chi Yeol</creatorcontrib><creatorcontrib>Cho, Yong-Hee</creatorcontrib><creatorcontrib>Tian, Huasong</creatorcontrib><creatorcontrib>Di Paolo, Gilbert</creatorcontrib><creatorcontrib>Choi, Kang-Yell</creatorcontrib><creatorcontrib>Min, Do Sik</creatorcontrib><title>Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1-miR-4496-β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis.</description><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Azoxymethane</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Blotting, Western</subject><subject>Carcinogenesis - metabolism</subject><subject>Dextran Sulfate</subject><subject>DNA Primers - genetics</subject><subject>Flow Cytometry</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Immunoprecipitation</subject><subject>In Situ Nick-End Labeling</subject><subject>Intestinal Neoplasms - metabolism</subject><subject>Intestinal Neoplasms - physiopathology</subject><subject>Mice</subject><subject>MicroRNAs - metabolism</subject><subject>Mutagenesis, Site-Directed</subject><subject>Phospholipase D - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Signal Transduction - physiology</subject><subject>Tissue Array Analysis</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1TAQhS0EoreFHWuUJQtSZhzb8d0goUIBqRKbsrYcZ5K6SuyLnSB1wUvxIDwTDv0RrFh4LI-_OZ7xYewFwimCFm-uaT7lgAK5FI_YDqWAei8b_ZjtADivEaA9Ysc5X0OhhFRP2RFXyLlSzY79uLRppMWHsTpcxVzW5A82U_UeK7ssFFa7UK58KLFQdqqWdY7JjxQo-1x1N5WLYUlxmjaNXz9rVwqCD1X2Y8G3ZDk4Gxyl2ge_ePvnNUfTlJ-xJ4OdMj2_20_Y1_MPl2ef6osvHz-fvbuoncB2qbsee63IDkQaO6EbAtlzibLvperFnquOoAHHW90O1nWAihAH0SE0TindnLC3t7qHtZupd1Q6tpM5JD_bdGOi9ebfm-CvzBi_GyFRtXtRBF7dCaT4bS1fYWaftxFsoLhmgxq0UpxL-D_aFh9AtXxTfX2LuhRzTjQ8dIRgNnNNMdfcm1vwl39P8QDfu9n8Bk_WpHc</recordid><startdate>20150727</startdate><enddate>20150727</enddate><creator>Kang, Dong Woo</creator><creator>Choi, Chi Yeol</creator><creator>Cho, Yong-Hee</creator><creator>Tian, Huasong</creator><creator>Di Paolo, Gilbert</creator><creator>Choi, Kang-Yell</creator><creator>Min, Do Sik</creator><general>The Rockefeller University Press</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>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20150727</creationdate><title>Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells</title><author>Kang, Dong Woo ; Choi, Chi Yeol ; Cho, Yong-Hee ; Tian, Huasong ; Di Paolo, Gilbert ; Choi, Kang-Yell ; Min, Do Sik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-bd1d86eafee81b483e05d2515dd56d4926be030c2787facb016e11f4b103c6683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Azoxymethane</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Blotting, Western</topic><topic>Carcinogenesis - metabolism</topic><topic>Dextran Sulfate</topic><topic>DNA Primers - genetics</topic><topic>Flow Cytometry</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Immunoprecipitation</topic><topic>In Situ Nick-End Labeling</topic><topic>Intestinal Neoplasms - metabolism</topic><topic>Intestinal Neoplasms - physiopathology</topic><topic>Mice</topic><topic>MicroRNAs - metabolism</topic><topic>Mutagenesis, Site-Directed</topic><topic>Phospholipase D - metabolism</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Signal Transduction - physiology</topic><topic>Tissue Array Analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kang, Dong Woo</creatorcontrib><creatorcontrib>Choi, Chi Yeol</creatorcontrib><creatorcontrib>Cho, Yong-Hee</creatorcontrib><creatorcontrib>Tian, Huasong</creatorcontrib><creatorcontrib>Di Paolo, Gilbert</creatorcontrib><creatorcontrib>Choi, Kang-Yell</creatorcontrib><creatorcontrib>Min, Do Sik</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><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kang, Dong Woo</au><au>Choi, Chi Yeol</au><au>Cho, Yong-Hee</au><au>Tian, Huasong</au><au>Di Paolo, Gilbert</au><au>Choi, Kang-Yell</au><au>Min, Do Sik</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2015-07-27</date><risdate>2015</risdate><volume>212</volume><issue>8</issue><spage>1219</spage><epage>1237</epage><pages>1219-1237</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. 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| subjects | Animals Apoptosis - physiology Azoxymethane beta Catenin - genetics beta Catenin - metabolism Blotting, Western Carcinogenesis - metabolism Dextran Sulfate DNA Primers - genetics Flow Cytometry HEK293 Cells Humans Immunohistochemistry Immunoprecipitation In Situ Nick-End Labeling Intestinal Neoplasms - metabolism Intestinal Neoplasms - physiopathology Mice MicroRNAs - metabolism Mutagenesis, Site-Directed Phospholipase D - metabolism Real-Time Polymerase Chain Reaction Signal Transduction - physiology Tissue Array Analysis |
| title | Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells |
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