The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling

Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer–associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2020-12, Vol.159 (6), p.2146-2162.e33
Hauptverfasser: Chen, Baoqing, Dragomir, Mihnea P., Fabris, Linda, Bayraktar, Recep, Knutsen, Erik, Liu, Xu, Tang, Changyan, Li, Yongfeng, Shimura, Tadanobu, Ivkovic, Tina Catela, Cruz De los Santos, Mireia, Anfossi, Simone, Shimizu, Masayoshi, Shah, Maitri Y., Ling, Hui, Shen, Peng, Multani, Asha S., Pardini, Barbara, Burks, Jared K., Katayama, Hiroyuki, Reineke, Lucas C., Huo, Longfei, Syed, Muddassir, Song, Shumei, Ferracin, Manuela, Oki, Eiji, Fromm, Bastian, Ivan, Cristina, Bhuvaneshwar, Krithika, Gusev, Yuriy, Mimori, Koshi, Menter, David, Sen, Subrata, Matsuyama, Takatoshi, Uetake, Hiroyuki, Vasilescu, Catalin, Kopetz, Scott, Parker-Thornburg, Jan, Taguchi, Ayumu, Hanash, Samir M., Girnita, Leonard, Slaby, Ondrej, Goel, Ajay, Varani, Gabriele, Gagea, Mihai, Li, Chunlai, Ajani, Jaffer A., Calin, George A.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 2162.e33
container_issue 6
container_start_page 2146
container_title Gastroenterology (New York, N.Y. 1943)
container_volume 159
creator Chen, Baoqing
Dragomir, Mihnea P.
Fabris, Linda
Bayraktar, Recep
Knutsen, Erik
Liu, Xu
Tang, Changyan
Li, Yongfeng
Shimura, Tadanobu
Ivkovic, Tina Catela
Cruz De los Santos, Mireia
Anfossi, Simone
Shimizu, Masayoshi
Shah, Maitri Y.
Ling, Hui
Shen, Peng
Multani, Asha S.
Pardini, Barbara
Burks, Jared K.
Katayama, Hiroyuki
Reineke, Lucas C.
Huo, Longfei
Syed, Muddassir
Song, Shumei
Ferracin, Manuela
Oki, Eiji
Fromm, Bastian
Ivan, Cristina
Bhuvaneshwar, Krithika
Gusev, Yuriy
Mimori, Koshi
Menter, David
Sen, Subrata
Matsuyama, Takatoshi
Uetake, Hiroyuki
Vasilescu, Catalin
Kopetz, Scott
Parker-Thornburg, Jan
Taguchi, Ayumu
Hanash, Samir M.
Girnita, Leonard
Slaby, Ondrej
Goel, Ajay
Varani, Gabriele
Gagea, Mihai
Li, Chunlai
Ajani, Jaffer A.
Calin, George A.
description Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer–associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2′-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were
doi_str_mv 10.1053/j.gastro.2020.08.018
format Article
fullrecord <record><control><sourceid>pubmed_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_468875</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0016508520350575</els_id><sourcerecordid>32805281</sourcerecordid><originalsourceid>FETCH-LOGICAL-c628t-69cef29fac7e540a1fc5be788bd1f2b7bb1240432fa7f5a7a3c5cfdfd6833dcf3</originalsourceid><addsrcrecordid>eNp9kd1u1DAQhS0EokvhDRDkAUgY23Hs3CCl4a9i1aKyReLKchw76yUbV3a2qG-PV9sWegFXMxp_58zIB6GXGAoMjL7dFIOKc_AFAQIFiAKweIQWmBGRA2DyGC1SqXIGgh2hZzFuAKCmAj9FR5QISBxeoB-rtcmWfhqyMz9p37vUXZw1Wds2K5KdTv1Om5i16-C3PvqtGtMszqpzo5tvslWa74Z1dnL-FefN5cWXk-ybGyY1Jpvn6IlVYzQvbusxuvz4YdV-zpfnn07bZpnriog5r2ptLKmt0tywEhS2mnWGC9H12JKOdx0mJZSUWMUtU1xRzbTtbV8JSntt6THKD77xl7nadfIquK0KN9IrJ29HP1NnZFkJwVni3_yTf---N9KHQcadxDVQvMffHfDEbk2vzTQHNT5QPXyZ3FoO_lpyTlgtqmTw-mCgg4uzm-Tkg5IYgHJJoWY8EeUd4WMMxt67Y5D7rOVGHrKW-6wlCJmyTrJXf192L7oL98_pJn3_tTNBRu3MpE3vgtGz7L37_4bfXZq9XQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling</title><source>MEDLINE</source><source>NORA - Norwegian Open Research Archives</source><source>Elsevier ScienceDirect Journals</source><source>Alma/SFX Local Collection</source><source>SWEPUB Freely available online</source><creator>Chen, Baoqing ; Dragomir, Mihnea P. ; Fabris, Linda ; Bayraktar, Recep ; Knutsen, Erik ; Liu, Xu ; Tang, Changyan ; Li, Yongfeng ; Shimura, Tadanobu ; Ivkovic, Tina Catela ; Cruz De los Santos, Mireia ; Anfossi, Simone ; Shimizu, Masayoshi ; Shah, Maitri Y. ; Ling, Hui ; Shen, Peng ; Multani, Asha S. ; Pardini, Barbara ; Burks, Jared K. ; Katayama, Hiroyuki ; Reineke, Lucas C. ; Huo, Longfei ; Syed, Muddassir ; Song, Shumei ; Ferracin, Manuela ; Oki, Eiji ; Fromm, Bastian ; Ivan, Cristina ; Bhuvaneshwar, Krithika ; Gusev, Yuriy ; Mimori, Koshi ; Menter, David ; Sen, Subrata ; Matsuyama, Takatoshi ; Uetake, Hiroyuki ; Vasilescu, Catalin ; Kopetz, Scott ; Parker-Thornburg, Jan ; Taguchi, Ayumu ; Hanash, Samir M. ; Girnita, Leonard ; Slaby, Ondrej ; Goel, Ajay ; Varani, Gabriele ; Gagea, Mihai ; Li, Chunlai ; Ajani, Jaffer A. ; Calin, George A.</creator><creatorcontrib>Chen, Baoqing ; Dragomir, Mihnea P. ; Fabris, Linda ; Bayraktar, Recep ; Knutsen, Erik ; Liu, Xu ; Tang, Changyan ; Li, Yongfeng ; Shimura, Tadanobu ; Ivkovic, Tina Catela ; Cruz De los Santos, Mireia ; Anfossi, Simone ; Shimizu, Masayoshi ; Shah, Maitri Y. ; Ling, Hui ; Shen, Peng ; Multani, Asha S. ; Pardini, Barbara ; Burks, Jared K. ; Katayama, Hiroyuki ; Reineke, Lucas C. ; Huo, Longfei ; Syed, Muddassir ; Song, Shumei ; Ferracin, Manuela ; Oki, Eiji ; Fromm, Bastian ; Ivan, Cristina ; Bhuvaneshwar, Krithika ; Gusev, Yuriy ; Mimori, Koshi ; Menter, David ; Sen, Subrata ; Matsuyama, Takatoshi ; Uetake, Hiroyuki ; Vasilescu, Catalin ; Kopetz, Scott ; Parker-Thornburg, Jan ; Taguchi, Ayumu ; Hanash, Samir M. ; Girnita, Leonard ; Slaby, Ondrej ; Goel, Ajay ; Varani, Gabriele ; Gagea, Mihai ; Li, Chunlai ; Ajani, Jaffer A. ; Calin, George A.</creatorcontrib><description>Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer–associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2′-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients. We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors. [Display omitted]</description><identifier>ISSN: 0016-5085</identifier><identifier>ISSN: 1528-0012</identifier><identifier>EISSN: 1528-0012</identifier><identifier>DOI: 10.1053/j.gastro.2020.08.018</identifier><identifier>PMID: 32805281</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aneuploidy ; Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Aurora Kinase B - metabolism ; Azoxymethane - toxicity ; Carcinogenesis - genetics ; Cell Line, Tumor ; Chromosomal Instability ; Colon - cytology ; Colon - pathology ; Colorectal Neoplasms - chemically induced ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; Cytogenetic Analysis ; Dextrans - toxicity ; Drug Resistance, Neoplasm - genetics ; Female ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Intestinal Mucosa - cytology ; Intestinal Mucosa - pathology ; Male ; Mice ; Mice, Transgenic ; MSS ; Neoplasms, Experimental - chemically induced ; Neoplasms, Experimental - genetics ; Neoplasms, Experimental - pathology ; Noncoding RNA ; Organoids ; Primary Cell Culture ; Proto-Oncogene Proteins c-myc - metabolism ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Signal Transduction - genetics ; Tumorigenesis</subject><ispartof>Gastroenterology (New York, N.Y. 1943), 2020-12, Vol.159 (6), p.2146-2162.e33</ispartof><rights>2020 AGA Institute</rights><rights>Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.</rights><rights>info:eu-repo/semantics/openAccess</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c628t-69cef29fac7e540a1fc5be788bd1f2b7bb1240432fa7f5a7a3c5cfdfd6833dcf3</citedby><cites>FETCH-LOGICAL-c628t-69cef29fac7e540a1fc5be788bd1f2b7bb1240432fa7f5a7a3c5cfdfd6833dcf3</cites><orcidid>0000-0001-9571-4257 ; 0000-0002-6173-9074 ; 0000-0003-1897-9889 ; 0000-0002-9763-9366 ; 0000-0001-9946-0629 ; 0000-0003-3117-1390 ; 0000-0002-1595-6887 ; 0000-0001-5745-7587 ; 0000-0003-0352-3037 ; 0000-0002-5550-3516 ; 0000-0001-8349-8366 ; 0000-0003-4015-7056 ; 0000-0002-4903-0150 ; 0000-0002-4848-0168 ; 0000-0002-4464-8744 ; 0000-0003-0280-9500</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0016508520350575$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,550,776,780,881,3537,26544,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32805281$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-190315$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:145491194$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Baoqing</creatorcontrib><creatorcontrib>Dragomir, Mihnea P.</creatorcontrib><creatorcontrib>Fabris, Linda</creatorcontrib><creatorcontrib>Bayraktar, Recep</creatorcontrib><creatorcontrib>Knutsen, Erik</creatorcontrib><creatorcontrib>Liu, Xu</creatorcontrib><creatorcontrib>Tang, Changyan</creatorcontrib><creatorcontrib>Li, Yongfeng</creatorcontrib><creatorcontrib>Shimura, Tadanobu</creatorcontrib><creatorcontrib>Ivkovic, Tina Catela</creatorcontrib><creatorcontrib>Cruz De los Santos, Mireia</creatorcontrib><creatorcontrib>Anfossi, Simone</creatorcontrib><creatorcontrib>Shimizu, Masayoshi</creatorcontrib><creatorcontrib>Shah, Maitri Y.</creatorcontrib><creatorcontrib>Ling, Hui</creatorcontrib><creatorcontrib>Shen, Peng</creatorcontrib><creatorcontrib>Multani, Asha S.</creatorcontrib><creatorcontrib>Pardini, Barbara</creatorcontrib><creatorcontrib>Burks, Jared K.</creatorcontrib><creatorcontrib>Katayama, Hiroyuki</creatorcontrib><creatorcontrib>Reineke, Lucas C.</creatorcontrib><creatorcontrib>Huo, Longfei</creatorcontrib><creatorcontrib>Syed, Muddassir</creatorcontrib><creatorcontrib>Song, Shumei</creatorcontrib><creatorcontrib>Ferracin, Manuela</creatorcontrib><creatorcontrib>Oki, Eiji</creatorcontrib><creatorcontrib>Fromm, Bastian</creatorcontrib><creatorcontrib>Ivan, Cristina</creatorcontrib><creatorcontrib>Bhuvaneshwar, Krithika</creatorcontrib><creatorcontrib>Gusev, Yuriy</creatorcontrib><creatorcontrib>Mimori, Koshi</creatorcontrib><creatorcontrib>Menter, David</creatorcontrib><creatorcontrib>Sen, Subrata</creatorcontrib><creatorcontrib>Matsuyama, Takatoshi</creatorcontrib><creatorcontrib>Uetake, Hiroyuki</creatorcontrib><creatorcontrib>Vasilescu, Catalin</creatorcontrib><creatorcontrib>Kopetz, Scott</creatorcontrib><creatorcontrib>Parker-Thornburg, Jan</creatorcontrib><creatorcontrib>Taguchi, Ayumu</creatorcontrib><creatorcontrib>Hanash, Samir M.</creatorcontrib><creatorcontrib>Girnita, Leonard</creatorcontrib><creatorcontrib>Slaby, Ondrej</creatorcontrib><creatorcontrib>Goel, Ajay</creatorcontrib><creatorcontrib>Varani, Gabriele</creatorcontrib><creatorcontrib>Gagea, Mihai</creatorcontrib><creatorcontrib>Li, Chunlai</creatorcontrib><creatorcontrib>Ajani, Jaffer A.</creatorcontrib><creatorcontrib>Calin, George A.</creatorcontrib><title>The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling</title><title>Gastroenterology (New York, N.Y. 1943)</title><addtitle>Gastroenterology</addtitle><description>Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer–associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2′-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients. We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors. [Display omitted]</description><subject>Aneuploidy</subject><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Aurora Kinase B - metabolism</subject><subject>Azoxymethane - toxicity</subject><subject>Carcinogenesis - genetics</subject><subject>Cell Line, Tumor</subject><subject>Chromosomal Instability</subject><subject>Colon - cytology</subject><subject>Colon - pathology</subject><subject>Colorectal Neoplasms - chemically induced</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Cytogenetic Analysis</subject><subject>Dextrans - toxicity</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Intestinal Mucosa - cytology</subject><subject>Intestinal Mucosa - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>MSS</subject><subject>Neoplasms, Experimental - chemically induced</subject><subject>Neoplasms, Experimental - genetics</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Noncoding RNA</subject><subject>Organoids</subject><subject>Primary Cell Culture</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>RNA, Long Noncoding - genetics</subject><subject>RNA, Long Noncoding - metabolism</subject><subject>RNA-Binding Proteins - genetics</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Signal Transduction - genetics</subject><subject>Tumorigenesis</subject><issn>0016-5085</issn><issn>1528-0012</issn><issn>1528-0012</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>3HK</sourceid><sourceid>D8T</sourceid><recordid>eNp9kd1u1DAQhS0EokvhDRDkAUgY23Hs3CCl4a9i1aKyReLKchw76yUbV3a2qG-PV9sWegFXMxp_58zIB6GXGAoMjL7dFIOKc_AFAQIFiAKweIQWmBGRA2DyGC1SqXIGgh2hZzFuAKCmAj9FR5QISBxeoB-rtcmWfhqyMz9p37vUXZw1Wds2K5KdTv1Om5i16-C3PvqtGtMszqpzo5tvslWa74Z1dnL-FefN5cWXk-ybGyY1Jpvn6IlVYzQvbusxuvz4YdV-zpfnn07bZpnriog5r2ptLKmt0tywEhS2mnWGC9H12JKOdx0mJZSUWMUtU1xRzbTtbV8JSntt6THKD77xl7nadfIquK0KN9IrJ29HP1NnZFkJwVni3_yTf---N9KHQcadxDVQvMffHfDEbk2vzTQHNT5QPXyZ3FoO_lpyTlgtqmTw-mCgg4uzm-Tkg5IYgHJJoWY8EeUd4WMMxt67Y5D7rOVGHrKW-6wlCJmyTrJXf192L7oL98_pJn3_tTNBRu3MpE3vgtGz7L37_4bfXZq9XQ</recordid><startdate>20201201</startdate><enddate>20201201</enddate><creator>Chen, Baoqing</creator><creator>Dragomir, Mihnea P.</creator><creator>Fabris, Linda</creator><creator>Bayraktar, Recep</creator><creator>Knutsen, Erik</creator><creator>Liu, Xu</creator><creator>Tang, Changyan</creator><creator>Li, Yongfeng</creator><creator>Shimura, Tadanobu</creator><creator>Ivkovic, Tina Catela</creator><creator>Cruz De los Santos, Mireia</creator><creator>Anfossi, Simone</creator><creator>Shimizu, Masayoshi</creator><creator>Shah, Maitri Y.</creator><creator>Ling, Hui</creator><creator>Shen, Peng</creator><creator>Multani, Asha S.</creator><creator>Pardini, Barbara</creator><creator>Burks, Jared K.</creator><creator>Katayama, Hiroyuki</creator><creator>Reineke, Lucas C.</creator><creator>Huo, Longfei</creator><creator>Syed, Muddassir</creator><creator>Song, Shumei</creator><creator>Ferracin, Manuela</creator><creator>Oki, Eiji</creator><creator>Fromm, Bastian</creator><creator>Ivan, Cristina</creator><creator>Bhuvaneshwar, Krithika</creator><creator>Gusev, Yuriy</creator><creator>Mimori, Koshi</creator><creator>Menter, David</creator><creator>Sen, Subrata</creator><creator>Matsuyama, Takatoshi</creator><creator>Uetake, Hiroyuki</creator><creator>Vasilescu, Catalin</creator><creator>Kopetz, Scott</creator><creator>Parker-Thornburg, Jan</creator><creator>Taguchi, Ayumu</creator><creator>Hanash, Samir M.</creator><creator>Girnita, Leonard</creator><creator>Slaby, Ondrej</creator><creator>Goel, Ajay</creator><creator>Varani, Gabriele</creator><creator>Gagea, Mihai</creator><creator>Li, Chunlai</creator><creator>Ajani, Jaffer A.</creator><creator>Calin, George A.</creator><general>Elsevier Inc</general><general>Elsevier</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>3HK</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>DG7</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0001-9571-4257</orcidid><orcidid>https://orcid.org/0000-0002-6173-9074</orcidid><orcidid>https://orcid.org/0000-0003-1897-9889</orcidid><orcidid>https://orcid.org/0000-0002-9763-9366</orcidid><orcidid>https://orcid.org/0000-0001-9946-0629</orcidid><orcidid>https://orcid.org/0000-0003-3117-1390</orcidid><orcidid>https://orcid.org/0000-0002-1595-6887</orcidid><orcidid>https://orcid.org/0000-0001-5745-7587</orcidid><orcidid>https://orcid.org/0000-0003-0352-3037</orcidid><orcidid>https://orcid.org/0000-0002-5550-3516</orcidid><orcidid>https://orcid.org/0000-0001-8349-8366</orcidid><orcidid>https://orcid.org/0000-0003-4015-7056</orcidid><orcidid>https://orcid.org/0000-0002-4903-0150</orcidid><orcidid>https://orcid.org/0000-0002-4848-0168</orcidid><orcidid>https://orcid.org/0000-0002-4464-8744</orcidid><orcidid>https://orcid.org/0000-0003-0280-9500</orcidid></search><sort><creationdate>20201201</creationdate><title>The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling</title><author>Chen, Baoqing ; Dragomir, Mihnea P. ; Fabris, Linda ; Bayraktar, Recep ; Knutsen, Erik ; Liu, Xu ; Tang, Changyan ; Li, Yongfeng ; Shimura, Tadanobu ; Ivkovic, Tina Catela ; Cruz De los Santos, Mireia ; Anfossi, Simone ; Shimizu, Masayoshi ; Shah, Maitri Y. ; Ling, Hui ; Shen, Peng ; Multani, Asha S. ; Pardini, Barbara ; Burks, Jared K. ; Katayama, Hiroyuki ; Reineke, Lucas C. ; Huo, Longfei ; Syed, Muddassir ; Song, Shumei ; Ferracin, Manuela ; Oki, Eiji ; Fromm, Bastian ; Ivan, Cristina ; Bhuvaneshwar, Krithika ; Gusev, Yuriy ; Mimori, Koshi ; Menter, David ; Sen, Subrata ; Matsuyama, Takatoshi ; Uetake, Hiroyuki ; Vasilescu, Catalin ; Kopetz, Scott ; Parker-Thornburg, Jan ; Taguchi, Ayumu ; Hanash, Samir M. ; Girnita, Leonard ; Slaby, Ondrej ; Goel, Ajay ; Varani, Gabriele ; Gagea, Mihai ; Li, Chunlai ; Ajani, Jaffer A. ; Calin, George A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c628t-69cef29fac7e540a1fc5be788bd1f2b7bb1240432fa7f5a7a3c5cfdfd6833dcf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aneuploidy</topic><topic>Animals</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Aurora Kinase B - metabolism</topic><topic>Azoxymethane - toxicity</topic><topic>Carcinogenesis - genetics</topic><topic>Cell Line, Tumor</topic><topic>Chromosomal Instability</topic><topic>Colon - cytology</topic><topic>Colon - pathology</topic><topic>Colorectal Neoplasms - chemically induced</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Cytogenetic Analysis</topic><topic>Dextrans - toxicity</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Intestinal Mucosa - cytology</topic><topic>Intestinal Mucosa - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>MSS</topic><topic>Neoplasms, Experimental - chemically induced</topic><topic>Neoplasms, Experimental - genetics</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Noncoding RNA</topic><topic>Organoids</topic><topic>Primary Cell Culture</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>RNA, Long Noncoding - genetics</topic><topic>RNA, Long Noncoding - metabolism</topic><topic>RNA-Binding Proteins - genetics</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Signal Transduction - genetics</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Baoqing</creatorcontrib><creatorcontrib>Dragomir, Mihnea P.</creatorcontrib><creatorcontrib>Fabris, Linda</creatorcontrib><creatorcontrib>Bayraktar, Recep</creatorcontrib><creatorcontrib>Knutsen, Erik</creatorcontrib><creatorcontrib>Liu, Xu</creatorcontrib><creatorcontrib>Tang, Changyan</creatorcontrib><creatorcontrib>Li, Yongfeng</creatorcontrib><creatorcontrib>Shimura, Tadanobu</creatorcontrib><creatorcontrib>Ivkovic, Tina Catela</creatorcontrib><creatorcontrib>Cruz De los Santos, Mireia</creatorcontrib><creatorcontrib>Anfossi, Simone</creatorcontrib><creatorcontrib>Shimizu, Masayoshi</creatorcontrib><creatorcontrib>Shah, Maitri Y.</creatorcontrib><creatorcontrib>Ling, Hui</creatorcontrib><creatorcontrib>Shen, Peng</creatorcontrib><creatorcontrib>Multani, Asha S.</creatorcontrib><creatorcontrib>Pardini, Barbara</creatorcontrib><creatorcontrib>Burks, Jared K.</creatorcontrib><creatorcontrib>Katayama, Hiroyuki</creatorcontrib><creatorcontrib>Reineke, Lucas C.</creatorcontrib><creatorcontrib>Huo, Longfei</creatorcontrib><creatorcontrib>Syed, Muddassir</creatorcontrib><creatorcontrib>Song, Shumei</creatorcontrib><creatorcontrib>Ferracin, Manuela</creatorcontrib><creatorcontrib>Oki, Eiji</creatorcontrib><creatorcontrib>Fromm, Bastian</creatorcontrib><creatorcontrib>Ivan, Cristina</creatorcontrib><creatorcontrib>Bhuvaneshwar, Krithika</creatorcontrib><creatorcontrib>Gusev, Yuriy</creatorcontrib><creatorcontrib>Mimori, Koshi</creatorcontrib><creatorcontrib>Menter, David</creatorcontrib><creatorcontrib>Sen, Subrata</creatorcontrib><creatorcontrib>Matsuyama, Takatoshi</creatorcontrib><creatorcontrib>Uetake, Hiroyuki</creatorcontrib><creatorcontrib>Vasilescu, Catalin</creatorcontrib><creatorcontrib>Kopetz, Scott</creatorcontrib><creatorcontrib>Parker-Thornburg, Jan</creatorcontrib><creatorcontrib>Taguchi, Ayumu</creatorcontrib><creatorcontrib>Hanash, Samir M.</creatorcontrib><creatorcontrib>Girnita, Leonard</creatorcontrib><creatorcontrib>Slaby, Ondrej</creatorcontrib><creatorcontrib>Goel, Ajay</creatorcontrib><creatorcontrib>Varani, Gabriele</creatorcontrib><creatorcontrib>Gagea, Mihai</creatorcontrib><creatorcontrib>Li, Chunlai</creatorcontrib><creatorcontrib>Ajani, Jaffer A.</creatorcontrib><creatorcontrib>Calin, George A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>NORA - Norwegian Open Research Archives</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Stockholms universitet</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Baoqing</au><au>Dragomir, Mihnea P.</au><au>Fabris, Linda</au><au>Bayraktar, Recep</au><au>Knutsen, Erik</au><au>Liu, Xu</au><au>Tang, Changyan</au><au>Li, Yongfeng</au><au>Shimura, Tadanobu</au><au>Ivkovic, Tina Catela</au><au>Cruz De los Santos, Mireia</au><au>Anfossi, Simone</au><au>Shimizu, Masayoshi</au><au>Shah, Maitri Y.</au><au>Ling, Hui</au><au>Shen, Peng</au><au>Multani, Asha S.</au><au>Pardini, Barbara</au><au>Burks, Jared K.</au><au>Katayama, Hiroyuki</au><au>Reineke, Lucas C.</au><au>Huo, Longfei</au><au>Syed, Muddassir</au><au>Song, Shumei</au><au>Ferracin, Manuela</au><au>Oki, Eiji</au><au>Fromm, Bastian</au><au>Ivan, Cristina</au><au>Bhuvaneshwar, Krithika</au><au>Gusev, Yuriy</au><au>Mimori, Koshi</au><au>Menter, David</au><au>Sen, Subrata</au><au>Matsuyama, Takatoshi</au><au>Uetake, Hiroyuki</au><au>Vasilescu, Catalin</au><au>Kopetz, Scott</au><au>Parker-Thornburg, Jan</au><au>Taguchi, Ayumu</au><au>Hanash, Samir M.</au><au>Girnita, Leonard</au><au>Slaby, Ondrej</au><au>Goel, Ajay</au><au>Varani, Gabriele</au><au>Gagea, Mihai</au><au>Li, Chunlai</au><au>Ajani, Jaffer A.</au><au>Calin, George A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling</atitle><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle><addtitle>Gastroenterology</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>159</volume><issue>6</issue><spage>2146</spage><epage>2162.e33</epage><pages>2146-2162.e33</pages><issn>0016-5085</issn><issn>1528-0012</issn><eissn>1528-0012</eissn><abstract>Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer–associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2′-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients. We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors. [Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32805281</pmid><doi>10.1053/j.gastro.2020.08.018</doi><orcidid>https://orcid.org/0000-0001-9571-4257</orcidid><orcidid>https://orcid.org/0000-0002-6173-9074</orcidid><orcidid>https://orcid.org/0000-0003-1897-9889</orcidid><orcidid>https://orcid.org/0000-0002-9763-9366</orcidid><orcidid>https://orcid.org/0000-0001-9946-0629</orcidid><orcidid>https://orcid.org/0000-0003-3117-1390</orcidid><orcidid>https://orcid.org/0000-0002-1595-6887</orcidid><orcidid>https://orcid.org/0000-0001-5745-7587</orcidid><orcidid>https://orcid.org/0000-0003-0352-3037</orcidid><orcidid>https://orcid.org/0000-0002-5550-3516</orcidid><orcidid>https://orcid.org/0000-0001-8349-8366</orcidid><orcidid>https://orcid.org/0000-0003-4015-7056</orcidid><orcidid>https://orcid.org/0000-0002-4903-0150</orcidid><orcidid>https://orcid.org/0000-0002-4848-0168</orcidid><orcidid>https://orcid.org/0000-0002-4464-8744</orcidid><orcidid>https://orcid.org/0000-0003-0280-9500</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0016-5085
ispartof Gastroenterology (New York, N.Y. 1943), 2020-12, Vol.159 (6), p.2146-2162.e33
issn 0016-5085
1528-0012
1528-0012
language eng
recordid cdi_swepub_primary_oai_swepub_ki_se_468875
source MEDLINE; NORA - Norwegian Open Research Archives; Elsevier ScienceDirect Journals; Alma/SFX Local Collection; SWEPUB Freely available online
subjects Aneuploidy
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Aurora Kinase B - metabolism
Azoxymethane - toxicity
Carcinogenesis - genetics
Cell Line, Tumor
Chromosomal Instability
Colon - cytology
Colon - pathology
Colorectal Neoplasms - chemically induced
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Cytogenetic Analysis
Dextrans - toxicity
Drug Resistance, Neoplasm - genetics
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Intestinal Mucosa - cytology
Intestinal Mucosa - pathology
Male
Mice
Mice, Transgenic
MSS
Neoplasms, Experimental - chemically induced
Neoplasms, Experimental - genetics
Neoplasms, Experimental - pathology
Noncoding RNA
Organoids
Primary Cell Culture
Proto-Oncogene Proteins c-myc - metabolism
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Signal Transduction - genetics
Tumorigenesis
title The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-29T21%3A47%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20Long%20Noncoding%20RNA%20CCAT2%20Induces%20Chromosomal%20Instability%20Through%20BOP1-AURKB%20Signaling&rft.jtitle=Gastroenterology%20(New%20York,%20N.Y.%201943)&rft.au=Chen,%20Baoqing&rft.date=2020-12-01&rft.volume=159&rft.issue=6&rft.spage=2146&rft.epage=2162.e33&rft.pages=2146-2162.e33&rft.issn=0016-5085&rft.eissn=1528-0012&rft_id=info:doi/10.1053/j.gastro.2020.08.018&rft_dat=%3Cpubmed_swepu%3E32805281%3C/pubmed_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/32805281&rft_els_id=S0016508520350575&rfr_iscdi=true