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...
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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 |
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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 - 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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> |
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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 |
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