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dc.contributor.authorChen, Baoqing
dc.contributor.authorDragomir, Mihnea Paul
dc.contributor.authorFabris, Linda
dc.contributor.authorBayraktar, Recep
dc.contributor.authorKnutsen, Erik
dc.contributor.authorLiu, Xu
dc.contributor.authorTang, Changyan
dc.contributor.authorLi, Yongfeng
dc.contributor.authorShimura, Tadanobu
dc.contributor.authorIvkovic, Tina Catela
dc.contributor.authorCruz De los Santos, Mireia
dc.contributor.authorAnfossi, Simone
dc.contributor.authorShimizu, Masayoshi
dc.contributor.authorShah, Maitri Y.
dc.contributor.authorLing, Hui
dc.contributor.authorShen, Peng
dc.contributor.authorMultani, Asha S.
dc.contributor.authorPardini, Barbara
dc.contributor.authorBurks, Jared K.
dc.contributor.authorKatayama, Hiroyuki
dc.contributor.authorReineke, Lucas C.
dc.contributor.authorHuo, Longfei
dc.contributor.authorSyed, Muddassir
dc.contributor.authorSong, Shumei
dc.contributor.authorFerracin, Manuela
dc.contributor.authorOki, Eiji
dc.contributor.authorFromm, Bastian
dc.contributor.authorIvan, Cristina
dc.contributor.authorBhuvaneshwar, Krithika
dc.contributor.authorGusev, Yuriy
dc.contributor.authorMimori, Koshi
dc.contributor.authorMenter, David
dc.contributor.authorSen, Subrata
dc.contributor.authorMatsuyama, Takatoshi
dc.contributor.authorUetake, Hiroyuki
dc.contributor.authorVasilescu, Catalin
dc.contributor.authorKopetz, Scott
dc.contributor.authorParker-Thornburg, Jan
dc.contributor.authorTaguchi, Ayumu
dc.contributor.authorHanash, Samir M.
dc.contributor.authorGirnita, Leonard
dc.contributor.authorSlaby, Ondrej
dc.contributor.authorGoel, Ajay
dc.contributor.authorVarani, Gabriele
dc.contributor.authorGagea, Mihai
dc.contributor.authorLi, Chunlai
dc.contributor.authorAjani, Jaffer A.
dc.contributor.authorCalin, George A.
dc.date.accessioned2023-09-12T11:49:26Z
dc.date.available2023-09-12T11:49:26Z
dc.date.issued2020-08-15
dc.description.abstractBackground & Aims - 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.<p> <p>Methods - 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.<p> <p>Results - 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.<p> <p>Conclusions - 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.en_US
dc.identifier.citationChen, Dragomir, Fabris, Bayraktar, Knutsen, Liu, Tang, Li, Shimura, Ivkovic, Cruz De los Santos, Anfossi, Shimizu, Shah, Ling, Shen, Multani, Pardini, Burks, Katayama, Reineke, Huo, Syed, Song, Ferracin, Oki, Fromm, Ivan, Bhuvaneshwar, Gusev, Mimori, Menter, Sen, Matsuyama, Uetake, Vasilescu, Kopetz, Parker-Thornburg, Taguchi, Hanash, Girnita, Slaby, Goel, Varani, Gagea, Li, Ajani, Calin. The long noncoding RNA CCAT2 induces chromosomal instability through BOP1-AURKB signaling. Gastroenterology. 2020;159(6):2146-2162en_US
dc.identifier.cristinIDFRIDAID 1861897
dc.identifier.doi10.1053/j.gastro.2020.08.018
dc.identifier.issn0016-5085
dc.identifier.issn1528-0012
dc.identifier.urihttps://hdl.handle.net/10037/30957
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalGastroenterology
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2020 The Author(s)en_US
dc.titleThe long noncoding RNA CCAT2 induces chromosomal instability through BOP1-AURKB signalingen_US
dc.type.versionacceptedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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