• Je něco špatně v tomto záznamu ?

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

B. Chen, MP. Dragomir, L. Fabris, R. Bayraktar, E. Knutsen, X. Liu, C. Tang, Y. Li, T. Shimura, TC. Ivkovic, M. Cruz De Los Santos, S. Anfossi, M. Shimizu, MY. Shah, H. Ling, P. Shen, AS. Multani, B. Pardini, JK. Burks, H. Katayama, LC. Reineke,...

. 2020 ; 159 (6) : 2146-2162.e33. [pub] 20200815

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.

Perzistentní odkaz   https://www.medvik.cz/link/bmc21019723

Grantová podpora
R35 GM126942 NIGMS NIH HHS - United States
R01 CA202797 NCI NIH HHS - United States
U54 CA096297 NCI NIH HHS - United States
UH3 TR000943 NCATS NIH HHS - United States
R50 CA211121 NCI NIH HHS - United States
U54 CA096300 NCI NIH HHS - United States
R01 GM121487 NIGMS NIH HHS - United States
R01 CA072851 NCI NIH HHS - United States
R01 CA182905 NCI NIH HHS - United States
P30 CA016672 NCI NIH HHS - United States
R01 CA222007 NCI NIH HHS - United States
P30 CA051008 NCI NIH HHS - United States
R01 GM122775 NIGMS NIH HHS - United States
R01 CA181572 NCI NIH HHS - United States
R50 CA243707 NCI NIH HHS - United States

BACKGROUND & 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. 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. 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. 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.

Carol Davila University of Medicine and Pharmacy Bucharest Romania

Center for Gastrointestinal Research

Center for RNA Interference and Non Coding RNAs The University of Texas MD Anderson Cancer Center Houston Texas

Center for Translational Genomics and Oncology Baylor Scott and White Research Institute Charles A Sammons Cancer Center Baylor University Medical Center Dallas Texas

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Chemistry University of Washington Seattle Washington

Department of Clinical Cancer Prevention University of Texas MD Anderson Cancer Center Houston Texas

Department of Experimental Diagnostic and Specialty Medicine University of Bologna Bologna Italy

Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston Texas

Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas

Department of Gastrointestinal Surgery Tokyo Medical and Dental University Graduate School of Medicine Tokyo Japan

Department of General Surgery Fundeni Clinical Hospital Carol Davila University of Medicine and Pharmacy Bucharest Romania

Department of Genetics The University of Texas MD Anderson Cancer Center Houston Texas

Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas

Department of Medical Biology Faculty of Health Sciences The Arctic University of Norway Tromsø Norway

Department of Neuroscience Baylor College of Medicine Houston Texas

Department of Oncology Nanfang Hospital Southern Medical University Guangzhou China

Department of Oncology Pathology Bioclinicum Karolinska Institute and Karolinska University Hospital Stockholm Sweden

Department of Radiation Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat sen University Cancer Center Guangzhou Guangdong China

Department of Specialized Surgeries Graduate School Tokyo Medical and Dental University Tokyo Japan

Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan

Department of Surgery Kyushu University Beppu Hospital Beppu Japan

Department of Thoracic Oncology Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu Sichuan China

Department of Thoracic Surgery The 1st Affiliated Hospital of Xi'an Jiaotong University Xi'an China

Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer Center Houston Texas

Department of Tumor Biology Institute for Cancer Research The Norwegian Radium Hospital Oslo University Hospital Oslo Norway

Department of Veterinary Medicine and Surgery The University of Texas MD Anderson Cancer Center Houston Texas

Innovation Center for Biomedical Informatics Georgetown University Washington District of Columbia

Science for Life Laboratory Department of Molecular Biosciences The Wenner Gren Institute Stockholm University Stockholm Sweden

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc21019723
003      
CZ-PrNML
005      
20210830101324.0
007      
ta
008      
210728s2020 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1053/j.gastro.2020.08.018 $2 doi
035    __
$a (PubMed)32805281
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Chen, Baoqing $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
245    14
$a The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling / $c B. Chen, MP. Dragomir, L. Fabris, R. Bayraktar, E. Knutsen, X. Liu, C. Tang, Y. Li, T. Shimura, TC. Ivkovic, M. Cruz De Los Santos, S. Anfossi, M. Shimizu, MY. Shah, H. Ling, P. Shen, AS. Multani, B. Pardini, JK. Burks, H. Katayama, LC. Reineke, L. Huo, M. Syed, S. Song, M. Ferracin, E. Oki, B. Fromm, C. Ivan, K. Bhuvaneshwar, Y. Gusev, K. Mimori, D. Menter, S. Sen, T. Matsuyama, H. Uetake, C. Vasilescu, S. Kopetz, J. Parker-Thornburg, A. Taguchi, SM. Hanash, L. Girnita, O. Slaby, A. Goel, G. Varani, M. Gagea, C. Li, JA. Ajani, GA. Calin
520    9_
$a BACKGROUND & 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. 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. 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. 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.
650    _2
$a zvířata $7 D000818
650    _2
$a protokoly protinádorové kombinované chemoterapie $x farmakologie $x terapeutické užití $7 D000971
650    _2
$a aurora kinasa B $x metabolismus $7 D064107
650    _2
$a azoxymethan $x toxicita $7 D001397
650    _2
$a karcinogeneze $x genetika $7 D063646
650    _2
$a nádorové buněčné linie $7 D045744
650    12
$a chromozomální nestabilita $7 D043171
650    _2
$a kolon $x cytologie $x patologie $7 D003106
650    _2
$a kolorektální nádory $x chemicky indukované $x genetika $x patologie $7 D015179
650    _2
$a cytogenetické vyšetření $7 D020732
650    _2
$a dextrany $x toxicita $7 D003911
650    _2
$a chemorezistence $x genetika $7 D019008
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a regulace genové exprese u nádorů $7 D015972
650    _2
$a genový knockdown $7 D055785
650    _2
$a lidé $7 D006801
650    _2
$a střevní sliznice $x cytologie $x patologie $7 D007413
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a myši $7 D051379
650    _2
$a myši transgenní $7 D008822
650    _2
$a experimentální nádory $x chemicky indukované $x genetika $x patologie $7 D009374
650    _2
$a organoidy $7 D009940
650    _2
$a primární buněčná kultura $7 D061251
650    _2
$a protoonkogenní proteiny c-myc $x metabolismus $7 D016271
650    _2
$a RNA dlouhá nekódující $x genetika $x metabolismus $7 D062085
650    _2
$a proteiny vázající RNA $x genetika $x metabolismus $7 D016601
650    _2
$a signální transdukce $x genetika $7 D015398
655    _2
$a časopisecké články $7 D016428
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
655    _2
$a práce podpořená grantem $7 D013485
655    _2
$a Research Support, U.S. Gov't, Non-P.H.S. $7 D013486
700    1_
$a Dragomir, Mihnea P $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of General Surgery, Fundeni Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
700    1_
$a Fabris, Linda $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Bayraktar, Recep $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Knutsen, Erik $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway
700    1_
$a Liu, Xu $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
700    1_
$a Tang, Changyan $u Department of Chemistry, University of Washington, Seattle, Washington
700    1_
$a Li, Yongfeng $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Shimura, Tadanobu $u Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
700    1_
$a Ivkovic, Tina Catela $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic
700    1_
$a Cruz De Los Santos, Mireia $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Anfossi, Simone $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Shimizu, Masayoshi $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Shah, Maitri Y $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Ling, Hui $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Shen, Peng $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
700    1_
$a Multani, Asha S $u Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Pardini, Barbara $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Burks, Jared K $u Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Katayama, Hiroyuki $u Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Reineke, Lucas C $u Department of Neuroscience, Baylor College of Medicine, Houston, Texas
700    1_
$a Huo, Longfei $u Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Syed, Muddassir $u Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
700    1_
$a Song, Shumei $u Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Ferracin, Manuela $u Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
700    1_
$a Oki, Eiji $u Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
700    1_
$a Fromm, Bastian $u Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
700    1_
$a Ivan, Cristina $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Bhuvaneshwar, Krithika $u Innovation Center for Biomedical Informatics, Georgetown University, Washington, District of Columbia
700    1_
$a Gusev, Yuriy $u Innovation Center for Biomedical Informatics, Georgetown University, Washington, District of Columbia
700    1_
$a Mimori, Koshi $u Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
700    1_
$a Menter, David $u Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Sen, Subrata $u Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Matsuyama, Takatoshi $u Department of Gastrointestinal Surgery, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan
700    1_
$a Uetake, Hiroyuki $u Department of Specialized Surgeries, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
700    1_
$a Vasilescu, Catalin $u Department of General Surgery, Fundeni Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
700    1_
$a Kopetz, Scott $u Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Parker-Thornburg, Jan $u Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Taguchi, Ayumu $u Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Hanash, Samir M $u Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Girnita, Leonard $u Department of Oncology-Pathology, Bioclinicum, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
700    1_
$a Slaby, Ondrej $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Goel, Ajay $u Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
700    1_
$a Varani, Gabriele $u Department of Chemistry, University of Washington, Seattle, Washington
700    1_
$a Gagea, Mihai $u Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
700    1_
$a Li, Chunlai $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: CLi10@mdanderson.org
700    1_
$a Ajani, Jaffer A $u Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: jajani@mdanderson.org
700    1_
$a Calin, George A $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: gcalin@mdanderson.org
773    0_
$w MED00001877 $t Gastroenterology $x 1528-0012 $g Roč. 159, č. 6 (2020), s. 2146-2162.e33
856    41
$u https://pubmed.ncbi.nlm.nih.gov/32805281 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20210728 $b ABA008
991    __
$a 20210830101324 $b ABA008
999    __
$a ok $b bmc $g 1690519 $s 1140169
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2020 $b 159 $c 6 $d 2146-2162.e33 $e 20200815 $i 1528-0012 $m Gastroenterology $n Gastroenterology $x MED00001877
GRA    __
$a R35 GM126942 $p NIGMS NIH HHS $2 United States
GRA    __
$a R01 CA202797 $p NCI NIH HHS $2 United States
GRA    __
$a U54 CA096297 $p NCI NIH HHS $2 United States
GRA    __
$a UH3 TR000943 $p NCATS NIH HHS $2 United States
GRA    __
$a R50 CA211121 $p NCI NIH HHS $2 United States
GRA    __
$a U54 CA096300 $p NCI NIH HHS $2 United States
GRA    __
$a R01 GM121487 $p NIGMS NIH HHS $2 United States
GRA    __
$a R01 CA072851 $p NCI NIH HHS $2 United States
GRA    __
$a R01 CA182905 $p NCI NIH HHS $2 United States
GRA    __
$a P30 CA016672 $p NCI NIH HHS $2 United States
GRA    __
$a R01 CA222007 $p NCI NIH HHS $2 United States
GRA    __
$a P30 CA051008 $p NCI NIH HHS $2 United States
GRA    __
$a R01 GM122775 $p NIGMS NIH HHS $2 United States
GRA    __
$a R01 CA181572 $p NCI NIH HHS $2 United States
GRA    __
$a R50 CA243707 $p NCI NIH HHS $2 United States
LZP    __
$a Pubmed-20210728

Najít záznam

Citační ukazatele

Možnosti archivace