机构:[1]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston,TX 77030, USA[2]Department of Radiation Oncology, State Key Laboratory of Oncology in South China, CollaborativeInnovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong,China[3]Department of General Surgery, Fundeni Clinical Hospital, Carol Davila University of Medicine andPharmacy, Bucharest, Romania[4]Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø,Norway[5]Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China[6]Department of Chemistry, University of Washington, Seattle, WA 98195, USA[7]Center for Gastrointestinal Research[8]Center for Translational Genomics and Oncology, Baylor Scott &White Research Institute, Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, USA[8]Central European Institute of Technology, Masaryk University, Brno, Czech Republic[9]Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China[10]Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[11]Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[12]Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX,USA[13]Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA[14]Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center,Houston, TX, USA[15]Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126Bologna, Italy[16]Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka,Japan[17]Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, StockholmUniversity, Stockholm, Sweden[18]Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, OsloUniversity Hospital, Oslo, Norway[19]Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center,Houston, TX 77030, USA[20]Innovation Center for Biomedical Informatics, Georgetown University, Washington, DC, USA[21]Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan[22]Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center,Houston, TX, 77030, USA[23]Department of Gastrointestinal Surgery, Tokyo Medical and Dental University Graduate School ofMedicine, Tokyo, Japan[24]Department of Specialized Surgeries, Graduate School, Tokyo Medical and Dental University, Tokyo,Japan[25]“Carol Davila University of Medicine and Pharmacy”, Bucharest, Romania26 Department of Oncology-Pathology, Bioclinicum, Karolinska Institute and Karolinska University Hospital,SE-171 647 Stockholm, Sweden[27]Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic28 Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center,Houston Texas 77030, USA[29]Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West ChinaHospital, Sichuan University, Chengdu, Sichuan, China[30]Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy[31]pCandiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy[32]Department of Molecular Diagnostics and Experimental Therapeutics, BeckmanResearch Institute of City of Hope Comprehensive Cancer Center, Duarte, CA
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 sulphate sodium (DSS) 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 pulldown, RNA immunoprecipitation, and SHAPE 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 to organoids from control mice. The transgenic mice given azoxymethane and DSS 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 (AURKB), which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice, compared to 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 non-tumor 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 AURKB. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.
基金:
National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NCI grants 1R01 CA182905-01 and
1R01CA222007-01A1, an NIGMS 1R01GM122775-01 grant, a U54 grant #CA096297/CA096300 –UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1)grant, a Chronic Lymphocytic Leukemia Moonshot Flagship project, the UT MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment, a Sister Institution Network Fund (SINF) 2017 grant, and the Estate of C. G. Johnson, Jr. Dr. Pardini is recipient of a Fulbright Research Scholarships (year 2018). Work at the University of Washington was supported by NIGMS R35 GM121487.The work of Dr. Baoqing Chen is supported by National Natural Science Foundation of China (No.81902462). The work in Dr. Goel’s lab is supported by the grants CA72851, CA181572 and CA202797 from the National Cancer Institute, National Institute of Health. The work of Dr. Parker-Thornburg was supported by the grants 5R50CA211121-03 and CCSG for the GEMF core.
第一作者机构:[1]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston,TX 77030, USA[2]Department of Radiation Oncology, State Key Laboratory of Oncology in South China, CollaborativeInnovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong,China[29]Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West ChinaHospital, Sichuan University, Chengdu, Sichuan, China
共同第一作者:
通讯作者:
通讯机构:[1]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston,TX 77030, USA[14]Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center,Houston, TX, USA[19]Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center,Houston, TX 77030, USA[*1]Department of Experimental Therapeutics, Center for RNA Interference and Non-Coding RNAs, Department of Experimental Therapeutics - Unit 1950, The University of Texas MD Anderson Cancer Center, P.O. Box 301429, Houston, Texas 77030-1429[*2]Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[*3]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
推荐引用方式(GB/T 7714):
Baoqing Chen,Mihnea P. Dragomir,Linda Fabris,et al.The Long Noncoding RNA CCAT2 induces chromosomal instability through BOP1 - AURKB signaling.[J].GASTROENTEROLOGY.2020,159(6):2146-2195.doi:10.1053/j.gastro.2020.08.018.
APA:
Baoqing Chen,Mihnea P. Dragomir,Linda Fabris,Recep Bayraktar,Erik Knutsen...&George A. Calin.(2020).The Long Noncoding RNA CCAT2 induces chromosomal instability through BOP1 - AURKB signaling..GASTROENTEROLOGY,159,(6)
MLA:
Baoqing Chen,et al."The Long Noncoding RNA CCAT2 induces chromosomal instability through BOP1 - AURKB signaling.".GASTROENTEROLOGY 159..6(2020):2146-2195