PMID- 30836096
OWN - NLM
STAT- MEDLINE
DCOM- 20190628
LR  - 20240111
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 156
IP  - 8
DP  - 2019 Jun
TI  - GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 
      Signaling and Down-regulating Expression of GNAI2.
PG  - 2297-2312
LID - S0016-5085(19)32508-9 [pii]
LID - 10.1053/j.gastro.2019.02.040 [doi]
AB  - BACKGROUND & AIMS: Interleukin 6 (IL6) and tumor necrosis factor contribute to 
      the development of colitis-associated cancer (CAC). We investigated these 
      signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), 
      GNAI2, and GNAI3 in the development of CAC in mice and humans. METHODS: B6;129 
      wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or 
      conditional disruption of Gnai2 in CD11c(+) or epithelial cells were given 
      dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to 
      induce carcinogenesis; some mice were given an antibody against IL6. Feces were 
      collected from mice, and the compositions of microbiomes were analyzed by 
      polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor 
      cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow 
      cytometry. We performed immunoprecipitation and immunoblot analyses of colon 
      tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression 
      levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with 
      proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 
      messenger RNA by CD11c(+) cells in the colonic lamina propria by PrimeFlow, 
      expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera 
      and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor 
      and matched nontumor tissues from 83 patients with colorectal cancer having 
      surgery in China and 35 patients with CAC in the United States. Mouse and human 
      colon tissues were analyzed by histology, immunoblot, immunohistochemistry, 
      and/or RNA-sequencing analyses. RESULTS: GNAI1 and GNAI3 (GNAI1;3) 
      double-knockout (DKO) mice developed more severe colitis after administration of 
      DSS and significantly more colonic tumors than control mice after administration 
      of AOM plus DSS. Development of increased tumors in DKO mice was not associated 
      with changes in fecal microbiomes but was associated with activation of nuclear 
      factor (NF) kappaB and signal transducer and activator of transcription (STAT) 3; 
      increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of 
      CD4(+) DCs and MDSCs; and decreased numbers of CD8(+) DCs. IL6 was mainly 
      produced by CD4(+)/CD11b(+), but not CD8(+), DCs in DKO mice. Injection of DKO 
      mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the 
      number of tumors that developed after CAC induction. Incubation of MDSCs or mouse 
      embryonic fibroblasts with IL6 induced activation of either NF-kappaB by a 
      JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation 
      resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) 
      and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of 
      these proteins and expansion of MDSCs were further increased by the absence of 
      GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c(+) cells of 
      DKO mice prevented activation of NF-kappaB and STAT3 and changes in numbers of DCs 
      and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 
      and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further 
      analysis of a public human colorectal tumor DNA microarray database (GSE39582) 
      showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger 
      RNA expression were significantly associated with decreased relapse-free 
      survival. CONCLUSIONS: GNAI1;3 suppresses DSS-plus-AOM-induced colon tumor 
      development in mice, whereas expression of GNAI2 in CD11c(+) cells and IL6 in 
      CD4(+)/CD11b(+) DCs appears to promote these effects. Strategies to induce 
      GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy 
      of CAC in patients.
CI  - Copyright (c) 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Li, Zhi-Wei
AU  - Li ZW
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Sun, Beicheng
AU  - Sun B
AD  - Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of 
      Nanjing University Medical School, Nanjing, Jiangsu, China.
FAU - Gong, Ting
AU  - Gong T
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Guo, Sheng
AU  - Guo S
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii; 
      Department of Endocrine, Genetics and Metabolism, Shanghai Children's Hospital, 
      Shanghai Jiao Tong University, Shanghai, China.
FAU - Zhang, Jianhua
AU  - Zhang J
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii; 
      Department of Pediatrics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Wang, Junlong
AU  - Wang J
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Sugawara, Atsushi
AU  - Sugawara A
AD  - Institute for Biogenesis Research, John A. Burns School of Medicine, University 
      of Hawaii, Honolulu, Hawaii.
FAU - Jiang, Meisheng
AU  - Jiang M
AD  - Department of Molecular and Medical Pharmacology, University of California, Los 
      Angeles, California.
FAU - Yan, Junjun
AU  - Yan J
AD  - Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, Jiangsu, China.
FAU - Gurary, Alexandra
AU  - Gurary A
AD  - Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. 
      Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
FAU - Zheng, Xin
AU  - Zheng X
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Gao, Bifeng
AU  - Gao B
AD  - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Xiao, Shu-Yuan
AU  - Xiao SY
AD  - Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 
      China; Department of Pathology, University of Chicago, Chicago, Illinois.
FAU - Chen, Wenlian
AU  - Chen W
AD  - Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Ma, Chi
AU  - Ma C
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Farrar, Christine
AU  - Farrar C
AD  - The Microscopy, Imaging, and Flow Cytometry Shared Resource, University of Hawaii 
      Cancer Center, Honolulu, Hawaii.
FAU - Zhu, Chenjun
AU  - Zhu C
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Chan, Owen T M
AU  - Chan OTM
AD  - Pathology Core, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Xin, Can
AU  - Xin C
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Winnicki, Andrew
AU  - Winnicki A
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Winnicki, John
AU  - Winnicki J
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Tang, Mingxin
AU  - Tang M
AD  - Center for Cardiovascular Research, John A. Burns School of Medicine, University 
      of Hawaii, Honolulu, Hawaii.
FAU - Park, Ryan
AU  - Park R
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Winnicki, Mary
AU  - Winnicki M
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Diener, Katrina
AU  - Diener K
AD  - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Wang, Zhanwei
AU  - Wang Z
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Liu, Qicai
AU  - Liu Q
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii; 
      Department of Cardiology and Heart Center, Zhujiang Hospital, Southern Medical 
      University, Guangzhou, Guangdong, China.
FAU - Chu, Catherine H
AU  - Chu CH
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Arter, Zhaohui L
AU  - Arter ZL
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Yue, Peibin
AU  - Yue P
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Alpert, Lindsay
AU  - Alpert L
AD  - Department of Pathology, University of Chicago, Chicago, Illinois.
FAU - Hui, George S
AU  - Hui GS
AD  - Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. 
      Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
FAU - Fei, Peiwen
AU  - Fei P
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Turkson, James
AU  - Turkson J
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Yang, Wentian
AU  - Yang W
AD  - Department of Orthopedics, Rhode Island Hospital, Brown University Alpert Medical 
      School, Providence, Rhode Island.
FAU - Wu, Guangyu
AU  - Wu G
AD  - Department of Pharmacology and Toxicology, Augusta University, Augusta, Georgia.
FAU - Tao, Ailin
AU  - Tao A
AD  - The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, 
      Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Guangzhou 
      Medical University, Guangzhou, Guangdong, China.
FAU - Ramos, Joe W
AU  - Ramos JW
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Moisyadi, Stefan
AU  - Moisyadi S
AD  - Institute for Biogenesis Research, John A. Burns School of Medicine, University 
      of Hawaii, Honolulu, Hawaii.
FAU - Holcombe, Randall F
AU  - Holcombe RF
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Jia, Wei
AU  - Jia W
AD  - Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
FAU - Birnbaumer, Lutz
AU  - Birnbaumer L
AD  - Neurobiology Laboratory, National Institute of Environmental Health Sciences, 
      Research Triangle Park, North Carolina; Institute for Biomedical Research 
      (BIOMED), Universidad Catolica Argentina, Buenos Aires, Argentina.
FAU - Zhou, Xiqiao
AU  - Zhou X
AD  - Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, Jiangsu, China. Electronic address: zhouxiqiao@njmu.edu.cn.
FAU - Chu, Wen-Ming
AU  - Chu WM
AD  - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii; The 
      Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, 
      Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Guangzhou 
      Medical University, Guangzhou, Guangdong, China. Electronic address: 
      wchu@cc.hawaii.edu.
LA  - eng
GR  - U01 CA188387/CA/NCI NIH HHS/United States
GR  - R01 GM118915/GM/NIGMS NIH HHS/United States
GR  - P30 GM114737/GM/NIGMS NIH HHS/United States
GR  - Z01 ES101643/ImNIH/Intramural NIH HHS/United States
GR  - P20 GM103457/GM/NIGMS NIH HHS/United States
GR  - P30 CA071789/CA/NCI NIH HHS/United States
GR  - R01 AI054128/AI/NIAID NIH HHS/United States
GR  - R01 CA188251/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190302
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Gnai1 protein, mouse)
RN  - 0 (Interleukin-16)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
RN  - EC 3.6.5.1 (Gnai3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Biopsy, Needle
MH  - Carcinogenesis
MH  - Cell Transformation, Neoplastic/*genetics
MH  - Colitis/genetics/*pathology
MH  - Colonic Neoplasms/genetics/*pathology
MH  - Disease Models, Animal
MH  - Down-Regulation/genetics
MH  - Female
MH  - GTP-Binding Protein alpha Subunits, Gi-Go/*genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Immunohistochemistry
MH  - Interleukin-16/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Random Allocation
MH  - Reference Values
MH  - Sensitivity and Specificity
MH  - Signal Transduction/genetics
PMC - PMC6628260
MID - NIHMS1035122
OTO - NOTNLM
OT  - CAC
OT  - IBD
OT  - Mouse Model
OT  - Transcription Factor
COIS- Conflicts of interest The authors disclose no conflicts.
EDAT- 2019/03/06 06:00
MHDA- 2019/06/30 06:00
PMCR- 2020/06/01
CRDT- 2019/03/06 06:00
PHST- 2018/05/08 00:00 [received]
PHST- 2019/02/06 00:00 [revised]
PHST- 2019/02/28 00:00 [accepted]
PHST- 2019/03/06 06:00 [pubmed]
PHST- 2019/06/30 06:00 [medline]
PHST- 2019/03/06 06:00 [entrez]
PHST- 2020/06/01 00:00 [pmc-release]
AID - S0016-5085(19)32508-9 [pii]
AID - 10.1053/j.gastro.2019.02.040 [doi]
PST - ppublish
SO  - Gastroenterology. 2019 Jun;156(8):2297-2312. doi: 10.1053/j.gastro.2019.02.040. 
      Epub 2019 Mar 2.