Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis

doi:10.1016/j.stem.2020.01.020

. 2020 May 7;26(5):739-754.e8.

doi: 10.1016/j.stem.2020.01.020. Epub 2020 Mar 5.

Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis

Wenju Chang¹, Hongshan Wang², Woosook Kim³, Yang Liu⁴, Huan Deng⁵, Haibo Liu³, Zhengyu Jiang³, Zhengchuan Niu⁶, Weiwei Sheng³, Osmel Companioni Nápoles³, Yihong Sun⁷, Jianmin Xu⁸, Antonia Sepulveda⁹, Yoku Hayakawa¹⁰, Adam J Bass⁴, Timothy C Wang¹¹

Affiliations

¹ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Colorectal Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
² Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; Gastric Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
⁴ Division of Molecular and Cellular Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02138, USA.
⁵ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; The Fourth Affiliated Hospital of Nanchang University, Nanchang 330003, China.
⁶ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
⁷ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Gastric Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁸ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Colorectal Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁹ Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
¹⁰ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
¹¹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.

PMID: 32142681
PMCID: PMC7214188
DOI: 10.1016/j.stem.2020.01.020

Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis

Wenju Chang et al. Cell Stem Cell. 2020.

. 2020 May 7;26(5):739-754.e8.

doi: 10.1016/j.stem.2020.01.020. Epub 2020 Mar 5.

Authors

Affiliations

¹ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Colorectal Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
² Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; Gastric Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
⁴ Division of Molecular and Cellular Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02138, USA.
⁵ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; The Fourth Affiliated Hospital of Nanchang University, Nanchang 330003, China.
⁶ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
⁷ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Gastric Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁸ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Colorectal Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁹ Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
¹⁰ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
¹¹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.

PMID: 32142681
PMCID: PMC7214188
DOI: 10.1016/j.stem.2020.01.020

Abstract

Cancer is believed to arise from stem cells, but mechanisms that limit the acquisition of mutations and tumor development have not been well defined. We show that a +4 stem cell (SC) in the gastric antrum, marked by expression of Cck2r (a GPCR) and Delta-like ligand 1 (DLL1), is a label-retaining cell that undergoes predominant asymmetric cell division. This +4 antral SC is Notch1^low/ Numb⁺ and repressed by signaling from gastrin-expressing endocrine (G) cells. Chemical carcinogenesis of the stomach is associated with loss of G cells, increased symmetric stem cell division, glandular fission, and more rapid stem cell lineage tracing, a process that can be suppressed by exogenous gastrin treatment. This hormonal suppression is associated with a marked reduction in gastric cancer mutational load, as revealed by exomic sequencing. Taken together, our results show that gastric tumorigenesis is associated with increased symmetric cell division that facilitates mutation and is suppressed by GPCR signaling.

Keywords: Cck2r; asymmetric division; carcinogenesis; gastric neoplasm; gastrin; gene mutation; notch signaling; stem cell; symmetric division.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1.. Antral +4 Cck2r⁺ stem cells are DLL1⁺ and Numb⁺.**
(A) *Cck2r* labels + 4 stem cells. Immunofluorescence of antral sections from induced *Cck2r*-CreERT;*R26*-tdTomato mice stained with DAPI (white), anti-Cck2r antibody (green), and tdTomato⁺ (red). Day1 (left), Day 2 (middle), Day 14 (right). (B) Co-localization of Cck2r⁺ cells (red) and Lgr5-GFP⁺ cells (green) in the antrum of induced *Lgr5*-DTR-GFP;*Cck2r*-CreERT;*R26*-tdTomato mice on Day 1 without DT (left). Lineage tracing from Cck2r⁺ antral cells at Day 3 after TAM and DT-mediated Lgr5⁺ cell ablation (right). (C) Confocal images of immunostained organoids from single *Cck2r*⁺ antral cells (red) from *Cck2r*-CreERT;R26-tdTomato mice. Organoids were stained for MUC5AC (green), Chromogranin A (ChgA, green) or Gastrin (green). Left three panels: White arrows show positive immunostained cells. Right: arrow shows pit cells stained with periodic acid-Schiff (PAS red). (D) Cck2r⁺ cells express DLL1. Relative mRNA expression (qPCR) levels of DLL1 and other genes in sorted single *Cck2r*-CreERT⁺ cells and *Lgr5*-GFP⁺ cells. Cells are sorted from *Cck2r*-CreERT;R26-tdTomato mice on Day 1 after TAM. Data are expressed as mean ± SD of three independent experiments. (E) Imunofluorescent staining of antral sections for DLL1 and Cck2r (left), and for DLL1 of *Lgr5*-DTR-GFP antral sections (right). Yellow arrows show double positive cells. (F) Cck2r⁺ cells are Numb⁺. Numb antibody staining of antral sections from *Cck2r*-CreERT;*R26*-tdTomato mice (left; n=4) and *Lgr5*-DTR-GFP mice (right; n=4). Mice were sacrificed 24h after TAM. Yellow arrows show double positive cells. (G) Quantitation by cell position of Numb⁺ cells and Numb⁺*Cck2r*-CreERT⁺ cells in antral glands at 24h after TAM of *Cck2r*-CreERT;*R26*-tdTomato mice (n=4). Twenty-five antral glands were analyzed per mouse. Data are expressed as mean ± SD. (H) The percentage of Numb⁺ cells in *Cck2r*-CreERT⁺ cells (n=100) and *Lgr5*-GFP⁺ cells (n=100), based on immunostaining from *Cck2r*-CreERT;*R26*-tdTomato and *Lgr5*-DTR-GFP mice. Data are expressed as mean ± SD. (I) Representative images of *Cck2r*-CreERT⁺ traced paired-cells with Numb immunostaining from antral sections of *Cck2r*-CreERT;*R26*-tdTomato mice (n=4), showing segregation of Numb protein at Day 2 after TAM. (J) The proportion of asymmetric (AD, black) and symmetric (SD, red) cell division in *Cck2r*-CreERT⁺/Numb⁺ paired-cells in antral glands *in vivo* from *Cck2r*-CreERT;*R26*-tdTomato mice (n=3). Data are expressed as mean ± SD of 150 paired cells from three mice. Scale bars represent 25μm (C) and 10μm (A, B, E, F and I). *P<0.05, **P<0.01, ***P<0.001. See also Figure S1.

**Figure 2.. Antral +4 stem cells are label retaining cells, undergo asymmetric cell division, and are regulated by gastrin.**
(A) *Cck2r*-CreERT⁺ cells undergo predominant asymmetric cell division. *Cck2r*-CreERT⁺ antral cells from *Cck2r*-CreERT;*R26*-tdTomato mice were sorted as single cells, cultured *in vitro,* and paired-cells then analyzed using immunofluorescent staining for Numb (green) (Bu et al., 2013; Bultje et al., 2009). (B) The percentage of Cck2r⁺ stem cells undergoing symmetric division (Numb⁺/Numb⁺, C/C; 18.9%), asymmetric division (Numb⁺/Numb⁻, C/D; 70.8%) and two Numb⁻ (D/D; 10.3%) in Figure 2A. Data are expressed as mean ± SD of three independent experiments, and a total 106 *Cck2r*-CreERT⁺ paired-cells were analyzed. (C) Schematic diagram of the BrdU label retaining protocol in *Cck2r*-CreERT;*R26*-tdTomato mice (n=6). BrdU was given by i.p. injection every 8 hours over 3 days, along with 2 oral gavages of MNU. Following a 2 weeks’ washout period and 24h after TAM, BrdU staining was performed on antral sections. (D) Quantitation by cell position of BrdU⁺ label retaining cells (LRCs) in the gastric antrum. (E) Representative images of Brdu⁺/Cck2r⁺ LRCs in the gastric antrum of *Cck2r*-CreERT;*R26*-tdTomato mice. (F) Schematic diagram showing the protocol for gastrin infusion via osmotic pump, followed by TAM. (ns: nature saline) (G) Immunostaining for EdU (green) in *Cck2r*-CreERT;*R26*-tdTomato mice treated with vehicle (middle), gastrin pump (10 nmol/Kg/hour, for 4 weeks) (right), and crossed to GAS-KO mice (left). Lineage tracing (red) from Cck2r⁺ cells was observed at day 7 after TAM (n=4 mice per group). (H-I) Quantification of EdU⁺ labeled cells (shown in G) as a percentage (%) of *Cck2r*-CreERT⁺ traced cells per antrum gland (H) and linage tracing events per gland from *Cck2r*-CreERT⁺ cells (I) in the three groups of mice. Ten antral glands were analyzed per mouse. Data are expressed as mean ± SD. (J) Lineage tracing from *Lgr5*-CreERT;*R26*-tdTomato mice treated with gastrin infusion (10 nmol/Kg/hour) or vehicle at day 4 (n=4) and day 6 (n=4) after induction. (K) Quantification of tracing ratio of *Lgr5*-CreERT⁺ cells in (I). Twenty-five antral glands are analyzed per mouse. Data are expressed as mean ± SD. Scale bars represent 10 μm (E) and 50 μm (G, J). *P<0.05, **P<0.01. See also Figure S2.

**Figure 3.. Antral +4 stem cells are regulated by Notch indirectly through niche gastrin cells.**
(A) Representative images of Ki67 stained antral epithelium in vehicle treated mice, DBZ treated mice (5 doses) and *Eef1a1*-LSL-*Notch1(IC)* mice (Notch1(IC) mice). Each group had 4 mice. (B) Immunofluorescent images of DAPI-stained antral gastric sections from *Lgr5*-DTR-GFP mice treated with vehicle or DBZ, or *Lgr5*-DTR-GFP crossed to Notch1(IC) mice (n=4 per group). (C) Quantification by FACS of Cck2r⁺ cells after Notch modulation in *Cck2r*-CreERT;*R26*-tdTomato mice. FACS plots showing relative numbers of Cck2r⁺ cells (red) in vehicle treated mice, DBZ treated mice or *Cck2r*-CreERT crossed to Notch1(IC) mice at 24h after TAM. (D) Quantification of lineage tracing events/gland in *Cck2r*-CreERT;*R26*-tdTomato mice treated with DBZ or vehicle, or crossed to Notch1(IC) mice on Day 7 after TAM (n=4 per group). (E) *Cck2r*, *Lgr5*, *Dll1*, *Notch1* and *Gastrin* gene expression levels as measured by qPCR in three groups of mice from (D). data are expressed as mean ± SD. (F) Representative images of antral sections from *Cck2r*-CreERT;*R26*-tdTomato mice immunostained for gastrin (green) and DAPI (blue). Mice were treated with DBZ or vehicle, or crossed to Notch1(IC) mice on Day 7 after TAM (n=4 per group). (G) Quantification of gastrin⁺ cell numbers in the three groups of mice from (F). Twenty-five antral glands are analyzed per mouse. (H) Representative lineage tracing at day 7 post-TAM in *Cck2r*-CreERT;*R26*-tdTomato mice treated with DBZ, vehicle, or with DBZ after crosses to GAS-KO mice, n=4 per group. (I) Quantification of Cck2r tracing events per gland in the three groups of mice in (H). Twenty-five antral glands are analyzed per mouse. (J) Gastrin suppresses proliferation of antral spheroids in 3D culture in vitro. Representative images of double staining for E-cadherin (green) and EdU (red) of antral spheroids cultured with or without gastrin (G-17, 0 nM or 100 nM). (K) Quantification of the percentage of EdU⁺ cells in response to four different gastrin concentrations. Data are expressed as mean ± SD of three independent experiments. (L) Effect of gastrin on colony-forming unit (CFU) efficiency from single *Cck2r*-CreERT⁺ cells. CFU was calculated for each of the three groups as the percentage of colonies/ total number of seeded cells. The three groups included Cck2r⁺ cells treated with vehicle, gastrin (100 nM), or gastrin + YF476 (1 uM) in the culture medium, respectively. Data are expressed as mean ± SD of three independent experiments. Scale bars represent 50 μm (J), 25 μm (A, B, H and K) and 10 μm (F). *P<0.05, **P<0.01, ***P<0.001. See also Figure S2, S3.

**Figure 4.. Cck2r⁺ cells give rise to intestinal-type metaplasia and cancer**
(A) Beta-catenin immunohistochemical staining of antral sections from *Cck2r*-CreERT;Rd 26-tdTomato;*Apc*^flox/flox mice at Day 3 to Day 28 after TAM. Black arrows show accumulation of β-catenin (brown). Red arrows indicate β-catenin⁺ gastric adenomas, which express high levels of Ki67 (blue arrow). (B) Gross image of macroscopic tumors (black arrow) from *Cck2r*-CreERT;*R26*-tdTomato;*Apc*^flox/flox mice at 4 month after TAM. (C) Representative images of antral sections from *Cck2r*-CreERT;*R26*-tdTomato;Apc^flox/flox mice at 4 months post TAM. TdTomato lineage tracing (left, red), Alcian Blue staining (middle, blue), and β-catenin immunostaining (right, brown) in tumors. (D) H&E staining of antral sections from *Cck2r*-CreERT;*R26*-tdTomato;*Apc*^flox/flox mice at 4 months after TAM. Inset boxes show high power magnification, demonstrating dysplasia in antrum glands. (E) Representative immunofluorescence image from corpus gland in *Cck2r*-CreERT;*R26*-tdTomato mice at 24h after TAM, showing abundant single recombined cells (in red), with immunostaining for H/K-ATPase-expressing parietal cells shown in green. Yellow arrows indicate Cck2r-expressing parietal cells. (F) Representative H&E stained section (left) and immunofluorescence image (right) from *Cck2r*-CreERT;*R26*-tdTomato;*Apc*^flox/flox; LSL-*Trp53*^R172H mice at 2 month after TAM. Scale bars represent 10 μm (A, D, F), and 50 μm (B, E), and 100 um (C). Data are expressed as mean ± SD; * P<0.05, ** P<0.01, *** P<0.001.

**Figure 5.. Gastric carcinogenesis promotes Cck2r⁺ symmetric cell division and stem cell expansion, which are suppressed by gastrin.**
(A) Schematic diagram of protocol used for carcinogenesis studies in *Cck2r*-CreERT mice. Mice were treated with vehicle, MNU or gastrin, or both MNU and gastrin, and sacrificed at D1, D3 and D7 after TAM. (B) Representative immunofluorescent images of antral glands showing *Cck2r*-CreERT⁺ paired cells (red) with Ki67 antibody staining (white) at 24 hours after TAM and MNU treatment. DAPI (blue). (C) Representative immunofluorescence images of antral glands from *Cck2r*-CreERT;*R26*-tdTomato mice showing paired cells (red) at 24 hours after TAM, with MNU or without MNU (Vehicle) treatment. DAPI (white). Inset shows higher power image of paired cells. (D) The ratio (or percentage) of *Cck2r*-CreERT⁺ paired cells over the total recombined cells in *Cck2r*-CreERT;*R26*-tdTomato mice and GAS-KO; *Cck2r*-CreERT;*R26*-tdTomato mice, when treated with gastrin, MNU, neither or both. and twenty-five antral glands were analyzed for each mouse, n=4 per group. Data are expressed as mean ± SD. (E) Representative immunofluorescent images of antral glands from *Cck2r*-CreERT;*R26*-tdTomato mice showing *Cck2r*-CreERT⁺ paired cells with Numb staining (green), with symmetric cell division (red arrows) at 24 hours after TAM and MNU treatment. Inset shows higher power image of paired cells. (F) Proportion of symmetric division (SD, red) and asymmetric division (AD, yellow) among *Cck2r*-CreERT⁺/Numb⁺ paired cells in Numb-stained antral gland sections from *Cck2r*-CreERT;*R26*-tdTomato (WT) mice and GAS-KO; *Cck2r*-CreERT;*R26*-tdTomato mice. Mice were treated with gastrin infusion, MNU, neither or both, and sacrificed at 24 hours after TAM. Total 100 paired-cells were analyzed for each mouse, n=4 per group. Data are expressed as mean ± SD. (G) Effect of MNU on cell division of single sorted Cck2r⁺ cells *in vitro* by paired-cell analysis. Bar graph showing the relative proportion of cell pairs with two Numb⁺ (C/C), one Numb⁺ (C/D) or two Numb⁻ (D/D) cells, following in vitro culture and Numb immunostaining. *Cck2r*-CreERT;*R26*-tdTomato mice were divided into three groups (vehicle, MNU treatment and MNU + gastrin treatment, n=4 per group). *Cck2r*-tdTomato⁺ cells were isolated by FACS, and paired-cells were analyzed from vehicle-treated mice (n=75 paired cells), MNU-treated mice (n=45 paired cells), MNU plus gastrin mice (n=40 paired cells). (H) The effect of gastrin on number of Numb⁺ AGS-E cells following in vitro culture. Data are expressed as mean ± SD of three independent experiments. (I) Effect of gastrin on the percentage of asymmetric divisions (AD) in AGS-E paired-cells based on Numb immunostaining. Data are expressed as mean ± SD of three independent experiments and total 45, 50, 40 and 45 AGS-E paired-cells were calculated for gastrin 0, 0.1, 1 and 10 mmol/L, respectively. Scale bars represent 100 μm (A) and 10 μm (B, C and E). *P<0.05, **P<0.01, ***P<0.001. See also Figure S5.

**Figure 6.. Antral gastric mutagenesis and tumorigenesis are suppressed by gastrin.**
(A) Schematic diagram of experimental protocol that includes TAM induction, *H. felis* infection, MNU treatment, and gastrin infusion in *Cck2r*-CreERT;*R26*-tdTomato mice and GAS-KO;*Cck2r*-CreERT; *R26*-tdTomato mice. (B) Histopathologic features with lineage tracing of gastric tumors in MNU-treated *Cck2r*-CreERT;*R26*-tdTomato mice at 36 weeks. Top shows H&E stained sections, while bottom show immunofluorescence microscopy images of tdTomato expression. Hyperplastic polyp (left); Adenoma (middle); Adenocarcinoma (right). (C) Representative gross images of resected stomachs with tumors from *Cck2r*-CreERT mice and GAS-KO;*Cck2r*-CreERT mice treated with *H. felis* infection and 5 cycles of MNU. Mice from each genotype were treated with either a gastrin pump or a vehicle pump, and sacrificed at 36 weeks after start of MNU, n=10 per group. (D) Tumor number (left) and maximum tumor size (right) from the four groups of mice shown in (C). (E) Proportion of mice with the most advanced histopathology in the four groups of mice shown in (C). Mice were classified according to the histologic grade of the most advanced tumor. (F) The percentage of Cck2r⁺ cells that were also Ki67⁺ (i.e. double positive cells) from GAS-KO;*Cck2r*-CreERT; *R26*-tdTomato mice, induced with tamoxifen and treated with *H. felis* infection and 5 cycles of MNU gavage. Mice received infusion with either gastrin pump (blue) or vehicle pump (red), and were sacrificed at 18 or 36 weeks. Ten random high power filed are analyzed per mouse, n=3 per group. Data are expressed as mean ± SD. (G) Representative immunofluorescence images of *Cck2r*-CreERT;*R26*-tdTomato glands following TAM. Left shows normal antral gland with lineage tracing, while right shows representative Cck2r⁺ cell-derived crypt fission image (yellow arrow). (H) The ratio of CreERT-traced gland fission events per total glands in the four groups of mice. *Cck2r*-CreERT mice and GAS-KO;*Cck2r*-CreERT mice were treated with gastrin pump or vehicle and analyzed 18 weeks after the start of MNU treatment. Total 50 labelled crypts per mouse were measured. Data are expressed as mean ± SD. Scale bars represent 50 μm (B) and 10 μm (G). *P<0.05, **P<0.01. See also Figure S6.

**Figure 7.. Decreased gastrin expression is associated with progression of human gastric antral neoplasia.**
(A) Immunohistochemical expression of gastrin in gastric antral preneoplastic lesions and gastric antral cancer. Patients with non-atrophic gastritis (n=10), atrophic gastritis (n=15), hyperplastic polyp (n=15), adenocarcinoma (n=10). Right panel shows a section of adjacent nontumorous tissue with rare gastrin⁺ cells (yellow arrows), while tumor is shown with black arrows. (B) Quantification of gastrin⁺ cells per high power field in the four groups of patients shown in (A). (C) Relationship between serum gastrin level and tumor location in patients with gastric cancer. Dot plot graph show gastrin levels (pg/ml) in patients with corpus cancer (n=13), antrum cancer (n=24), and healthy controls (n=20). (D) The average number of mutations in tumors from GAS-KO (n=5) and WT mice (n=7), based on exome sequencing. (E) Spectrum of mutations in antral tumors developing in GAS-KO mice compared to WT mice. Bar graph showing quantification and comparisons of major classes (missense, silence, nonsense and splice site) of exome mutations in antral tumors between GAS-KO (n=5) and WT (n=7) mice. (F, G) Bar graph showing quantification of mutations for two prominent COSMIC mutational signatures in GAS-KO (n=5) versus WT (n=7) antral tumors. Scale bars represent 50 μm (A). Data are expressed as the mean ± SD * P<0.05, ** P<0.01, *** P<0.001. See also Figure S6.

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Comment in

Gastrin Blocks Symmetric Stem-Cell Division and Gastric Tumorigenesis.
[No authors listed] [No authors listed] Cancer Discov. 2020 May;10(5):OF5. doi: 10.1158/2159-8290.CD-RW2020-038. Epub 2020 Mar 13. Cancer Discov. 2020. PMID: 32169876

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[1] Ai W, Liu Y, Langlois M, and Wang TC (2004). Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements. J Biol Chem 279, 8684–8693. - PubMed

[2] Ai W, Liu Y, Langlois M, and Wang TC (2004). Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements. J Biol Chem 279, 8684–8693. - PubMed

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Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis

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Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis

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