Reference SummaryLiu X, Gastroenterology 2017 Dec;153(6):1607-1620

Title

BMI1 and MEL18 Promote Colitis-Associated Cancer in Mice via REG3B and STAT3.

Authors

Liu X; Wei W; Li X; Shen P; Ju D; Wang Z; Zhang R; Yang F; Chen C; Cao K; Zhu G; Chen H; Chen L; Sui J; Zhang E; Wu K; Wang F; Zhao L; Xi R

Journal

Gastroenterology

Volume

153

Issue

6

Year

2017

Pages

1607-1620

Abstract

BACKGROUND & AIMS: Polycomb group proteins are epigenetic factors that silence gene expression; they are dysregulated in cancer cells and contribute to carcinogenesis by unclear mechanisms. We investigated whether BMI1 proto-oncogene, polycomb ring finger (BMI1), and polycomb group ring finger 2 (PCGF2, also called MEL18) are involved in the initiation and progression of colitis-associated cancer (CAC) in mice. METHODS: We generated mice containing floxed alleles of Bmi1 and/or Mel18 and/or Reg3b using the villin-Cre promoter (called Bmi1(DeltaIEC), Mel18(DeltaIEC), DKO, and TKO mice). We also disrupted Bmi1 and/or Mel18 specifically in intestinal epithelial cells (IECs) using the villin-CreER(T2)-inducible promoter. CAC was induced in cre-negative littermate mice (control) and mice with conditional disruption of Bmi1 and/or Mel18 by intraperitoneal injection of azoxymethane (AOM) followed by addition of dextran sulfate sodium (DSS) to drinking water. Colon tissues were collected from mice and analyzed by histology and immunoblots; IECs were isolated and used in cDNA microarray analyses. RESULTS: Following administration of AOM and DSS, DKO mice developed significantly fewer polyps than control, Bmi1(DeltaIEC), Mel18(DeltaIEC), Reg3b(DeltaIEC), or TKO mice. Adenomas in the colons of DKO mice were low-grade dysplasias, whereas adenomas in control, Bmi1(DeltaIEC), Mel18(DeltaIEC), Reg3b(DeltaIEC), or TKO mice were high-grade dysplasias with aggressive invasion of the muscularis mucosa. Disruption of Bmi1 and Mel18 (DKO mice) during late stages of carcinogenesis significantly reduced the numbers of large adenomas and the load of total adenomas, reduced proliferation, and increased apoptosis in colon tissues. IECs isolated from DKO mice after AOM and DSS administration had increased expression of Reg3b compared with control, Bmi1(DeltaIEC), or Mel18(DeltaIEC) mice. Expression of REG3B was sufficient to inhibit cytokine-induced activation of STAT3 in IECs. The human REG3beta protein, the functional counterpart of mouse REG3B, inhibited STAT3 activity in human 293T cells, and its expression level in colorectal tumors correlated inversely with pSTAT3 level and survival times of patients. CONCLUSIONS: BMI1 and MEL18 contribute to the development of CAC in mice by promoting proliferation and reducing apoptosis via suppressing expression of Reg3b. REG3B negatively regulates cytokine-induced activation of STAT3 in colon epithelial cells. This pathway might be targeted in patients with colitis to reduce carcinogenesis.

Links

J:262366 – Mouse Genome Informatics
28780076 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6 Intestine - Large Intestine - Colon adenoma
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenoma
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenoma
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenoma
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Reg3bem1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenoma
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Reg3bem1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenoma
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6 Intestine - Large Intestine - Colon dysplasia - high grade
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon dysplasia - high grade
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon dysplasia - high grade
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon dysplasia - low grade
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6 Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6 Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • tamoxifen (TAM)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6 Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
  • tamoxifen (TAM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Tg(Vil1-cre/ERT2)23Syr Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Tg(Vil1-cre/ERT2)23Syr Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

observed

C57BL/6-Cdkn2atm4Rdp Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Cdkn2atm4Rdp Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Cdkn2atm4Rdp Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6- Cdkn2atm4Rdp Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Reg3bem1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Reg3bem1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon polyp
  • dextran sulfate sodium (DSS)
  • azoxymethane (AOM)
Intestine - Large Intestine - Colon

observed

C57BL/6 Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

0

C57BL/6-Bmi1tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

0

C57BL/6-Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

0

C57BL/6-Bmi1tm1Rxi Pcgf2tm1Rxi Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

0