Determination of the Potential Tumor-Suppressive Effects of Gsdme in a Chemically Induced and in a Genetically Modified Intestinal Cancer Mouse Model

被引:33
作者
Croes, Lieselot [1 ,2 ]
Fransen, Erik [1 ,3 ]
Hylebos, Marieke [1 ,2 ]
Buys, Kimberly [1 ,2 ]
Hermans, Christophe [2 ]
Broeckx, Glenn [4 ]
Peeters, Marc [2 ,5 ]
Pauwels, Patrick [2 ,4 ]
de Beeck, Ken Op [1 ,2 ]
Van Camp, Guy [1 ,2 ]
机构
[1] Univ Antwerp, Ctr Med Genet, Prins Boudewijnlaan 43-6, BE-2650 Antwerp, Belgium
[2] Univ Antwerp, Ctr Oncol Res, Univ Pl 1, BE-2610 Antwerp, Belgium
[3] Univ Antwerp, StatUa Ctr Stat, Prinsstr 13, BE-2000 Antwerp, Belgium
[4] Antwerp Univ Hosp, Dept Pathol, Wilrijkstr 10, BE-2650 Antwerp, Belgium
[5] Antwerp Univ Hosp, Dept Med Oncol, Wilrijkstr 10, BE-2650 Antwerp, Belgium
关键词
Gsdme; Dfna5; knockout; mouse model; colorectal cancer; intestinal cancer; Apc; AOM; azoxymethane; inflammation; INDUCED COLON TUMORS; DFNA5; GENE; GASTROINTESTINAL-TRACT; PROMOTER METHYLATION; HEARING-LOSS; MICE; CARCINOGENESIS; AZOXYMETHANE; INFLAMMATION; EXPRESSION;
D O I
10.3390/cancers11081214
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Gasdermin E (GSDME), also known as deafness autosomal dominant 5 (DFNA5) and previously identified to be an inducer of regulated cell death, is frequently epigenetically inactivated in different cancer types, suggesting that GSDME is a tumor suppressor gene. In this study, we aimed to evaluate the tumor-suppressive effects of GSDME in two intestinal cancer mouse models. To mimic the silencing of GSDME by methylation as observed in human cancers, a Gsdme knockout (KO) mouse was developed. The effect of GSDME on tumorigenesis was studied both in a chemically induced and in a genetic intestinal cancer mouse model, as strong evidence shows that GSDME plays a role in human colorectal cancer and representative mouse models for intestinal cancer are available. Azoxymethane (AOM) was used to induce colorectal tumors in the chemically induced intestinal cancer model (n = 100). For the genetic intestinal cancer model, Apc1638N/+ mice were used (n = 37). In both experiments, the number of mice bearing microscopic proliferative lesions, the number and type of lesions per mouse and the histopathological features of the adenocarcinomas were compared between Gsdme KO and wild type (WT) mice. Unfortunately, we found no major differences between Gsdme KO and WT mice, neither for the number of affected mice nor for the multiplicity of proliferative lesions in the mice. However, recent breakthroughs on gasdermin function indicate that GSDME is an executioner of necrotic cell death. Therefore, it is possible that GSDME may be important for creating an inflammatory microenvironment around the tumor. This is in line with the trend towards more severe inflammation in WT compared to Gsdme KO mice, that we observed in our study. We conclude that the effect of GSDME in tumor biology is probably more subtle than previously thought.
引用
收藏
页数:20
相关论文
共 52 条
[1]   Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer [J].
Akino, Kimishige ;
Toyota, Minoru ;
Suzuki, Hiromu ;
Imai, Takashi ;
Maruyama, Reo ;
Kusano, Masanobu ;
Nishikawa, Noriko ;
Watanabe, Yoshiyuki ;
Sasaki, Yasushi ;
Abe, Tamaki ;
Yamamoto, Eiichiro ;
Tarasawa, Isao ;
Sonoda, Tomoko ;
Mori, Mitsuru ;
Imai, Kohzoh ;
Shinomura, Yasuhisa ;
Tokino, Takashi .
CANCER SCIENCE, 2007, 98 (01) :88-95
[2]   Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones [J].
Amos-Landgraf, James M. ;
Heijmans, Jarom ;
Wielenga, Mattheus C. B. ;
Dunkin, Elisa ;
Krentz, Kathy J. ;
Clipson, Linda ;
Ederveen, Antwan G. ;
Groothuis, Patrick G. ;
Mosselman, Sietse ;
Muncan, Vanesa ;
Hommes, Daniel W. ;
Shedlovsky, Alexandra ;
Dove, William F. ;
van den Brink, Gijs R. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (46) :16514-16519
[3]  
[Anonymous], 2019, R LANGUAGE ENV STAT
[4]   Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia [J].
Baek, Seung Joon ;
Okazaki, Ryuji ;
Lee, Seong-Ho ;
Martinez, Jeanelle ;
Kim, Jong-Sik ;
Yamaguchi, Kiyoshi ;
Mishina, Yuji ;
Martin, David W. ;
Shoieb, Ahmed ;
Mcentee, Michael F. ;
Eling, Thomas E. .
GASTROENTEROLOGY, 2006, 131 (05) :1553-1560
[5]   TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling [J].
Becker, C ;
Fantini, MC ;
Schramm, C ;
Lehr, HA ;
Wirtz, S ;
Nikolaev, A ;
Burg, J ;
Strand, S ;
Kiesslich, R ;
Huber, S ;
Ito, H ;
Nishimoto, N ;
Yoshizaki, K ;
Nishimoto, N ;
Galle, PR ;
Blessing, M ;
Rose-John, S ;
Neurath, MF .
IMMUNITY, 2004, 21 (04) :491-501
[6]  
Betton G.R., 2001, GASTROINTESTINAL TRA
[7]   Pathology of mouse models of intestinal cancer: Consensus report and recommendations [J].
Boivin, GP ;
Washington, K ;
Yang, K ;
Ward, JM ;
Pretlow, TP ;
Russell, R ;
Besselsen, DG ;
Godfrey, VL ;
Doetschman, T ;
Dove, WF ;
Pitot, HC ;
Halberg, RB ;
Itzkowitz, SH ;
Groden, J ;
Coffey, RJ .
GASTROENTEROLOGY, 2003, 124 (03) :762-777
[8]   Large-scale analysis of DFNA5 methylation reveals its potential as biomarker for breast cancer [J].
Croes, Lieselot ;
Beyens, Matthias ;
Fransen, Erik ;
Ibrahim, Joe ;
Berghe, Wim Vanden ;
Suls, Arvid ;
Peeters, Marc ;
Pauwels, Patrick ;
Van Camp, Guy ;
de Beeck, Ken Op .
CLINICAL EPIGENETICS, 2018, 10
[9]  
Croes L, 2017, ONCOTARGET, V8, P31948, DOI 10.18632/oncotarget.16654
[10]  
de Beeck KO, 2012, ANN OTO RHINOL LARYN, V121, P197