Id2 deletion attenuates <i>Apc</i>-deficient ileal tumor formation

Biyajima, Kyoko; Kakizaki, Fumihiko; Shen, Xiaodong; Mori, Kentaro; Sugai, Manabu; Taketo, Makoto Mark; Yokota, Yoshifumi

doi:10.1242/bio.012252

Cited by 4 publications

(5 citation statements)

References 31 publications

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“…APC mutation occurs in most human colorectal cancers. We recently reported that Id2 is involved in the tumor initiation process, and Id2 deficiency does not promote carcinogenesis of intestinal adenoma induced by Apc gene mutation ( 43 ). In addition, we observed no carcinoma development until 20 weeks of age.…”

Section: Discussionmentioning

confidence: 99%

Id2 Determines Intestinal Identity through Repression of the Foregut Transcription Factor Irx5

Mori

Nakamura

Kurooka

et al. 2018

Molecular and Cellular Biology

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The cellular components and function of the gastrointestinal epithelium exhibit distinct characteristics depending on the region, e.g., stomach or intestine. How these region-specific epithelial characteristics are generated during development remains poorly understood. Here, we report on the involvement of the helix-loop-helix inhibitor Id2 in establishing the specific characteristics of the intestinal epithelium. Id2−/− mice developed tumors in the small intestine. Histological analysis indicated that the intestinal tumors were derived from gastric metaplasia formed in the small intestine during development. Heterotopic Id2 expression in developing gastric epithelium induced a fate change to intestinal epithelium. Gene expression analysis revealed that foregut-enriched genes encoding Irx3 and Irx5 were highly induced in the midgut of Id2−/− embryos, and transgenic mice expressing Irx5 in the midgut endoderm developed tumors recapitulating the characteristics of Id2−/− mice. Altogether, our results demonstrate that Id2 plays a crucial role in the development of regional specificity in the gastrointestinal epithelium.

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Section: Discussionmentioning

confidence: 99%

Id2 Determines Intestinal Identity through Repression of the Foregut Transcription Factor Irx5

Mori

Nakamura

Kurooka

et al. 2018

Molecular and Cellular Biology

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“…MAX dimerization protein 1 (MXD1) belongs to the MAX dimerization protein family of proteins, which function as potent antagonists of c-Myc (Thomas et al, 2015). MXD1 contributes to tumor initiation in various tissues (Biyajima et al, 2015). However, the roles of MXD1 in lung cancer remain largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

An Aging-Related Gene Signature-Based Model for Risk Stratification and Prognosis Prediction in Lung Adenocarcinoma

Chen

2021

Front. Cell Dev. Biol.

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Aging is an inevitable time-dependent process associated with a gradual decline in many physiological functions. Importantly, some studies have supported that aging may be involved in the development of lung adenocarcinoma (LUAD). However, no studies have described an aging-related gene (ARG)-based prognosis signature for LUAD. Accordingly, in this study, we analyzed ARG expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). After LASSO and Cox regression analyses, a six ARG-based signature (APOC3, EPOR, H2AFX, MXD1, PLCG2, and YWHAZ) was constructed using TCGA dataset that significantly stratified cases into high- and low-risk groups in terms of overall survival (OS). Cox regression analysis indicated that the ARG signature was an independent prognostic factor in LUAD. A nomogram based on the ARG signature and clinicopathological factors was developed in TCGA cohort and validated in the GEO dataset. Moreover, to visualize the prediction results, we established a web-based calculator yurong.shinyapps.io/ARGs_LUAD/. Calibration plots showed good consistency between the prediction of the nomogram and actual observations. Receiver operating characteristic curve and decision curve analyses indicated that the ARG nomogram had better OS prediction and clinical net benefit than the staging system. Taken together, these results established a genetic signature for LUAD based on ARGs, which may promote individualized treatment and provide promising novel molecular markers for immunotherapy.

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“…2E). Gene sets associated with upregulation of ID1 and ID2, HLH factors that counteract E protein activity and increase stemness in intestinal homeostasis and cancer 40,[88][89][90][91][92][93] , were not enriched. These data demonstrated a strong induction of E protein-mediated transcription in the absence of repression by MTG16.…”

Section: Mtg16 Is Required For Attenuation Of E Protein Activity In the Colonmentioning

confidence: 99%

“…2E, Table S3). Gene sets associated with upregulation of Id1 and Id2, which counteract E protein activity and increase stemness in colon cancer (23,(49)(50)(51)(52), were not enriched (Fig. 2E).…”

Section: Mtg16-driven Goblet Cell Differentiation Is Dependent On Its...mentioning

confidence: 99%

MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

Brown

Jacobse

Anant

et al. 2021

Preprint

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Aberrant epithelial differentiation and regeneration pathways contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 interaction partners include E box-binding basic helix-loop-helix transcription factors (E proteins). MTG16-deficient mice exhibit worse colitis and increased tumor burden in inflammatory carcinogenesis. In this study, we sought to understand the role of MTG16 colonic epithelial homeostasis and the mechanisms by which MTG16 protects the epithelium in colitis and CAC. We demonstrated that MTG16 deficiency enabled enteroendocrine cell differentiation from secretory precursor cells at the expense of goblet cells. Transcriptomic analysis implicated dysregulated E protein function in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation (Mtg16P209T), we established that enteroendocrine:goblet cell balance was dependent on MTG16:E protein interactions and that the shift in lineage allocation was associated with enhanced expression of Neurog3, the central driver of enteroendocrine lineage specification. Furthermore, Mtg16 was upregulated in the previously described Ascl2+, de-differentiating cells that replenish the stem cell compartment in response to colon injury. Mtg16 expression was also increased in dextran sulfate sodium (DSS)-treated mouse colon crypts and in IBD patients compared to unaffected controls. We determined that the effects of MTG16 in regeneration are also dependent on its repression of E proteins, as the colonic epithelium failed to regenerate following DSS-induced injury in our novel mutant mouse model. Finally, we revealed that uncoupling MTG16:E protein interactions contributes to the enhanced tumorigenicity in Mtg16-/- colon in the azoxymethane(AOM)/DSS-induced model of CAC. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colonic differentiation and regeneration.

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Id2 deletion attenuates Apc-deficient ileal tumor formation

Cited by 4 publications

References 31 publications

Id2 Determines Intestinal Identity through Repression of the Foregut Transcription Factor Irx5

Id2 Determines Intestinal Identity through Repression of the Foregut Transcription Factor Irx5

An Aging-Related Gene Signature-Based Model for Risk Stratification and Prognosis Prediction in Lung Adenocarcinoma

MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

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