PUBLICATION

Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression

Authors

Jung, I.H., Jung, D.E., Chung, Y.Y., Kim, K.S., Park, S.W.

ID

ZDB-PUB-190827-4

Date

2019

Source

Neoplasia (New York, N.Y.) 21: 1003-1014 (Journal)

Registered Authors

Park, Seung Woo

Keywords

none

MeSH Terms

Phenotype
Cell Cycle/genetics*
Cell Transformation, Neoplastic/genetics
Cell Transformation, Neoplastic/metabolism
Immunophenotyping
Genes, Tumor Suppressor*
Organ Specificity/genetics
Cell Line, Tumor
Homeodomain Proteins/genetics*
Homeodomain Proteins/metabolism
Humans
Gene Expression
Gene Targeting
Gene Knockout Techniques
Immunohistochemistry
Zebrafish
Gene Expression Profiling
Genetic Loci
Animals
Transcription Factors/genetics*
Transcription Factors/metabolism

(all 21)

PubMed

31450023 Full text @ Neoplasia

Abstract

Iroquois homeobox 1 (IRX1) belongs to the Iroquois homeobox family known to play an important role during embryonic development. Interestingly, however, recent studies have suggested that IRX1 also acts as a tumor suppressor. Here, we use homozygous knockout mutants of zebrafish to demonstrate that the IRX1 gene is a true tumor suppressor gene and mechanism of the tumor suppression is mediated by repressing cell cycle progression. In this study, we found that knockout of zebrafish Irx1 gene induced hyperplasia and tumorigenesis in the multiple organs where the gene was expressed. On the other hands, overexpression of the IRX1 gene in human tumor cell lines showed delayed cell proliferation of the tumor cells. These results suggest that the IRX1 gene is truly involved in tumor suppression. In an attempt to identify the genes regulated by the transcription factor IRX1, we performed microarray assay using the cRNA obtained from the knockout mutants. Our result indicated that the highest fold change of the differential genes fell into the gene category of cell cycle regulation, suggesting that the significant canonical pathway of IRX1 in antitumorigenesis is done by regulating cell cycle. Experiment with cell cycle blockers treated to IRX1 overexpressing tumor cells showed that the IRX1 overexpression actually delayed the cell cycle. Furthermore, Western blot analysis with cyclin antibodies showed that IRX1 overexpression induced decrease of cyclin production in the cancer cells. In conclusion, our in vivo and in vitro studies revealed that IRX1 gene functionally acts as a true tumor suppressor, inhibiting tumor cell growth by regulating cell cycle.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
ccnd1	irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	whole organism	RTPCR	Fig. 5
ccne1	irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	whole organism	RTPCR	Fig. 5
cdkn1a	irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	whole organism	RTPCR	Fig. 5
cdkn2a/b	irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	whole organism	RTPCR	Fig. 5
cdkn2c	irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	whole organism	RTPCR	Fig. 5
cdkn2d	irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	whole organism	RTPCR	Fig. 5
il6	irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	whole organism	RTPCR	Fig. 5
irx1a	AB	standard conditions	Long-pec	brain	ISH	Fig. 2
irx1a	AB	standard conditions	Day 5	brain	ISH	Fig. 2
irx1a	AB	standard conditions	Adult	intervillus pockets	ISH	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
irx1a^{zf3177/zf3177} (AB)	standard conditions	Protruding-mouth	embryo development process quality, normal	Fig. 1
irx1a^{zf3177/zf3177} (AB)	standard conditions	Protruding-mouth	whole organism morphology, normal	Fig. 1
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Protruding-mouth	whole organism morphology, abnormal	Fig. 1
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	intestine carcinoma present, abnormal	Fig. 3
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	intestine carcinoma present, abnormal	Fig. 4
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	intrahepatic bile duct carcinoma present, abnormal	Fig. 4
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	kidney carcinoma present, abnormal	Fig. 3
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	ovary cystic, abnormal	Fig. 3
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	pancreas carcinoma present, abnormal	Fig. 4
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)	standard conditions	Adult	testis carcinoma present, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
zf3176		Indel	irx1b
zf3177		Insertion	irx1a

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
cancer			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
irx1a	TALEN1-irx1a	TALEN
irx1b	CRISPR1-irx1b	CRISPR

Fish

Fish
AB
irx1a^{zf3177/zf3177} (AB)
irx1a^{zf3177/zf3177}; irx1b^{zf3176/zf3176} (AB)
irx1b^{zf3176/zf3176} (AB)

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Jung et al., 2019 ZDB-PUB-190827-4 PMID:31450023

Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression

Jung et al., 2019

ZDB-PUB-190827-4
PMID:31450023