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 Table of Contents  
MINI REVIEW
Year : 2017  |  Volume : 3  |  Issue : 1  |  Page : 29-33

The genomic organization and function of IRX1 in tumorigenesis and development


1 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
3 Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
4 Cipher Ground, North Brunswick, NJ, USA
5 Department of Administrative, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
6 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Date of Submission01-Oct-2016
Date of Acceptance16-Jan-2017
Date of Web Publication23-Feb-2017

Correspondence Address:
Yanyang Tu
Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, No.569, Xinsi Road, Xi'an 710038, Shaanxi

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.200856

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  Abstract 

Iroquois homeobox (IRX), containing transcription factor family of homologous genes and proteins, is widely expressed in both vertebrates and invertebrates embryonic tissue expression profiles. They play a crucial role in the regionalization and patterning of tissues and organs during metazoan development. IRX1, belonging to the IRX gene family, codes for active proteins involved in the development of vertebrate nervous system and plays an important role in the development of various other organs during embryo development. It also plays a critical role in the tumor formation and is identified as both the oncogene or tumor suppressor gene in a variety of tumors. This review summarizes the recent discoveries on the genomic structure of IRX1 and the type classification in different species. More specifically, we focused on explaining the key role of IRX1 in tumorigenesis, and development of tumor and influence in biological processes of metazoans, which we hope will provide a better understanding of the mechanism of IRX1.

Keywords: Genomic organization, IRX1, tumor biomarker, tumorigenesis and development


How to cite this article:
Zhang P, Yang H, Wang X, Wang L, Cheng Y, Zhang Y, Tu Y. The genomic organization and function of IRX1 in tumorigenesis and development. Cancer Transl Med 2017;3:29-33

How to cite this URL:
Zhang P, Yang H, Wang X, Wang L, Cheng Y, Zhang Y, Tu Y. The genomic organization and function of IRX1 in tumorigenesis and development. Cancer Transl Med [serial online] 2017 [cited 2017 Oct 21];3:29-33. Available from: http://www.cancertm.com/text.asp?2017/3/1/29/200856


  Introduction Top


Iroquois homeobox (IRX) genes were first found in Drosophilamelanogaster and encoded a family of homeoproteins spread from nematodes to humans.[1],[2],[3],[4] IRX1, belonging to the IRX gene family, demonstrates a pattern formation in the embryo, and in combination with few transcription factors (TFs), codes for the proteins associated with nervous system development.[5] IRX1 gene is known to play different and important roles in the development of a variety of tumors. In recent studies, IRX1 was recognized as a potential tumor suppressor gene in head and neck squamous cell carcinoma (HNSCC),[6],[7] lung development,[8] and gastric cancer.[6],[7],[8],[9],[10],[11],[12] However, it also functions as a prometastatic gene in osteosarcoma and a tumor oncogene in human hepatocellular carcinoma.[13],[14] Furthermore, IRX1 is involved in limb development and the etiology of kyphoscoliosis, suggesting that the aberrant IRX1 expression may contribute to abnormal bone formation.[15],[16]

In this paper, we made an effort to summarize the previously identified genomic structure and the type classification of IRX1 in different species such as human, mouse, chicken, zebrafish, and pufferfish. Then, specifically, we focused on explaining the key role of IRX1 in tumorigenesis and development of tumor and influence in biological processes of metazoans.


  Genomic Organization of IRX Top


IRX gene family members encode highly conserved homeodomain (HD), such as TFs, which play basic "prepatterning" roles in various developmental processes of invertebrates and vertebrates.[5],[17],[18 In contrast to typical DNA-binding HD TFs, which are composed by sixty amino-acid residues with three alpha helices,[19] IRX TFs contain an atypical HD with 3-amino acid loop extension family between the first and second alpha helices [Figure 1]a,[4] and a conserved motif (Iro-box) with 13 amino-acid residues in the C-terminal region.[20],[21]
Figure 1: IRX genes. (a) Schematic illustration of Iroquois protein structure. (b) Schematic representation of the genomic organization of IRX genes in human, mouse, chick, and Drosophila. (c) Schematic representation of genomic organization of IRX genes in zebrafish and pufferfish. The orientation and distance of the arrows depict the direction of the gene and a brief estimation of chromosomal location of IRX genes, respectively. IRX: Iroquois homeobox

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In general, IRX genes were found in genomic clusters and are expressed in varying amount in various species. There is only one IRO/IRX gene in Caenorhabditiselegans, while there are three closely related proteins, namely araucan, caupolican, and mirror, expressed in Drosophila.[2],[22] However, in vertebrates, there are six well-defined IRX genes, clustered as IRXA (IRX1, IRX2, and IRX4) and its duplicate IRXB (IRX3, IRX5, and IRX6) [Figure 1]b. In other words, IRX1 and 3, IRX2 and 5, and IRX4 and 6 are paralogs. The speculation regarding mechanism is likely that the two vertebrate clusters were derived as a result of a chromosomal duplication event from a single ancestral IRX cluster, and an independent duplication event gave rise to three-gene clusters in the ancestors of insect and vertebrate lineages.[5],[23],[24],[25],[26],[27],[28]

In mouse, clusters IRXA and IRXB are located at 25 cM of chromosome 13 and 43 cM of chromosome 8, respectively, and the corresponding human orthologs are located in the human equivalent regions 5p15.33 (IRXA) and 16q11.2-q13 (IRXB), respectively [Figure 1]b.[28] Besides, a complete set of six genes had not been identified in Xenopus and chicken until 2009, when a fragment of a sixth chicken Iroquois gene was revealed.[28],[29] In the zebrafish genome, 11 IRX genes, which were organized into four clusters apart from one isolated gene zIRX7, have been found. These four clusters, including IRXAa (IRX1a, 2a, and 4a), IRXAb (IRX1b and 4b), IRXBa (IRX3a, 5a, and 6a), and IRXBb (IRX3b and 5b), appear to be originating by duplication of the ancestors of the two mammalian clusters [Figure 1]c.[25]


  Function of IRX1 in Metazoan Development Process Top


IRX genes play a crucial role in the regionalization and patterning of tissues and organs during metazoan development. IRX1 is closely related to the embryo development and encodes for the active protein family involved in the development of vertebrate nervous system.[5] The gene is further known to play an important role in the metazoan development such as embryonic foregut, toe, Drosophila wing, body wall, eyes and other organs,[26] and also participate in the development of foregut-derived lung bud, bronchia,[26] myocardium,[30] renal segment,[31] and so on.

The results of recent studies on the expression pattern of IRX1 gene during limb development and morphogenesis in mouse, chicken, and other species showed that during the hand plate development in human, chicken, and mouse embryos, IRX1 was expressed during digital formation.[16] In the limb of chick embryo, IRX1 expression was observed only in the digital area.[16],[32],[33] During the mouse limb development, IRX1 expression was observed in the posterior digital condensation, delimited distally by the undifferentiated zone, and then this expression expands into anterior digits and finally into presumptive joint sites.[26] Otherwise, it is known that IRX1 is coordinately expressed with IRX2 and regulated by retinoic and transforming growth factor (TGF-β) signaling during chick hind limb development, similar to other species of vertebrates. These results support the notion that the genomic architecture of IRX clusters is conserved in vertebrates.[32]


  Function of IRX1 in Tumorigenesis and Development Top


IRX1 inactivation is a common phenomenon in tumorigenesis, due to a combination of allelic deletion and promoter methylation. Frequent methylation and the absence or deactivation of certain important TFs are the major mechanisms of carcinogenesis in human cancer. In recent years, studies have shown that the IRX gene family plays different roles, oncogenes or tumor suppressor genes [Table 1], in the development of various tumors.
Table 1: The tumorigenic mechanism of IRX1

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IRX1 in head and neck squamous cell carcinoma

HNSCC is an aggressive variant of human cancer. Studies showed that the IRX1 expression was lost or reduced in HNSCC, with IRX1 promoter methylation being the important mechanism for gene inactivation, resulting in disruption of TGF-β signaling pathway.[7],[34] Bennett et al.[7] identified that the IRX1 was frequently methylated and downregulated in the HNSCC biopsies through global methylation analysis. 5-aza-2'-deoxycytidine treatment was able to restore IRX1 expression, and this increased expression of IRX1 could suppress the cell proliferation and tumorigenesis in HNSCC. These results suggest that IRX1 functions as a tumor suppressor gene in HNSCC.[7],[34]

IRX1 in gastric cancer

IRX1 expression is markedly reduced in gastric cancer cells, and it correlates with its promoter methylation and gene copy number deletion.[9],[10],[11],[12],[35] Guo et al.[9] showed that restoring IRX1 expression inhibited gastric cell proliferation, migration, invasion, and tumorigenesis, under both in vitro and in vivo. The mechanism of the tumor suppressor activity of IRX1 was found associated with the target genes FGF7, BDKRB2, and HIST2H2BE, which are involved in decreasing angiogenesis, cell proliferation, and invasion. Besides, IRX1 promoter hypermethylation in peripheral blood of gastric cancer patients suggests IRX1 as a potential biomarker for the gastric cancer.[9]

Further, another study by Guo et al.[35] characterized the hypermethylation of tumor suppressor IRX1 promoter in chronic gastritis with Helicobacterpylori infection, to investigate if IRX1 DNA methylation is an early molecular event before gastric carcinogenesis. The results showed that the H.pylori infection resulted in morphologic alteration and activation of gastric epithelial cells, induced IRX1 promoter methylation, and downregulation of promoter activity and gene expression. Because DNA methylation is a reversible epigenetic event, combined eradication of H.pylori with demethylation treatment may be a potential strategy for restoring IRX1 activity.

At last, Jiang et al.[11] proposed that IRX1 suppresses peritoneal spreading and long distance metastasis, through inhibiting BDKRB2 and its effector PAK1-dependent angiogenesis or vasculogenic mimicry mechanisms, in gastric cancer. When they inhibited BDKRB2 expression through specific RNAi, a remarkable reduction of neovascularization was observed. IRX1/BDKRB2 might be a potential target for antitumor strategy in gastric cancer.

IRX1 in osteosarcoma

Osteosarcoma is a common malignant tumor of bone, accompanied with a propensity to metastasize to the lungs. Lu et al.[13] identified hypomethylated IRX1 as a prometastatic gene that promotes lung metastasis of osteosarcoma through CXCL14/NF-κB signal activation. Further, they found that the presence of IRX1 hypomethylation in circulating tumor DNA, within the serum of osteosarcoma patients, reduced the lung metastasis-free survival. Above all, they identified IRX1 as a prometastatic gene, implied IRX1 hypomethylation as a potential biomarker for lung metastasis, and suggest that epigenetic reversion of IRX1 activation may be beneficial in controlling osteosarcoma metastasis.

IRX1 in hepatocellular carcinoma

Yang et al.[14] revealed that both the expression levels of IRX1 gene and protein were higher in hepatocellular carcinoma tissue and were related to the differentiation level of carcinoma. IRX1 might be involved in the regulation of onset and progress of HCC and the fact that its expression was related to the differentiation of carcinoma indicates that IRX1 might be used as an indicator for evaluation of prognosis and differentiation level of the condition. It may also serve as a target for molecular therapy of HCC.

IRX1 in acute lymphoblastic leukemia

The acute lymphoblastic leukemia with positive MLL-AF4 exhibits worst prognosis. This kind of leukemia is characterized with t-(4;11)-(q21;q23) chromosomal abnormalities, forming MLL-AF4 fusion gene resistant to chemotherapy. It also demonstrates easy relapse after treatment and hence becomes the focus of blood disease research. Recent studies have shown that by directly targeting HOXB4 and indirectly targeting EGR, IRX1 can activate their transcriptional activity and inhibit functions of MLL-AF4. HOXB4, as the downstream target gene of WNT, c-KIT, and TPO signaling pathways, is indispensable to hematopoietic stem cells for their maintenance and expansion. EGR proteins regulate hematopoietic stem cells through p21-dependent quiescence program. These two proteins may help t-(4;11) leukemia cells to establish a stem cell compartment.[36]

IRX1 in other conditions

Lung development is directly regulated by mesenchymal–epithelial interactions, which harmonized the temporal and spatial expression of multiple regulatory factors necessary for proper lung formation. IRX genes have been involved in the patterning and specification of lung development. Becker et al.[37] indicated that IRX1 is expressed during early lung development. Then, studies showed that the pulmonary IRX1 was upregulated during branching lung morphogenesis in early gestation in the nitrofen-induced hypoplastic lung.[8],[37],[38],[39]

A study by Alarcón et al.[31] showed that IRX1 is expressed and required during different stages of Xenopus pronephros development. IRX1 mRNA expression is found downregulated in pancreatic cancer, and it is related to promoter CpG islands hypermethylation.[40]

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, with synovial fibroblasts (RASFs) being the key player cells in its pathogenesis. The findings by Park et al.[41] suggest that methylation-associated downregulation of EBF3 and IRX1 genes may play an important role in the pathogenic effect of TGF-β on RASFs. A recent study showed that a variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of rheumatoid factor (RF), and IRX1 and HLA–DRB1 are the strongest genetic factors for RF production in RA.[42]


  Conclusion Top


IRX genes exist in genomic clusters, at varying amounts, in various species. It plays an active role during embryo development and a crucial but contradicting role in the development of a variety of tumors. IRX1 gene acts as a tumor suppressor gene in HNSCC and gastric cancer, while as an oncogene in primary liver cancer and osteosarcoma. IRX1 is also involved in the process of lung metastasis of osteosarcoma and peritoneal metastasis and expansion of gastric cancer. Therefore, it is evident that the IRX1 gene carries a potential value as a tumor prognostic marker, helpful in early diagnosis, and as a target for molecular therapy, helpful in devising an appropriate treatment to the cancer patients. In this regards, further studies are essential for a deeper understanding of the IRX1s molecular mechanism.

Financial support and sponsorship

Nil.

Conflict of interest

There are no conflicts of interest.

 
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