The Proangiogenic Effect of Iroquois Homeobox Transcription Factor Irx3 in Human Microvascular Endothelial Cells

Scarlett, Kisha A.; Pattabiraman, Vaishnavi; Barnett, Petrina; Liu, Dongdong; Anderson, Leonard

doi:10.1074/jbc.m114.601146

Cited by 17 publications

(21 citation statements)

References 53 publications

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“…Whether these mechanisms are involved in the deregulation of IRX3 in HCC needs further investigation. Moreover, IRX3 as a transcriptional factor has been reported to act as either an activator or suppressor of gene expression (23)(24)(25). The functional transcription targets of IRX3 remain to be elucidated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma

et al. 2016

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Iroquois homeobox (IRX) gene family, which plays essential roles in embryonic development, has recently been reported to be involved in tumor progression. However, the association of IRX3, a member of the IRX family, with hepatocellular carcinoma (HCC) has not previously been studied. In the present study, we found that IRX3 was upregulated in HCC cell lines (HepG2 and SMMC7721). We investigated the regulatory mechanism of IRX3 in HCC cells. Western blot and luciferase reporter assays identified that IRX3 is a direct target of miR-377. In addition, miR-377 was downregulated in HepG2 and SMMC7721 cell lines, and overexpression of miR-377 inhibited HepG2 cell proliferation, migration and invasion. Moreover, miR-377 restoration significantly abrogated IRX3-induced proliferation, migration and invasion of SMMC7721 cells. These findings demonstrate the tumor-promoting potential of IRX3, and that downregulation of miR-377 may contribute to the upregulation of IRX3 in HCC. The present study provides insights into HCC progression and a novel potential therapeutic target of HCC treatment.

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Section: Discussionmentioning

confidence: 99%

Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma

et al. 2016

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“…These findings suggest that IRX3 has the potential to promote tumor progression in liver cancer . Studies have shown that VEGF can stimulate the expression of IRX3 in human microvascular endothelial cells, suggesting that IRX3 may contribute to tumor angiogenesis in cancer . IRX4 inhibited cell proliferation, suggesting its tumor‐suppressive effect in prostate cancer and oral squamous cell carcinoma …”

Section: Introductionmentioning

confidence: 92%

“…19 Studies have shown that VEGF can stimulate the expression of IRX3 in human microvascular endothelial cells, suggesting that IRX3 may contribute to tumor angiogenesis in cancer. 20 IRX4 inhibited cell proliferation, suggesting its tumorsuppressive effect in prostate cancer and oral squamous cell carcinoma. 21,22 A previous study showed that IRX5 promoted G1/S-phase transition in vascular smooth muscle cells via CDK2-dependent activation, 23 and IRX5 negatively regulated the transforming growth factor β (TGF-β) pathway, thus promoting the transformation of adenoma to cancer.…”

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confidence: 99%

IRX5 promotes colorectal cancer metastasis by negatively regulating the core components of the RHOA pathway

Zhu

Yang

et al. 2019

Molecular Carcinogenesis

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Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. As tumor metastasis is the leading cause of death in patients with CRC, it is important to elucidate the molecular mechanisms that drive CRC metastasis. Studies have shown a close relationship between Iroquois homeobox (IRX) family genes and multiple cancers, while the mechanism by which IRX5 promotes CRC metastasis is unclear. Therefore, we focused on the involvement of IRX5 in CRC metastasis. In this study, analyses of clinical data indicated that the expression of IRX5 was coincided with metastatic colorectal tumors tissues and was negatively correlated with the overall survival of patients with CRC. Functional analysis showed that IRX5 promoted the migration and invasion of CRC cells, accompanied by a large number of cellular protrusions. IRX5‐overexpressing cells were more likely to form metastatic tumors in nude mice. Further analysis demonstrated that the core components of the RHOA/ROCK1/LIMK1 pathway were significantly inhibited in IRX5‐overexpressing cells. Overexpression of LIMK1 effectively reversed the enhanced cellular motility caused by IRX5 overexpression. Moreover, we found that high levels of IRX5 in intestinal tissues were correlated with the inflammatory response. IRX5 was significantly increased in azoxymethane/dextran sodium sulfate intestinal tissue of mice and IRX5‐overexpressing may also enhance chemokines CXCL1 and CXCL8. In summary, our findings suggested that IRX5 promoted CRC metastasis by inhibiting the RHOA‐ROCK1‐LIMK1 axis, which correlates with a poor prognosis.

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“…We then went on to examine a link between Irx3b and Notch, as the Irx factors have been implicated as both positive and negative regulators of Notch signalling (Dominguez & de Celis, 1998;Scarlett, Pattabiraman, Barnett, Liu, & Anderson, 2015). In addition, Notch has recently been linked to CS gland development (B. E. Drummond, Li, Marra, Cheng, & Wingert, 2016) and Notch components are expressed in CS cells (Fig.S4).…”

Section: Irx3b Suppresses Cs Cell Formationmentioning

confidence: 99%

“…This may occur by promoting one Notch-Ligand pairing over another or by altering the strength of the Notch signal. It is also interesting to note that cross-regulatory interactions between Notch and Irx3 have been shown in human microvascular endothelial cells where Irx3 induces expression of Delta-like ligand 4 but is in turn repressed by the Notch mediator Hey1 via direct binding to the Irx3 promoter(Scarlett et al, 2015). How the proposed repressive effects of Irx3b on Notch signalling are overcome so that the DE-to-CS transdifferentiation event can be initiated at the appropriate time during development remain to be determined in future studies.…”

mentioning

confidence: 99%

A novel mechanism of gland formation in zebrafish involving transdifferentiation of renal epithelial cells and live cell extrusion

Naylor

Davidson

2018

Preprint

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Transdifferentiation is the poorly understood phenomenon whereby a terminally differentiated cell acquires a completely new identity. Here, we describe a rare example of a naturally occurring transdifferentiation in zebrafish in which kidney distal tubule epithelial cells are converted into an endocrine gland known as the Corpuscles of Stannius (CS). We find that this process requires Notch signalling and is associated with the cytoplasmic sequestration of the Hnf1b transcription factor, a master-regulator of renal tubule fate. A deficiency in the Irx3b transcription factor results in ectopic transdifferentiation of distal tubule cells to a CS identity but in a Notch-dependent fashion. Using live-cell imaging we show that CS cells undergo apical constriction en masse and are then extruded from the tubule to form a distinct organ.This system provides a valuable new model to understand the molecular and morphological basis of transdifferentiation and will advance efforts to exploit this rare phenomenon therapeutically.

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The Proangiogenic Effect of Iroquois Homeobox Transcription Factor Irx3 in Human Microvascular Endothelial Cells

Cited by 17 publications

References 53 publications

Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma

Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma

IRX5 promotes colorectal cancer metastasis by negatively regulating the core components of the RHOA pathway

A novel mechanism of gland formation in zebrafish involving transdifferentiation of renal epithelial cells and live cell extrusion

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