Gene Summary

Gene:PAX6; paired box 6
Aliases: AN, AN1, AN2, FVH1, MGDA, WAGR, ASGD5, D11S812E
Summary:This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:paired box protein Pax-6
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Wilms TumourPAX6 and Wilms Tumour View Publications35
WAGR SyndromePAX6 deletions in WAGR Syndrome
Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome (WAGR) is a contiguous gene syndrome caused by deletions at chromosome 11p13 in a region containing the WT1 and PAX6 genes.
View Publications29
Brain Tumours, ChildhoodPAX6 and Brain Tumours View Publications15
Eye CancerPAX6 and Uveal Neoplasms View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PAX6 (cancer-related)

Wang Q, Wang J, Niu S, et al.
MicroRNA-664 targets paired box protein 6 to inhibit the oncogenicity of pancreatic ductal adenocarcinoma.
Int J Oncol. 2019; 54(5):1884-1896 [PubMed] Related Publications
The abnormal expression of microRNAs (miRNAs or miRs) with oncogenic or tumor‑suppressive roles in pancreatic ductal adenocarcinoma (PDAC) has been widely reported in recent years, and these dysregulated miRNAs are implicated in the formation and progression of PDAC. Therefore, an investigation into the functional roles of miRNAs in PDAC may facilitate the identification of effective therapeutic targets. miRNA‑664 (miR‑664) has been found to be aberrantly expressed and to play crucial roles in several human cancer types. However, the expression pattern and functional roles of miR‑664 in the malignant capacity of PDAC have yet to be elucidated. In this study, the results revealed that miR‑664 was clearly downregulated in PDAC tissues and cell lines. The low miR‑664 expression was strongly associated with pathological T stage and lymph node metastasis of the patients with PDAC. Patients with PDAC with a low miR‑664 expression had a poorer overall survival and a worse disease‑free survival than those patients with a high miR‑664 level. Functional experiments suggested that exogenous miR‑664 expression suppressed the growth and metastasis of PDAC cells in vitro, whereas miR‑664 downregulation exerted the opposite effects. In addition, miR‑664 suppressed the tumor growth of PDAC cells in vivo. Mechanistically, paired box protein 6 (PAX6) was identified as a direct target gene of miR‑664 in PDAC cells. Furthermore, PAX6 was upregulated in PDAC tissues, and its upregulation inversely correlated with miR‑664 levels. Moreover, the silencing of PAX6 mimicked the effects of miR‑664 upregulation in PDAC cells, and the recovered expression of PAX6 eliminated the effects of miR‑664 on PDAC cells. Notably, miR‑664 could inhibit the activation of PI3K/Akt pathway in PDAC cells in vitro and in vivo. Cumulatively, these results indicate an important role of the miR‑664/PAX6 pathway in suppressing the aggressiveness of PDAC cells, suggesting that miR‑664 may be an attractive therapeutic target for the treatment of patients with this fatal disease.

Qian Z, Zhang Q, Hu Y, et al.
Investigating the mechanism by which SMAD3 induces PAX6 transcription to promote the development of non-small cell lung cancer.
Respir Res. 2018; 19(1):262 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study investigated the function of SMAD3 (SMAD family member 3) in regulating PAX6 (paired box 6) in non-small cell lung cancer.
METHODS: First, qRT-PCR was employed to detect SMAD3 expression in cancer tissues along with normal tissues and four cell lines, including BEAS-2B, H125, HCC827 and A549 cells. SMAD3 was knocked down by small interference RNA (siRNA), and then its expression was determined via qRT-PCR and Western blot analysis. The correlation between SMAD3 and PAX6 was determined by double luciferase reporter experiments and chromatin immunoprecipitation (ChIP) assay. Cell viability was evaluated by CCK-8 and colony forming assays, while cell migration and invasion were detected by Transwell analysis.
RESULTS: SMAD3 and PAX6 were upregulated in lung cancer tissues and cancer cells. Knocking down SMAD3 and PAX6 by transfection with siRNAs specifically suppressed the expression of SMAD3 and PAX6 mRNA and protein levels. SMAD3 could promote PAX6 transcriptional activity by binding to its promoter. Reduced expression of SMAD3 led to the downregulation of PAX6 mRNA and protein levels along with decreased cell migration, invasion, proliferation and viability in A549 and HCC827 cells. PAX6 overexpression altered the si-SMAD3-induced inhibition of cell migration, invasion, proliferation and viability in A549 and HCC827 cells. Additionally, PAX6 knockdown alone also repressed the cell migration, invasion, proliferation and viability of the cell lines.
CONCLUSIONS: SMAD3 promotes the progression of non-small cell lung cancer by upregulating PAX6 expression.

Zhang S, Wang Q, Li D, et al.
MicroRNA‑509 targets PAX6 to inhibit cell proliferation and invasion in papillary thyroid carcinoma.
Mol Med Rep. 2019; 19(2):1403-1409 [PubMed] Related Publications
MicroRNAs (miRNAs/miRs) negatively regulate the expression of numerous genes and therefore contribute to the occurrence and development of papillary thyroid carcinoma (PTC). Hence, further investigation into the specific roles of miRNAs in PTC is valuable for developing effective therapeutic methods for patients with this disease. MiRNA‑509 is dysregulated and serves pivotal roles in several types of human cancer; however, the expression and roles of miR‑509 in PTC and its underlying mechanism require further investigation. In the present study, the expression of miR‑509 in PTC tissues and cell lines was detected and the specific functions of miR‑509 in the progression of PTC were investigated. Additionally, the molecular mechanisms underlying the action of miR‑509 in PTC were determined. The present study demonstrated that miR‑509 was significantly downregulated in PTC tissues and cell lines. MiR‑509 upregulation inhibited the PTC cell proliferation and invasion. Mechanistically, paired box 6 (PAX6) was identified as a novel target of miR‑509 in PTC cells. In clinical PTC samples, miR‑509 was significantly overexpressed and inversely correlated with PAX6 expression. PAX6 restoration effectively reversed the inhibitory effects of miR‑509 overexpression on PTC cell proliferation and invasion. These results demonstrated that miR‑509 may act as a tumor suppressor in PTC by directly targeting PAX6. Thus, miR‑509 may be a potential therapeutic target for the treatment of patients with PTC.

Koso H, Tsuhako A, Matsubara D, et al.
Ras activation in retinal progenitor cells induces tumor formation in the eye.
Exp Eye Res. 2019; 180:39-42 [PubMed] Related Publications
The RAS gene family members, H-RAS, K-RAS, and N-RAS, are frequently mutated in human cancer. A subset of retinal tumors displays K-RAS mutations; however, the specific role of RAS activation on retinal tumor formation is unclear. To examine the role of RAS in retinal development, we overexpressed the mutant H-RAS gene (G12V) in retinal progenitor cells (RPCs), a multipotent progenitor cell population that gives rise to all six neuron types in the retina and to the Muller glia. The Msi1

Urrutia G, Laurito S, Campoy E, et al.
PAX6 Promoter Methylation Correlates with MDA-MB-231 Cell Migration, and Expression of MMP2 and MMP9
Asian Pac J Cancer Prev. 2018; 19(10):2859-2866 [PubMed] Free Access to Full Article Related Publications
Objective: Breast cancer is a heterogeneous disease characterized by an accumulation of genetic and epigenetic alterations that lead tumor cells to acquire characteristics like the capacity for invasion and metastasis. Metastasis remains a major challenge in cancer management and understanding of its molecular basis should result in improved prevention, diagnosis, and treatment of breast cancer patients. The aim of this study was to investigate how promoter DNA methylation regulates PAX6 gene expression and influences breast carcinoma cell migration. Methods: PAX6 promoter methylation was detected by Methyl Specific-Multiplex Ligation Probe Amplification (MS-MLPA). Gene expression was evaluated using qRT-PCR, while the effect of PAX6 on migration was ssessed by wound healing assay. In addition, MMP2 and MMP9 genes were studied using different bioinformatic tools. Results: The PAX6 promoter is methylated in breast cancer cell lines and methylation in this region impacts on its expression. Migration assays revealed that PAX6 overexpression promotes cell migration, while PAX6 inhibition decreases it. More importantly, we found that migration is affected by PAX6 methylation status. Employing bioinformatic analysis, binding sites for PAX6 on the regulatory regions of the MMP2 and MMP9 genes were established, PAX6 overexpression increasing MMP2 and MMP9 expression at the mRNA level. Conclusion: Our study provides novel insights into epigenetic events that regulate PAX6 expression and molecular mechanisms by which PAX6 modifies the migration capacity of breast cancer cells.

Dugnani E, Sordi V, Pellegrini S, et al.
Gene expression analysis of embryonic pancreas development master regulators and terminal cell fate markers in resected pancreatic cancer: A correlation with clinical outcome.
Pancreatology. 2018; 18(8):945-953 [PubMed] Related Publications
BACKGROUND: Despite the recent introduction of new drugs and the development of innovative multi-target treatments, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. Even when PDAC is resectable, the rate of local or widespread disease recurrence remains particularly high. Currently, reliable prognostic biomarkers of recurrence are lacking. We decided to explore the potential usefulness of pancreatic developmental regulators as biomarkers of PDAC relapse.
METHODS: We analyzed by quantitative real-time PCR the mRNA of selected factors involved either in pancreatic organogenesis (ISL1, NEUROD1, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1 and PTF1α) or associated with terminally committed pancreatic cells (CHGA, CHGB, GAD2, GCG, HNF6α, INS, KRT19, SYP) in 17 PDAC cell lines and in frozen tumor samples from 41 PDAC patients.
RESULTS: High baseline levels of the ISL1, KRT19, PAX6 and PDX1 mRNAs in PDAC cell lines, were risk factors for time-dependent xenograft appearance after subcutaneous injection in CD1-Nude mice. Consistently, in human PDAC samples, high levels of KRT19 mRNA were associated with reduced overall survival and earlier recurrence. Higher levels of PDX1 or PAX6 mRNAs were instead associated with a higher frequency of local recurrence.
CONCLUSIONS: Our findings suggest that selected factors associated with pancreas development or its terminal differentiation might be implicated in mechanisms of PDAC progression and/or metastatic spread and that the measurement of their mRNA in tumors might be potentially used to improve patient prognostic stratification and prediction of the relapse site.

Li J, You X
MicroRNA‑758 inhibits malignant progression of retinoblastoma by directly targeting PAX6.
Oncol Rep. 2018; 40(3):1777-1786 [PubMed] Related Publications
Accumulated studies have highlighted that the dysregulation of microRNAs (miRNAs) in retinoblastoma (RB) is a leading cause for tumourigenesis and tumour development. Therefore, the elucidation of the expression, functional roles and underlying mechanisms of miRNAs in RB will help the development of promising therapeutic methods to improve the prognosis of RB patients. The aim of this study was to detect miRNA‑758 (miR‑758) expression in RB tissues and cell lines, and to determine the effects and underlying mechanisms of miR‑758 on RB progression. The results demonstrated that miR‑758 was downregulated in both RB tissues and cell lines. In vitro functional experiments revealed that upregulation of miR‑758 inhibited cell proliferation, migration and invasion, and induced apoptosis in RB. In addition, paired box protein 6 (PAX6) was a direct target gene of miR‑758 in RB. Furthermore, PAX6 was upregulated in RB tissues, and this upregulation was inversely associated with the expression level of miR‑758. In addition, PAX6 reintroduction abrogated the tumour‑suppressive effects of miR‑758 overexpression on RB cell proliferation, migration, invasion and apoptosis. Furthermore, miR‑758 overexpression inactivated the PI3K/Akt pathway in RB cells by inhibiting PAX6. In conclusion, our current study provided sufficient evidence to demonstrate that miR‑758 inhibits the progression of RB by directly targeting PAX6 and regulating the PI3K/Akt pathway, thereby suggesting that this miRNA may be developed as a therapeutic target for treating patients with RB.

Ooki A, Dinalankara W, Marchionni L, et al.
Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma.
Oncogene. 2018; 37(45):5967-5981 [PubMed] Free Access to Full Article Related Publications
It remains unclear whether PAX6 acts as a crucial transcription factor for lung cancer stem cell (CSC) traits. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties in lung adenocarcinoma (LUAD). Mechanistically, PAX6 promotes GLI transcription, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene. The overexpressed SOX2 enhances the expression of key pluripotent factors (OCT4 and NANOG) and suppresses differentiation lineage factors (HOPX and NKX2-1), driving cancer cells toward a stem-like state. In contrast, in the differentiated non-CSCs, PAX6 is transcriptionally silenced by its promoter methylation. In human lung cancer tissues, the positive linear correlations of PAX6 expression with GLI and SOX2 expression and its negative correlations with HOPX and NKX2-1 expression were observed. Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy. Furthermore, a methylation panel including the PAX6 gene yielded a sensitivity of 79.1% and specificity of 83.3% for cancer detection using serum DNA from stage IA LUAD. Our findings provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis with chemotherapy as an effective therapeutic strategy and support the clinical utility of PAX6 gene promoter methylation as a biomarker for early lung cancer detection.

Nemlich Y, Baruch EN, Besser MJ, et al.
ADAR1-mediated regulation of melanoma invasion.
Nat Commun. 2018; 9(1):2154 [PubMed] Free Access to Full Article Related Publications
Melanoma cells use different migratory strategies to exit the primary tumor mass and invade surrounding and subsequently distant tissues. We reported previously that ADAR1 expression is downregulated in metastatic melanoma, thereby facilitating proliferation. Here we show that ADAR1 silencing enhances melanoma cell invasiveness and ITGB3 expression. The enhanced invasion is reversed when ITGB3 is blocked with antibodies. Re-expression of wild-type or catalytically inactive ADAR1 establishes this mechanism as independent of RNA editing. We demonstrate that ADAR1 controls ITGB3 expression both at the post-transcriptional and transcriptional levels, via miR-22 and PAX6 transcription factor, respectively. These are proven here as direct regulators of ITGB3 expression. miR-22 expression is controlled by ADAR1 via FOXD1 transcription factor. Clinical relevance is demonstrated in patient-paired progression tissue microarray using immunohistochemistry. The novel ADAR1-dependent and RNA-editing-independent regulation of invasion, mediated by ITGB3, strongly points to a central involvement of ADAR1 in cancer progression and metastasis.

Diao J, Su X, Cao L, et al.
MicroRNA‑874 inhibits proliferation and invasion of pancreatic ductal adenocarcinoma cells by directly targeting paired box 6.
Mol Med Rep. 2018; 18(1):1188-1196 [PubMed] Related Publications
Studies have demonstrated that a number of microRNAs (miRNAs) are dysregulated in pancreatic ductal adenocarcinoma (PDAC), and alterations in their expression may affect the onset and progression of PDAC. Therefore, the expression patterns, biological functions and associated molecular mechanisms of miRNAs in PDAC should be elucidated for the development of novel therapeutic methods. Previous studies reported significant miRNA‑874 (miR‑874) dysregulation in multiple types of human cancer. However, the expression pattern, possible roles and underlying mechanisms of miR‑874 in PDAC remain to be elucidated. This study evaluated miR‑874 expression in PDAC and examined its biological functions and underlying mechanism of action in PDAC progression. miR‑874 expression was downregulated in PDAC tissues and cell lines. Functional experiments demonstrated that upregulation of miR‑874 inhibited cell proliferation and invasion in PDAC. Additionally, paired box 6 (PAX6) was predicted as a putative target of miR‑874 using bioinformatics analysis. Further experiments demonstrated that PAX6 may be the direct target gene of miR‑874 in PDAC. PAX6 knockdown exhibited similar inhibitory effects to miR‑874 overexpression in PDAC cells. In addition, restored PAX6 expression may reverse the suppressive roles of miR‑874 overexpression in PDAC cells. The results demonstrated that miR‑874 may serve tumor suppressive roles in PDAC by directly targeting PAX6. Therefore, miR‑874 may exhibit potential applications for treatment of patients with PDAC.

Hegge B, Sjøttem E, Mikkola I
Generation of a PAX6 knockout glioblastoma cell line with changes in cell cycle distribution and sensitivity to oxidative stress.
BMC Cancer. 2018; 18(1):496 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transcription factor PAX6 is expressed in various cancers. In anaplastic astrocytic glioma, PAX6 expression is inversely related to tumor grade, resulting in low PAX6 expression in Glioblastoma, the highest-grade astrocytic glioma. The aim of the present study was to develop a PAX6 knock out cell line as a tool for molecular studies of the roles PAX6 have in attenuating glioblastoma tumor progression.
METHODS: The CRISPR-Cas9 technique was used to knock out PAX6 in U251 N cells. Viral transduction of a doxycycline inducible EGFP-PAX6 expression vector was used to re-introduce (rescue) PAX6 expression in the PAX6 knock out cells. The knock out and rescued cells were rigorously characterized by analyzing morphology, proliferation, colony forming abilities and responses to oxidative stress and chemotherapeutic agents.
RESULTS: The knock out cells had increased proliferation and colony forming abilities compared to wild type cells, consistent with clinical observations indicating that PAX6 functions as a tumor-suppressor. Cell cycle distribution and sensitivity to H
CONCLUSIONS: The U251 N PAX6 knock out cell lines generated can be used as a tool to study the molecular functions and mechanisms of PAX6 as a tumor suppressor with regard to tumor progression and treatment of glioblastoma.

Pavlaki I, Alammari F, Sun B, et al.
The long non-coding RNA
EMBO J. 2018; 37(10) [PubMed] Free Access to Full Article Related Publications
Many long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their

Yan F, Tu Z, Duan L, et al.
MicroRNA-383 suppresses cell proliferation and invasion in colorectal cancer by directly targeting paired box 6.
Mol Med Rep. 2018; 17(5):6893-6901 [PubMed] Related Publications
Colorectal cancer (CRC) is the third-most prevalent cancer and the fourth‑most common cause of cancer-associated fatality worldwide. The expression and biological roles of microRNAs (miRNAs/miRs) in tumourigenesis, and their regulatory function in a number of biological processes correlated with cancer have been investigated. miR‑383 has been reported to be deregulated in several human cancer types. However, the involvement and effects of miR‑383 on CRC progression and its underlying mechanism remain unknown. Therefore, the present study aimed to examine miR‑383 expression, investigate the biological functions of miR‑383 and identify its mechanism of action in CRC cells. In the present study, miR‑383 was significantly downregulated in CRC tissues and cell lines. Low miR‑383 expression was negatively associated with tumour size, lymph node metastasis and TNM stage. Function experiments demonstrated that miR‑383 upregulation inhibited the proliferation and invasion of CRC cells. Paired box 6 (PAX6) was confirmed as a direct target of miR‑383. PAX6 was upregulated in CRC tissues and was negatively correlated with miR‑383 expression. Induced PAX6 overexpression effectively rescued the tumour‑suppressing roles of miR‑383 on CRC cell proliferation and invasion. These findings suggested that miR‑383 may act as a tumour suppressor in CRC by directly targeting PAX6 and may serve as a promising therapeutic target for CRC treatment.

Zhang M, Li Q, Pan Y, et al.
MicroRNA-655 attenuates the malignant biological behaviours of retinoblastoma cells by directly targeting PAX6 and suppressing the ERK and p38 MAPK signalling pathways.
Oncol Rep. 2018; 39(4):2040-2050 [PubMed] Related Publications
Numerous studies have indicated that microRNAs (miRNAs) regulate signalling molecules by acting as oncogenes or tumour-suppressor genes in retinoblastoma (RB). Therefore, investigation of the expression pattern, biological roles and associated mechanisms of cancer-related miRNAs in RB may provide novel therapeutic targets for patients with this disease. miRNA-655 (miR-655) has been reported to be aberrantly expressed in many types of cancers. However, the expression pattern, detailed biological function and underlying molecular mechanisms of miR-655 in RB remain to be clarified. Therefore, the aims of the present study were to detect miR-655 in RB, investigate its biological roles in RB and determine the underlying molecular mechanisms. The results of the present study showed that miR-655 was significantly downregulated in RB tissues and cell lines. Overexpression of miR-655 inhibited the proliferation and invasion ability while it increased the apoptosis of RB cells. Additionally, paired box 6 (PAX6) was identified as a direct target of miR-655 in RB. Furthermore, PAX6 was highly expressed in RB tissues and was negatively correlated with miR-655 expression. PAX6 knockdown recapitulated effects similar to those observed following miR-655 overexpression regarding the proliferation, invasion and apoptosis of RB cells. Rescue experiments demonstrated that restoration of PAX6 expression reversed the tumour-suppressing roles of miR-655 in RB cells. Moreover, upregulation of miR-655 reduced activation of the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase signalling pathways in RB cells through PAX6 regulation. Therefore, restoration of miR-655 expression may be a promising therapeutic strategy for treating patients with RB in the future.

Meng Q, Dai M, Nie X, et al.
MicroRNA-19 contributes to the malignant phenotypes of osteosarcoma in vitro by targeting Pax6.
Tumour Biol. 2018; 40(1):1010428317744704 [PubMed] Related Publications
This study was conducted to detect the expression of miR-19 and Pax6 (Paired box protein 6) in human osteosarcoma cells and the effects on biological characteristics of osteosarcoma cells. Quantitative real-time polymerase chain reaction was used to detect the expression of Pax6 and miR-19 in normal human osteoblasts (hFOB 1.19) and osteosarcoma cell lines (U2OS, Saos-2, and MG-63). Results showed that miR-19 was significantly upregulated in osteosarcoma cell lines compared with that in hFOB 1.19 cells, while the expression of Pax6 messenger RNA was significantly downregulated. Pax6 was defined as the target gene of miR-19 which was validated by luciferase reporter gene analysis. Results indicated that miR-19 had an interaction with Pax6 3'-untranslated region. At the same time, the protein expression of Pax6 was significantly decreased in the MG-63 cells transfected with miR-19 mimic and was notably enhanced in osteosarcoma MG-63 cells transfected with miR-19 inhibitor. These data suggested that Pax6 was a target of miR-19 in osteosarcoma MG-63 cells. The effects of miR-19 on the biological behavior of MG-63 cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and Transwell assay. Results showed that the downregulation of miR-19 inhibited cell viability, reduced the percentage of cells in S phase and the number of cells passing through the Transwell chamber, and increased the number of apoptotic cells. Western blot analysis showed that the inhibition of miR-19 significantly increased the expression of epithelial proteins (E-cadherin and β-catenin) and decreased the expression of mesenchymal protein (Vimentin), extracellular signal-regulated kinase, and phosphorylated extracellular signal-regulated kinase in MG-63 cells. MiR-19 inhibitor and Pax6 small interfering RNA were simultaneously transfected into MG-63 cells. Results from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and Transwell assay demonstrated that the inhibition of Pax6 expression in MG-63 cells could reverse the cell biological effects induced by the inhibition of miR-19 expression. Based on these findings, it was suggested that miR-19, upregulated in osteosarcoma cells, negatively regulated the expression of Pax6, which can promote the malignant phenotypes of osteosarcoma cells via activation of the extracellular signal-regulated kinase signaling pathways. Therefore, miR-19/Pax6 may offer potential for use as a target for the treatment of osteosarcoma.

Liao XH, Yin WL, Wang F, et al.
[Construction of a lentiviral vector carrying short?hairpin RNA targeting PAX6 and its effect on proliferation of glioma U251 cells in vitro].
Nan Fang Yi Ke Da Xue Xue Bao. 2017; 37(12):1603-1608 [PubMed] Related Publications
OBJECTIVE: To construct a lentiviral vector for delivering short hairpin RNA (shRNA) targeting PAX6 and investigate its effect on the proliferation of glioma U251 cells in vitro.
METHODS: Two small interfering RNA sequences targeting PAX6 gene were designed based on the reported sequence of PAX6 and annealed to form a double?stranded chain, which was inserted into a lentiviral vector to construct the recombinant lentiviral vector shRNA?PAX6. The recombinant vector was infected into U251 cells, and the expression of PAX6 mRNA and protein in the cells was detected by real?time PCR and Western blotting, respectively. The changes in the proliferation of U251 cells after the infection was assessed using MTT assay.
RESULTS: Double enzyme digestion of the lentiviral vector pLKD?CMV?G&NR?U6?shRNA yielded an 8208?bp fragment, and colony PCR and sequencing analysis confirmed successful construction of the lentiviral vector shRNA?PAX6. Infection of the cells with shRNA?PAX6 caused a significant reduction of the expressions of PAX6 mRNA and protein (P<0.05) and resulted in obviously increased proliferation of U251 cells (P<0.05).
CONCLUSION: We successfully constructed the recombinant vector shRNA?PAX6 for silencing PAX6 gene. PAX6 gene silencing results in increased proliferation of U251 cells in vitro.

Gillman AS, Gardiner CK, Koljack CE, Bryan AD
Body mass index, diet, and exercise: testing possible linkages to breast cancer risk via DNA methylation.
Breast Cancer Res Treat. 2018; 168(1):241-248 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To examine DNA methylation as a mechanism linking diet, physical activity, weight status, and breast cancer risk.
METHODS: Insufficiently active women of varying weight status, without a history of cancer, completed a maximal exercise test, clinical measurement of height and weight, and a dietary intake measure. They also provided blood samples, which were analyzed to ascertain average methylation of candidate genes related to breast cancer (BRCA1, RUNX3, GALNT9, and PAX6) and inflammation (TLR4 and TLR6).
RESULTS: Elevated weight status (r = - .18, p < .05) and poorer aerobic fitness (r = .24, p < .01) were each associated with decreased methylation of inflammation genes. Methylation of inflammation genes statistically mediated the relationship between weight status and cancer gene methylation (standardized indirect effect = .12, p < .05) as well as between cardiorespiratory fitness and cancer gene methylation (standardized indirect effect = - .172, p < .01). However, recent dietary behavior was not associated with methylation of either inflammation or cancer genes.
CONCLUSIONS: Both weight status and cardiovascular fitness are associated with methylation of genes associated with both inflammation and cancer. Methylation of inflammatory genes might serve as a mechanistic link between lifestyle factors and methylation changes in genes that increase risk for breast cancer.

Zheng XR, Pan X, Zhang J, Cao X
Hyperinsulinemia-induced PAX6 expression promotes endometrial epithelial cell proliferation via negatively modulating p27 signaling.
Biomed Pharmacother. 2018; 97:802-808 [PubMed] Related Publications
Polycystic ovarian syndrome (PCOS) is thought to involve hyperinsulinism (insulin resistance, IR) and high prevalence of endometrial epithelial hyperplasia, but how these two pathologies are synergistically regulated in endometrial epithelial cells remains largely unknown. Here, we report a key role for the transcription factor PAX6 in the modulation of PCOS-induced endometrial epithelial proliferation. PAX6 was significantly induced in the endometrial tissues from PCOS patients, and this induction, regulated upstream by high levels of insulin, was closely correlated to the pathogenesis of IR in endometrial epithelial cells. Overexpression of the exogenous PAX6 potentiated the insulin-elicited accumulation of S phase in endometrial epithelial cells and thereby promoted endometrial epithelial proliferation. In parallel, by using luciferase reporter and ChIP assay, we found that PAX6 directly bound to the promoter of CDKN1B gene (the gene encoding p27 protein, a negative regulator of cell cycle) and inhibited CDKN1B transcription in the insulin-stimulated endometrial epithelial cells. We conclude that excessive PAX6 expression in insulin-challenged endometrial epithelial cells may contribute to the uncontrollable endometrial epithelial proliferation. Our results also provide a mechanistic explanation for the functional link between hyperinsulinemia and p27 loss in the pathogenesis of endometrial epithelial hyperplasia in PCOS patients.

Takada Y, Sakai Y, Matsushita Y, et al.
Sustained endocrine profiles of a girl with WAGR syndrome.
BMC Med Genet. 2017; 18(1):117 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined.
CASE PRESENTATION: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions.
CONCLUSIONS: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.

Dou D, Zhao H, Li Z, et al.
CHD1L Promotes Neuronal Differentiation in Human Embryonic Stem Cells by Upregulating PAX6.
Stem Cells Dev. 2017; 26(22):1626-1636 [PubMed] Related Publications
Chromodomain helicase DNA-binding protein 1-like gene (CHD1L) was initially isolated as a candidate oncogene in hepatocellular carcinoma, and it has been associated with many malignancies. Knockdown of Chd1l in zygote-stage mouse embryos resulted in developmental arrest, suggesting that Chd1l is required for mouse early development. However, the exact role of CHD1L in development, especially in humans, has not been reported. In this study, we found that overexpression of CHD1L in human embryonic cells (hESCs) upregulated the expression of ectoderm genes, especially PAX6. Furthermore, ectopic expression of CHD1L promoted hESCs to differentiate into neuroepithelium both in embryoid bodies and in directed neuronal differentiation. Knockdown of CHD1L significantly impaired neuroepithelial differentiation of hESCs. Interestingly, Chd1l colocalized with a PAX6-positive cell population and was highly expressed in the ventricular (germinal) zone of fetal mice. Taken together, these data suggest that CHD1L promotes neuronal differentiation of hESCs and may play an important role in nervous system development.

Berdasco M, Gómez A, Rubio MJ, et al.
DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders.
Sci Rep. 2017; 7(1):11762 [PubMed] Free Access to Full Article Related Publications
This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and children (uveal melanoma and retinoblastoma, respectively). We observed that hypermethylation of tumor suppressor genes is a frequent event in ocular tumors, but also unmethylation is associated with tumorogenesis. Interestingly, unmethylation of the proto-oncogen RAB31 was a predictor of metastasis risk in uveal melanoma. Loss of methylation of the oncogenic mir-17-92 cluster was detected in primary tissues but also in blood from patients.

Wu X, Miao J, Jiang J, Liu F
Analysis of methylation profiling data of hyperplasia and primary and metastatic endometrial cancers.
Eur J Obstet Gynecol Reprod Biol. 2017; 217:161-166 [PubMed] Related Publications
OBJECTIVE: Endometrial cancer is a prevalent cancer, and its metastasis causes low survival rate. This study aims to utilize DNA methylation data to investigate the mechanism of the development and metastasis of endometrial cancer.
STUDY DESIGN: Methylation profiling data were down-loaded from Gene Expression Omnibus, including 8 hyperplasias, 33 primary and 53 metastatic endometrial cancers. COHCAP package and annotation files were utilized to identify differentially methylated genes (DMGs) and CpG islands between the three different endometrial diseases. STRING database and Cytoscape were used to analyze and visualize protein-protein interactions (PPIs) between DMGs. CytoNCA plugin was utilized to identify key nodes in PPI network.
RESULTS: A total of 610, 1076, and 501 DMGs were identified between primary endometrial cancer and hyperplasia, metastatic endometrial cancer and hyperplasia, as well as metastatic and primary endometrial cancers, respectively. For the three DMG sets, 53 common hypermethylated DMGs (e.g. PAX6 and INSR) and 6 common hypomethylated DMGs (e.g. PRDM8, KLHL14, and DUSP6) were found. For primary-hyperplasia DMG set and metastasis-hyperplasia DMG set, 527 common DMGs were found. For these common DMGs, a PPI network involving 692 PPIs was constructed. For DMGs between metastatic and primary endometrial cancers, a PPI network involving 673 PPIs was established, with PAX6 and INSR in the top 20 DMGs in both networks. PRDM8, KLHL14, and DUSP6 had hypomethylated CpG islands.
CONCLUSION: DMGs comparison, PPI network analysis, and analysis of differentially methylated CpG islands indicated that PAX6, INSR, PRDM8, KLHL14, and DUSP6 might participate in the development and metastasis of endometrial cancer.

Justice ED, Barnum SJ, Kidd T
The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene.
PLoS Genet. 2017; 13(8):e1006865 [PubMed] Free Access to Full Article Related Publications
WAGR syndrome is characterized by Wilm's tumor, aniridia, genitourinary abnormalities and intellectual disabilities. WAGR is caused by a chromosomal deletion that includes the PAX6, WT1 and PRRG4 genes. PRRG4 is proposed to contribute to the autistic symptoms of WAGR syndrome, but the molecular function of PRRG4 genes remains unknown. The Drosophila commissureless (comm) gene encodes a short transmembrane protein characterized by PY motifs, features that are shared by the PRRG4 protein. Comm intercepts the Robo axon guidance receptor in the ER/Golgi and targets Robo for degradation, allowing commissural axons to cross the CNS midline. Expression of human Robo1 in the fly CNS increases midline crossing and this was enhanced by co-expression of PRRG4, but not CYYR, Shisa or the yeast Rcr genes. In cell culture experiments, PRRG4 could re-localize hRobo1 from the cell surface, suggesting that PRRG4 is a functional homologue of Comm. Comm is required for axon guidance and synapse formation in the fly, so PRRG4 could contribute to the autistic symptoms of WAGR by disturbing either of these processes in the developing human brain.

Zhao Y, Min L, Xu C, et al.
Construction of disease-specific transcriptional regulatory networks identifies co-activation of four gene in esophageal squamous cell carcinoma.
Oncol Rep. 2017; 38(1):411-417 [PubMed] Related Publications
Even though various molecules may serve as biomarkers, little is known concerning the mechanisms underlying the carcinogenesis of ESCC, particularly the transcriptional regulatory network. Thus, in the present study, paired ESCC and non-cancerous (NC) tissues were assayed by Affymetrix microarray assays. Passing Attributes between Networks for Data Assimilation (PANDA) was used to construct networks between transcription factors (TFs) and their targets. AnaPANDA program was applied to compare the regulatory networks. A hypergeometric distribution model-based target profile similarity analysis was utilized to find co-activation effects using both TF-target networks and differential expression data. There were 1,116 genes upregulated and 1,301 genes downregulated in ESCC compared with NC tissues. In TF-target networks, 16,970 ESCC-specific edges and 9,307 NC-specific edges were identified. Edge enrichment analysis by AnaPANDA indicated 17 transcription factors (NFE2L2, ELK4, PAX6, TLX1, ESR1, ZNF143, TP53, REL, ELF5, STAT1, TBP, NHLH1, FOXL1, SOX9, STAT3, ELK1, and HOXA5) suppressed in ESCC and 5 (SPIB, BRCA1, MZF1, MAFG and NFE2L1) activated in ESCC. For SPIB, MZF1, MAFG and NFE2L1, a strong and significant co-activation effect among them was detected in ESCC. In conclusion, the construction of transcriptional regulatory networks found SPIB, MZF1, MAFG and NFE2L1 co-activated in ESCC, which provides distinctive insight into the carcinogenesis mechanism of ESCC.

Gan TQ, Chen WJ, Qin H, et al.
Clinical Value and Prospective Pathway Signaling of MicroRNA-375 in Lung Adenocarcinoma: A Study Based on the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Bioinformatics Analysis.
Med Sci Monit. 2017; 23:2453-2464 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Lung adenocarcinoma (LUAD) is the most frequent lung cancer. MicroRNAs (miRNAs) are believed to have fundamental roles in tumorigenesis of LUAD. Although miRNAs are broadly recognized in LUAD, the role of microRNA-375 in LUAD is still not fully elucidated. MATERIAL AND METHODS We evaluated the significance of miR-375 expression in LUAD by using analysis of a public dataset from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database and a literature review. Furthermore, we investigated the biological function of miR-375 by gene ontology enrichment and target prediction analysis. RESULTS MiR-375 expression was significantly higher in LUAD by TCGA data compared to normal lung tissue (p<0.0001). In addition, a common pattern of upregulation for miR-375 in LUAD was found in our review of the literature. A total of 682 genes, both LUAD-related and miR-375-related, were obtained from the analytical integration. Critical pathways were unveiled in the network analysis of the overlaps, such as pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and starch and sucrose metabolism. Furthermore, we identified covert miR-375 associated genes that might participate in LUAD by network analysis, such as FGF2 (fibroblast growth factor 2), PAX6 (paired box 6), and RHOJ. The expression of these three genes were all downregulated in LUAD. Finally, FGF2 was revealed to be negatively correlated with miR-375 in LUAD (r=-0.1821, p=0.0001). CONCLUSIONS Overall, our study provides evidence that miR-375 is essential for the progression of LUAD.

Huynh MT, Boudry-Labis E, Duban B, et al.
WAGR syndrome and congenital hypothyroidism in a child with a Mosaic 11p13 deletion.
Am J Med Genet A. 2017; 173(6):1690-1693 [PubMed] Related Publications
Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome, a rare genetic disorder, is caused by the loss of 11p13 region including PAX6 and WT1. We report novel findings in a 28-month-old boy with aniridia, Wilm's tumor, congenital hypothyroidism, and sublingual thyroid ectopia. He was found to have a mosaic 5.28 Mb interstitial deletion of chromosome 11p13 deleting PAX6 and WT1. In order to clarify the mechanism underlying his thyroid dysgenesis, sequence analysis of candidate thyroid developmental genes was performed. We identified a FOXE1: c.532_537delGCCGCC p.(Ala178_Ala179del) variant that predisposes to thyroid ectopia. Taken together, this is the first report of mosaic 11p13 deletion in association with thyroid dysgenesis. We also propose a model of complex interactions of different genetic variants for this particular phenotype in the present patient.

Karthikeyan AS, Lai YH, Khetan V
The Directions Are on the Box.
J Pediatr Ophthalmol Strabismus. 2017; 54(2):75-76 [PubMed] Related Publications

Vasilyeva TA, Voskresenskaya AA, Käsmann-Kellner B, et al.
Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations.
Clin Genet. 2017; 92(6):639-644 [PubMed] Related Publications
Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia. Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome). The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In 3 families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 of 91 probands lacking pathogenic variants in the gene.

Suebsoonthron J, Jaroonwitchawan T, Yamabhai M, Noisa P
Inhibition of WNT signaling reduces differentiation and induces sensitivity to doxorubicin in human malignant neuroblastoma SH-SY5Y cells.
Anticancer Drugs. 2017; 28(5):469-479 [PubMed] Related Publications
Neuroblastoma is one of the most common cancers in infancy, arising from the neuroblasts during embryonic development. This cancer is difficult to treat and resistance to chemotherapy is often found; therefore, clinical trials of novel therapeutic approaches, such as targeted-cancer signaling, could be an alternative for a better treatment. WNT signaling plays significant roles in the survival, proliferation, and differentiation of human neuroblastoma. In this report, WNT signaling of a malignant human neuroblastoma cell line, SH-SY5Y cells, was inhibited by XAV939, a specific inhibitor of the Tankyrase enzyme. XAV939 treatment led to the reduction of β-catenin within the cells, confirming its inhibitory effect of WNT. The inhibition of WNT signaling by XAV939 did not affect cell morphology, survival, and proliferation; however, the differentiation and sensitivity to anticancer drugs of human neuroblastoma cells were altered. The treatment of XAV939 resulted in the downregulation of mature neuronal markers, including β-tubulin III, PHOX2A, and PHOX2B, whereas neural progenitor markers (PAX6, TFAP2α, and SLUG) were upregulated. In addition, the combination of XAV939 significantly enhanced the sensitivity of SH-SY5Y and IMR-32 cells to doxorubicin in both 2D and 3D culture systems. Microarray gene expression profiling suggested numbers of candidate target genes of WNT inhibition by XAV939, in particular, p21, p53, ubiquitin C, ZBED8, MDM2, CASP3, and FZD1, and this explained the enhanced sensitivity of SH-SY5Y cells to doxorubicin. Altogether, these results proposed that the altered differentiation of human malignant neuroblastoma cells by inhibiting WNT signaling sensitized the cells to anticancer drugs. This approach could thus serve as an effective treatment option for aggressive brain malignancy.

Blanco-Kelly F, Palomares M, Vallespín E, et al.
Improving molecular diagnosis of aniridia and WAGR syndrome using customized targeted array-based CGH.
PLoS One. 2017; 12(2):e0172363 [PubMed] Free Access to Full Article Related Publications
Chromosomal deletions at 11p13 are a frequent cause of congenital Aniridia, a rare pan-ocular genetic disease, and of WAGR syndrome, accounting up to 30% of cases. First-tier genetic testing for newborn with aniridia, to detect 11p13 rearrangements, includes Multiplex Ligation-dependent Probe Amplification (MLPA) and karyotyping. However, neither of these approaches allow obtaining a complete picture of the high complexity of chromosomal deletions and breakpoints in aniridia. Here, we report the development and validation of a customized targeted array-based comparative genomic hybridization, so called WAGR-array, for comprehensive high-resolution analysis of CNV in the WAGR locus. Our approach increased the detection rate in a Spanish cohort of 38 patients with aniridia, WAGR syndrome and other related ocular malformations, allowing to characterize four undiagnosed aniridia cases, and to confirm MLPA findings in four additional patients. For all patients, breakpoints were accurately established and a contiguous deletion syndrome, involving a large number of genes, was identified in three patients. Moreover, we identified novel microdeletions affecting 3' PAX6 regulatory regions in three families with isolated aniridia. This tool represents a good strategy for the genetic diagnosis of aniridia and associated syndromes, allowing for a more accurate CNVs detection, as well as a better delineation of breakpoints. Our results underline the clinical importance of performing exhaustive and accurate analysis of chromosomal rearrangements for patients with aniridia, especially newborns and those without defects in PAX6 after diagnostic screening.

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