Gene Summary

Gene:PAX6; paired box 6
Aliases: AN, AN2, FVH1, MGDA, WAGR, ASGD5, D11S812E
Summary:This gene encodes a homeobox and paired domain-containing protein that binds DNA and functions as a regulator of 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 result in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:paired box protein Pax-6
Source:NCBIAccessed: 09 March, 2017


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 (1992-2017)
Graph generated 10 March 2017 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 09 March, 2017 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 Publications29
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 Publications23
Brain Tumours, ChildhoodPAX6 and Brain Tumours View Publications11
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)

Li X, Yang L, Shuai T, et al.
MiR-433 inhibits retinoblastoma malignancy by suppressing Notch1 and PAX6 expression.
Biomed Pharmacother. 2016; 82:247-55 [PubMed] Related Publications
Retinoblastoma (RB) is the most frequent primary intraocular cancer. It has been demonstrated by previous studies that retinoblastoma is initiated primarily by the inactivation of the retinoblastoma Rb1 gene in retinal cells. However, additional genetic alterations than Rb1 mutation could play important roles in the process of transforming benign retinal cells into retinoblastoma tumor cells. In this study, we identified that microRNA miR-433 is one of such genetic factors. We found that the expression levels of miR-433 were downregulated in RB tissues. We also determined that miR-433 negatively regulated RB cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis of RB cells. We used bioinformatics method to predict and confirmed that Notch1 and PAX6 were miR-433 target genes in RB cells. Importantly, we demonstrated that restoration of Notch1 and PAX6 expression partially rescued the inhibition of cell proliferation and metastasis induced by miR-433 overexpression, suggesting that miR-433 regulates RB cell proliferation and metastasis through suppressing the expression of Notch1 and PAX6.

Shih YL, Kuo CC, Yan MD, et al.
Quantitative methylation analysis reveals distinct association between PAX6 methylation and clinical characteristics with different viral infections in hepatocellular carcinoma.
Clin Epigenetics. 2016; 8:41 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Related to genetic alteration, frequent promoter hypermethylation is also a contributing factor in the development of human cancers. Recently, we discovered numerous novel genes that were aberrantly methylated in hepatocellular carcinoma (HCC) by using Infinium HumanMethylation27 BeadChip array. We utilized a quantitative methylation-specific PCR (Q-MSP) system for the evaluation of PAX6 methylation in 29 normal controls and 160 paired HCC tissues and their adjacent non-tumor tissues. We verified the correlation between the methylation status of PAX6 and clinical characteristics with different viral status.
RESULTS: Paired-box 6 promoter methylation was observed in 39.4 %, 15.6 %, and 3.4 % in primary HCCs, adjacent non-tumors, and normal control tissues, respectively. Methylation of the PAX6 promoter region in HCCs significantly increased compared with control tissues. PAX6 was frequently methylated in HCV-positive HCC tissues (61.3 %) and rarely methylated in HBV-positive (22.1 %) and double-negative HCC tissues (33.3 %).
CONCLUSIONS: Our data suggests that promoter hypermethylation of PAX6 is a common event in HCCs and the association of PAX6 methylation in clinicopathological features is divergent with different viral status.

Benevolenskaya EV, Islam AB, Ahsan H, et al.
DNA methylation and hormone receptor status in breast cancer.
Clin Epigenetics. 2016; 8:17 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA).
RESULTS: DNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African-American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity.
CONCLUSIONS: Higher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when evaluated on independent set of samples, with different racioethnic distribution, thus providing evidence that this set of DNA methylation biomarkers will likely generalize to prospective patient samples.

Zhao Y, Lu G, Ke X, et al.
miR-488 acts as a tumor suppressor gene in gastric cancer.
Tumour Biol. 2016; 37(7):8691-8 [PubMed] Related Publications
MicroRNAs (miRNAs) are small, non-coding RNAs that modulate development, cell proliferation, and apoptosis. The deregulated expression of microRNAs is found in carcinogenesis including gastric cancer (GC). In this study, we showed that the expression levels of miR-488 were downregulated in GC tissues compared to in non-tumor tissues. In addition, the expression of miR-488 was also lower in GC cell lines in contrast with the gastric epithelial cell line (GES). In addition, the expression level of miR-488 was negatively correlated with the TNM stage in GC patients, and lower miR-488 expression was found in tumors with advanced TNM stage. The ectopic expression of miR-488 suppressed the GC cell proliferation, cell cycle, colony information, and migration. PAX6 was identified as a direct target gene of miR-488 in HGC-27. Moreover, we found that the expression level of PAX6 was upregulated in the GC tissues compared with the non-tumor tissues. The PAX6 expression level was correlated with the cancer TNM stage, and higher PAX6 expression was found in tumors with advanced TNM stage. Furthermore, there was an inverse correlation between PAX6 and miR-488 expression levels in GC tissues. Therefore, these studies demonstrated that miR-488 might act as a tumor suppressor miRNA in the development of GC.

Zhang X, Yang X, Wang J, et al.
Down-regulation of PAX6 by promoter methylation is associated with poor prognosis in non small cell lung cancer.
Int J Clin Exp Pathol. 2015; 8(9):11452-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Promoter methylation is an alternative mechanism of gene silencing in human tumorigenesis. Although a number of methylated genes have been found in non small cell lung cancer (NSCLC), useful methylation markers for early prognostic evaluation of NSCLC remain largely unknown.
METHODS: Using methylation-specific PCR (MSP), we examined promoter methylation status of PAX6 gene, and explored their association with clinical features in NSCLC via chi-square test. NSCLC patient survival was assessed by Kaplan-Meier analyses and a Cox proportional hazard model was employed for multivariate analyses.
RESULTS: The methylation level of PAX6 gene was higher in tumor tissues than that in normal tissues. In addition, PAX6 promoter methylation showed a very significant correlation with differentiation (P = 0.002), distant metastasis (P = 0.024), and TNM stage (P = 0.002). PAX6 gene promoter hyper-methylation was found to be significantly associated with poor overall survival (P = 0.018) and to serve as an independent marker for prognosis using multivariate Cox regression analysis (HR: 2.254, 95% CI: 1.088-4.667, P = 0.029).
CONCLUSION: We found that PAX6 gene was specifically methylated in NSCLC, and demonstrated the effect of promoter methylation of PAX6 gene on clinical outcome in NSCLC, indicating the methylated PAX6 may be useful biomarkers for prognostic evaluation in NSCLC.

Luo J, Li H, Zhang C
MicroRNA-7 inhibits the malignant phenotypes of non‑small cell lung cancer in vitro by targeting Pax6.
Mol Med Rep. 2015; 12(4):5443-8 [PubMed] Related Publications
MicroRNA (miR)-7 has been reported to act as a suppressor in several types of cancer, including non-small cell lung cancer (NSCLC). In addition, paired box 6 (Pax6), a highly conserved transcriptional factor, has been implicated in NSCLC. However, the exact role of miR-7, and the association between miR-7 and Pax6 in NSCLC cells remain to be fully elucidated. The present study demonstrated that miR-7 was downregulated and Pax6 was upregulated in NSCLC cell lines. Subsequently, it was demonstrated that overexpression of miR-7 notably inhibited the protein expression of Pax6, while inhibition of miR-7 enhanced the protein expression of Pax6 in NSCLC A549 cells. Further investigation identified Pax6 as a target of miR-7 in A549 NSCLC cells. Ina ddition, the overexpression of miR-7 significantly inhibited A549 cell proliferation and invasion, which was reversed by upregulation of Pax6. Investigation of the underlying molecular mechanism revealed that the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways were downregulated in the miR-7-overexpressed A549 cells, but were activated in the Pax6-overexpressed A549 cells. Based on these findings, it was suggested that miR-7 negatively regulates the protein level of Pax6, which can promote the proliferation and invasion of NSCLC cells via activation of the ERK and MAPK signaling pathways. Therefore, miR-7/Pax6 may offer potential for use as a target for the treatment of NSCLC.

Walter RF, Mairinger FD, Werner R, et al.
SOX4, SOX11 and PAX6 mRNA expression was identified as a (prognostic) marker for the aggressiveness of neuroendocrine tumors of the lung by using next-generation expression analysis (NanoString).
Future Oncol. 2015; 11(7):1027-36 [PubMed] Related Publications
BACKGROUND: Neuroendocrine tumors of the lung (NELC) account for 25% of all lung cancer cases and transcription factors may drive dedifferentiation of these tumors. This study was conducted to identify supportive diagnostic and prognostic biomarkers.
MATERIALS & METHODS: A total of 16 TC, 13 AC, 16 large cell neuroendocrine carcinomas and 15 small cell lung cancer were investigated for the mRNA expression of 11 transcription factors and related genes (MYB, MYBBP1A, OCT4, PAX6, PCDHB, RBP1, SDCBP, SOX2, SOX4, SOX11, TEAD2).
RESULTS: SOX4 (p = 0.0002), SOX11 (p < 0.0001) and PAX6 (p = 0.0002) were significant for tumor type. Elevated PAX6 and SOX11 expression correlated with poor outcome in large cell neuroendocrine carcinomas and small cell lung cancer (p < 0.0001 and p = 0.0232, respectively) based on survival data of 34 patients (57%).
CONCLUSION: Aggressiveness of NELC correlated with increasing expression of transcription factors. SOX11 seems to be a highly valuable diagnostic and prognostic marker for aggressive NELC.

Urrutia G, Laurito S, Marzese DM, et al.
Epigenetic variations in breast cancer progression to lymph node metastasis.
Clin Exp Metastasis. 2015; 32(2):99-110 [PubMed] Related Publications
Breast cancer is a heterogeneous disease characterized by the accumulation of genetic and epigenetic alterations that contribute to the development of regional and distant metastases. Lymph node metastasis (LNM) status is the single most important prognostic factor. Metastatic cancer cells share common molecular alterations with those of the primary tumor, but in addition, they develop distinct changes that allow the cancer to progress. There is an urgent need for molecular studies which focus on identifying genomic and epigenomic markers that can predict the progression to metastasis. The objective of this study was to identify epigenetic similarities and differences between paired primary breast tumor (PBT) and LNM. We employed Methylation-Specific-MLPA (Multiplex ligation-dependent probe amplification) to assess the methylation status of 33 cancer-related genes in a cohort of 50 paired PBT and LNM specimens. We found that the methylation index, which represents the degree of aberrantly methylated genes in a specimen, was maintained during the progression to LNM. However, some genes presented differential methylation profiles. Interestingly, PAX6 presented a significant negative correlation between paired PBT and LNM (p = 0.03), which indicated a switch from methylated to unmethylated status in the progression from PBT to LNM. We further identified that the methylation status of PAX6 on the identified CpG site functionally affected the expression of PAX6 at the mRNA level. Our study unraveled significant epigenetic changes during the progression from PBT to LNM, which may contribute to improved prognosis, prediction and therapeutic management of metastatic breast cancer patients.

Benavente CA, Finkelstein D, Johnson DA, et al.
Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression.
Oncotarget. 2014; 5(20):9594-608 [PubMed] Free Access to Full Article Related Publications
The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK.

Meng Y, Zou Q, Liu T, et al.
microRNA-335 inhibits proliferation, cell-cycle progression, colony formation, and invasion via targeting PAX6 in breast cancer cells.
Mol Med Rep. 2015; 11(1):379-85 [PubMed] Related Publications
microRNAs (miRNAs) have been demonstrated to play crucial roles in tumorigenesis. However, the molecular mechanism underlying the roles of miRNAs in breast cancer remains largely unknown. In this study, we showed that miR-335 is downregulated in a number of breast cancer tissues and cell lines. Luciferase reporter assays identified the paired box 6 gene (PAX6) as a novel target of miR-335. Further investigation revealed that miR-335 negatively regulates the expression of PAX6 in human breast cancer MCF-7 cells. Our results further suggested that overexpression of miR-335 inhibits MCF-7 cell proliferation by inducing cell-cycle arrest at the G1 phase via targeting PAX6. Western blot analysis showed that overexpression of miR-335 promotes p27 protein expression but inhibits cyclin D1 expression in MCF-7 cells; however, overexpression of PAX6 decreased the p27 protein level but increased the cyclin D1 protein level in MCF-7 cells. Furthermore, miR-335 overexpression reduced colony formation and cellular invasion in MCF-7 cells, an effect that was reversed by PAX6 overexpression. In conclusion, this study provides novel insights into the in vitro regulatory patterns of miRNA-335 and PAX6 in breast cancer, and indicates that miRNA-335 may constitute a promising candidate for the treatment of breast cancer.

Conway K, Edmiston SN, May R, et al.
DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival.
Breast Cancer Res. 2014; 16(5):450 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood.
METHODS: A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer.
RESULTS: Consensus clustering using methylation (β) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset.
CONCLUSIONS: This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes.

Wang D, Yang PN, Chen J, et al.
Promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in invasive ductal breast carcinoma.
Mol Cell Biochem. 2014; 396(1-2):67-77 [PubMed] Related Publications
Hypermethylation of promoter CpG islands represents an alternative mechanism to inactivate tumor suppressor genes. This study was to detect promoter methylation status and mRNA expression levels of ARRDC3, ELP3, GATA5, and PAX6, and to explore the association between methylation and expression in invasive ductal carcinomas (IDCs) and matched normal tissues (MNTs) from breast cancer patients. Aberrant gene methylation was observed as follows: ARRDC3 in 38.5 %, ELP3 in 73.1 %, GATA5 in 48.1 %, and PAX6 in 50.0 % of IDCs. mRNA expression of ARRDC3, ELP3, and GATA5 in IDCs showed a lower level than that in MNTs (P < 0.001, P = 0.001 and P < 0.001, respectively). For ARRDC3, both methylated and unmethylated IDCs showed significantly lower expression values compared to MNTs (P = 0.001 and P = 0.007, respectively). For ELP3 and GATA5, methylated tumors only showed significantly lower expression values compared to MNTs (P = 0.001 and P < 0.001, respectively). For ARRDC3 and GATA5, methylation was associated with their less fold change in IDCs (P = 0.049 and P = 0.020, respectively). Methylation of ARRDC3 was significantly associated with grades and lymph node status of IDCs (P = 0.036 and P = 0.002, respectively). Methylation frequency of ELP3 was higher in lymph node positive versus lymph node negative tumors (P = 0.020); whereas methylation frequency of PAX6 was lower in tumors with the ER negative samples (P = 0.025). Our data suggested that promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in IDCs.

Sacristan R, Gonzalez C, Fernández-Gómez JM, et al.
Molecular classification of non-muscle-invasive bladder cancer (pTa low-grade, pT1 low-grade, and pT1 high-grade subgroups) using methylation of tumor-suppressor genes.
J Mol Diagn. 2014; 16(5):564-72 [PubMed] Related Publications
The role of epigenetics in distinguishing pathological and clinical subgroups in bladder cancer is not fully characterized. We evaluated whether methylation of tumor-suppressor genes (TSGs) would classify non-muscle-invasive (NMI) bladder cancer subgroups and predict outcome. A retrospective design included the following paraffin-embedded primary NMI tumor types (n = 251): pTa low grade (LG) (n = 79), pT1LG (n = 81), and pT1 high grade (HG) (n = 91). Methylation of 25 TSGs was measured using methylation-specific, multiplex, ligation-dependent probe amplification. The TSGs most frequently methylated in the overall series were STK11 (96.8%), MGMT2 (64.5%), RARB (63.0%), and GATA5 (63.0%). TSG methylation correlated to clinicopathological variables in each subgroup and in the overall NMI series. Methylation of RARB, CD44, PAX5A, GSTP1, IGSF4 (CADM1), PYCARD, CDH13, TP53, and GATA5 classified pTa versus pT1 tumors whereas RARB, CD44, GSTP1, IGSF4, CHFR, PYCARD, TP53, STK11, and GATA5 distinguished LG versus HG tumors. Multivariate analyses indicated that PAX5A, WT1, and BRCA1 methylation independently predicted recurrence in pTaLG, PAX6, ATM, CHFR, and RB1 in pT1LG disease; PYCARD, in pT1HG disease; and PAX5A and RB1, in the overall series. Methylation of TSGs provided a molecular classification of NMI disease according to clinicopathological factors. Furthermore, TSG methylation predicted recurrence in NMI subgroups.

Meng B, Wang Y, Li B
Suppression of PAX6 promotes cell proliferation and inhibits apoptosis in human retinoblastoma cells.
Int J Mol Med. 2014; 34(2):399-408 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to investigate the role of the transcription factor, PAX6, in the development of retinoblastoma. The expression of endogenous PAX6 was knocked down using PAX6-specific lentivirus in two human retinoblastoma cell lines, SO-Rb50 and Y79. Cell proliferation functional assays and apoptotic assays were performed on the cells in which PAX6 was knocked down. The results revealed that PAX6 knockdown efficiency was significant (P<0.01, n=3) in the SO-Rb50 and Y79 cells. The inhibition of PAX6 reduced tumor cell apoptosis (P<0.05, n=3), but induced cell cycle S phase arrest (SO-Rb50; P<0.05, n=3) and G2/M phase arrest (Y79; P<0.05, n=3). Western blot analysis indicated that the inhibition of PAX6 increased the levels of the anti-apoptotic proteins, Bcl-2, proliferating cell nuclear antigen (PCNA) and CDK1, but reduced the levels of the pro-apoptotic proteins, BAX and p21. In conclusion, our data demonstrate that the suppression of PAX6 increases proliferation and decreases apoptosis in human retinoblastoma cells by regulating several cell cycle and apoptosis biomarkers.

Shahi MH, Holt R, Rebhun RB
Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.
PLoS One. 2014; 9(5):e96593 [PubMed] Free Access to Full Article Related Publications
The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.

Cheng Q, Cao H, Chen Z, et al.
PAX6, a novel target of miR-335, inhibits cell proliferation and invasion in glioma cells.
Mol Med Rep. 2014; 10(1):399-404 [PubMed] Related Publications
Paired box 6 (PAX6), a highly conserved transcription factor, is important in glioma. However, the molecular mechanisms involved remain unclear. The present study demonstrated that the expression of PAX6 was significantly reduced with the malignancy of glioma and also identified PAX6 as a novel target of microRNA (miR)‑335, which was significantly upregulated in glioma. The inhibition of miR‑335 increased the protein expression of PAX6, whereas the upregulation of miR‑335 suppressed its expression in human glioma U251 and U87 cells. Furthermore, upregulation of miR-335 promoted U251 cell proliferation, colony formation and invasion, which was reversed by the overexpression of PAX6. Furthermore, the present study demonstrated that the effect of miR‑335 on U251 cell invasion was via the modulation of matrix metalloproteinase (MMP)‑2 and MMP‑9 expression by targeting PAX6. In conclusion, the present study demonstrated that PAX6, as a novel target of miR‑335, has an anti‑oncogenic function in glioma, and thus PAX6 may serve as a therapeutic target for glioma.

Kai Y, Peng W, Ling W, et al.
Reciprocal effects between microRNA-140-5p and ADAM10 suppress migration and invasion of human tongue cancer cells.
Biochem Biophys Res Commun. 2014; 448(3):308-14 [PubMed] Related Publications
ADAM10, overexpressed in tongue squamous cell carcinoma (TSCC), has been well documented for its role in tumor progression and metastasis. In the present study, we evaluated the inhibition effect of microRNAs (miRNAs) on the TSCC and identified that miR-140-5p could directly targets ADAM10 and inhibits the invasion and migration of TSCC cells. LAMC1, HDAC7 and PAX6, clustered into migration-related genes, were validated to be direct targets of miR-140-5p, while IGF1R and PSEN1 were not responsible to the regulation. Most intriguingly, ERBB4 was upregulated by miR-140-5p even though the interaction between ERBB4 3'UTR and miR-140-5p existed simultaneously. Meanwhile, ADAM10 is involved in the "positive" regulation of ERBB4 and negative regulation of PAX6 by miR-140-5p. Taken together, our results suggest that miR-140-5p play a role in TSCC cell migration and invasion, and two brand new relationships between miRNA and its targets emerged: (1) ADAM10 is not just a direct target of miR-140-5p, the repressed ADAM10 also helps to enhance the effect of miR-140-5p to other target genes: ERBB4 and PAX6; (2) ERBB4 is "positively" regulated by miR-140-5p.

Yang Q, Shao Y, Shi J, et al.
Concomitant PIK3CA amplification and RASSF1A or PAX6 hypermethylation predict worse survival in gastric cancer.
Clin Biochem. 2014; 47(1-2):111-6 [PubMed] Related Publications
OBJECTIVES: A large number of genetic and epigenetic alterations have been found in gastric cancer, but there is remarkably little consensus on the value of individual biomarker in diagnosis and prognosis of this cancer. This study was designed to illustrate the value of PIK3CA amplification in combination with promoter methylation of RASSF1A and PAX6 genes in early diagnosis and prognosis of gastric cancer.
DESIGN AND METHODS: Using real-time quantitative PCR, quantitative methylation-specific PCR (Q-MSP), and methylation-specific PCR (MSP) assays, we examined PIK3CA amplification and promoter methylation of RASSF1A and PAX6 genes in a cohort of gastric cancers, and explored the association of various (epi)genotypes with clinical outcomes of gastric cancer patients.
RESULTS: We demonstrated that PIK3CA gene was specifically amplified in gastric cancers, but not in normal gastric tissues. Moreover, frequent methylation of RASSF1A and PAX6 was also found in gastric cancers. Given the patients harboring diverse (epi)genotypes, we thus investigated the effect of various (epi)genotypes on poor prognosis in gastric cancer. The data showed that concomitant PIK3CA amplification and RASSF1A or PAX6 methylation were closely associated with poor clinical outcomes, particularly survival, as compared to other (epi)genotypes in gastric cancer.
CONCLUSIONS: We found frequent PIK3CA amplification and promoter methylation of RASSF1A and PAX6 genes in gastric cancers, and demonstrated that concomitant PIK3CA amplification and promoter methylation in any one of these two genes were significantly associated with worse survival in gastric cancer. Collectively, such (epi)genotypes may be strong and independent poor prognostic factors for gastric cancer patients.

Selvarajah S, Pyne S, Chen E, et al.
High-resolution array CGH and gene expression profiling of alveolar soft part sarcoma.
Clin Cancer Res. 2014; 20(6):1521-30 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis.
EXPERIMENTAL DESIGN: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL-TFE3 fusion and, hence, confirm the aCGH observations.
RESULTS: FISH analysis identified the ASPL-TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation.
CONCLUSION: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS.

Vance KW, Sansom SN, Lee S, et al.
The long non-coding RNA Paupar regulates the expression of both local and distal genes.
EMBO J. 2014; 33(4):296-311 [PubMed] Free Access to Full Article Related Publications
Although some long noncoding RNAs (lncRNAs) have been shown to regulate gene expression in cis, it remains unclear whether lncRNAs can directly regulate transcription in trans by interacting with chromatin genome-wide independently of their sites of synthesis. Here, we describe the genomically local and more distal functions of Paupar, a vertebrate-conserved and central nervous system-expressed lncRNA transcribed from a locus upstream of the gene encoding the PAX6 transcription factor. Knockdown of Paupar disrupts the normal cell cycle profile of neuroblastoma cells and induces neural differentiation. Paupar acts in a transcript-dependent manner both locally, to regulate Pax6, as well as distally by binding and regulating genes on multiple chromosomes, in part through physical association with PAX6 protein. Paupar binding sites are enriched near promoters and can function as transcriptional regulatory elements whose activity is modulated by Paupar transcript levels. Our findings demonstrate that a lncRNA can function in trans at transcriptional regulatory elements distinct from its site of synthesis to control large-scale transcriptional programmes.

Zhao X, Yue W, Zhang L, et al.
Downregulation of PAX6 by shRNA inhibits proliferation and cell cycle progression of human non-small cell lung cancer cell lines.
PLoS One. 2014; 9(1):e85738 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transcription factor PAX6 is primarily expressed in embryos. PAX6 is also expressed in several tumors and plays an oncogenic role. However, little is known about the role of PAX6 in lung cancer.
METHODS: The function of PAX6 in lung cancer cells was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation, anchorage-independent growth, and cell cycle arrest. The changes of cyclin D1, pRB, ERK1/2, p38 expression caused by PAX6 inhibition were detected using western-blotting. The PAX6 mRNA level in 52 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients and lung cancer cell lines was detected by real-time PCR.
RESULTS: Suppression of PAX6 expression inhibited cell growth and colony formation in A549 and H1299 cells. The percentage of cells in G1-phase increased when PAX6 expression was inhibited. The cyclin D1 protein level, as well as the pRB phosphorylation level, decreased as a result of PAX6 down-regulation. The activity of ERK1/2 and p38 was also suppressed in PAX6 knock-down cells. The PAX6 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines. In most patients (about 65%), the relative ratio of PAX6 mRNA in primary NSCLC versus adjacent tissues exceeded 100.
CONCLUSIONS: Our data implicated that PAX6 accelerates cell cycle progression by activating MAPK signal pathway. PAX6 mRNA levels were significantly elevated in primary lung cancer tissues compared to their matched adjacent tissues.

Yamamoto T, Togawa M, Shimada S, et al.
Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.
Am J Med Genet A. 2014; 164A(3):634-8 [PubMed] Related Publications
Interstitial deletions of the 11p13 region are known to cause WAGR (Wilms tumor, aniridia, genitourinary malformation, and "mental retardation") syndrome, a contiguous gene deletion syndrome due to haploinsufficiencies of the genes in this region, including WT1 and PAX6. Developmental delay and autistic features are major complications of this syndrome. Previously, some genes located in this region have been suggested as responsible for autistic features. In this study, we identified two patients who showed the chromosomal deletions involving 11p13. Patient 1, having an 8.6 Mb deletion of chr11p14.1p12:29,676,434-38,237,948, exhibited a phenotype typical of WAGR syndrome and had severe developmental delay and autistic behaviors. On the other hand, Patient 2 had a larger aberration region in 11p14.1-p12 which was split into two regions, that is, a 2.2-Mb region of chr11p14.1: 29,195,161-31,349,732 and a 10.5-Mb region of chr11p13p12: 32,990,627-43,492,580. As a consequence, 1.6 Mb region of the WAGR syndrome critical region was intact between the two deletions. This patient showed no symptom of WAGR syndrome and no autistic behaviors. Therefore, the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down to the region remaining intact in Patient 2. Thus, the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome.

Li Y, Li Y, Liu Y, et al.
PAX6, a novel target of microRNA-7, promotes cellular proliferation and invasion in human colorectal cancer cells.
Dig Dis Sci. 2014; 59(3):598-606 [PubMed] Related Publications
BACKGROUND: Paired box 6 (PAX6), a highly conserved transcriptional factor, has been implicated in tumorigenesis.
AIM: We aimed to explore the roles and molecular mechanisms of PAX6 and microRNA (miR-7) in colorectal cancer cells.
METHODS: Tissue microarray immunohistochemistry and Western blot were applied to examine the PAX6 expression. Real-time RT-PCR and Western blot were performed to determine the expression of miR-7 and PAX6. Luciferase reporter assay was used to determine whether PAX6 was a target of miR-7. Effects of miR-7 and PAX6 on colorectal cell proliferation, cell cycle progression, colony formation and invasion were then investigated. Western blot was used to determine the activities of the ERK and PI3K signal pathways, as well as the protein expression of MMP2 and MMP9.
RESULTS: The protein levels of PAX6 were gradually increased, while the expression of miR-7 was gradually reduced with malignancy of colorectal cancer. PAX6 was further identified as a target of miR-7, and its protein expression was negatively regulated by miR-7 in human colorectal cancer cells. Overexpression of PAX6 in Caco-2 and SW480 cells enhanced cellular proliferation, cell cycle progression, colony formation, and invasion, while miR-7 upregulation repressed these biological processes. Furthermore, the activities of ERK and PI3K signal pathways, as well as the protein levels of MMP2 and MMP9, were upregulated in PAX6-overexpressed Caco-2 and SW480 cells but deregulated in miR-7-overexpressed Caco-2 and SW480 cells.
CONCLUSIONS: Our study suggests that as a novel target of miR-7, PAX6 may serve as a promising therapeutic target for colorectal cancer.

Huang BS, Luo QZ, Han Y, et al.
microRNA-223 promotes the growth and invasion of glioblastoma cells by targeting tumor suppressor PAX6.
Oncol Rep. 2013; 30(5):2263-9 [PubMed] Related Publications
Glioblastoma is the most common primary central nervous system malignancy and its unique invasiveness hinders effective treatment. Its high invasiveness may be controlled partly by microRNAs (miRNAs, miRs) and their target genes. In the present study, we found that increased miR-223 expression and reduced PAX6 expression coexisted in glioblastoma as detected by quantitative PCR or tissue microarrays. We confirmed that miR-223 directly targets PAX6 through binding to its 3'-UTR using dual luciferase reporter assay. In U251 and U373 glioblastoma cells, overexpression of miR-223 decreased PAX6 mRNA and protein expression; however, inhibition of miR-223 increased PAX6 mRNA and protein expression. Moreover, overexpression of miR-223 led to effects similar to those of PAX6 knockdown: increased cell viability, increased percentage of cells in the G1 phase and increased cell invasiveness parallel with increased MMP2, MMP9 and VEGFA expression. In addition, inhibition of miR-223 resulted in effects similar to those of PAX6 overexpression: decreased cell viability, decreased percentage of cells in the G1 phase and decreased cell invasiveness parallel with reduced MMP2, MMP9 and VEGFA expression. The data presented here suggest that miR-223 promotes the growth and invasion of U251 and U373 glioblastoma cells by targeting PAX6, which serves as a tumor suppressor in glioblastoma exerting the functions of inhibition of cell cycle transition, and the expression of MMP2, MMP9 and VEGFA. In conclusion, the present study supports miR-223 and PAX6 as novel therapeutic targets for glioblastoma.

Wang J, Wang X, Wu G, et al.
MiR-365b-3p, down-regulated in retinoblastoma, regulates cell cycle progression and apoptosis of human retinoblastoma cells by targeting PAX6.
FEBS Lett. 2013; 587(12):1779-86 [PubMed] Related Publications
PAX6 contributes to the development and progression of retinoblastoma (RB), but the molecular mechanism underlying the regulation of PAX6 expression is unclear. Here we found that microRNA-365b-3p (miR-365b-3p) is downregulated in human RB tissues. Ectopic expression of miR-365b-3p significantly attenuates cell growth, induces cell cycle arrest in G1 phase and cell apoptosis through inhibiting the expression of PAX6 by directly binding its 3' untranslated regions. Furthermore, overexpression of miR-365b-3p upregulates p21 and p27 but downregulates cdc2 and Cyclin D1 protein levels. Elucidating the regulatory mechanism of PAX6 by microRNAs may give new clues to the therapy against RB.

Cui L, Guan Y, Qu Z, et al.
WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors.
J Clin Invest. 2013; 123(4):1647-61 [PubMed] Free Access to Full Article Related Publications
Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cell-derived (ESC-derived) cells. In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, overexpression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors.

Rodríguez-López R, Pérez JM, Balsera AM, et al.
The modifier effect of the BDNF gene in the phenotype of the WAGRO syndrome.
Gene. 2013; 516(2):285-90 [PubMed] Related Publications
Individuals who are carriers of deletions of various sizes that cause haploinsufficiency in the contiguous WT1 and PAX6 genes, located on chromosome 11p13 approximately 4 Mb centromeric to the BDNF gene, are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome). The molecular characterization of the wide deletion 11p15.1p12 arr (18676926-36576388) x1 dn in a child with 3 years and 4 months of age only affected by aniridia, predicts not only other serious associated diseases, but also allows us to hypothesize a specific phenotype of mental impairment, conduct alterations and childhood obesity, possibly added to the onset of metabolic alterations. The variable appearance and/or description of haploinsufficiency for obesity susceptibility in the WAGR syndrome mainly depends on the critical region located within 80 kb of exon 1 of BDNF. The relationship between genetic variation based on the genotype combinations of the 4 gene SNPs tagging the BDNF gene and the body mass index (BMI) was studied. The polymorphic variability was similarly distributed in 218 children suffering a severe and non-syndromic obesity from families at high risk for obesity, as compared with 198 controls. The corroborated role of the BDNF gene as highly susceptible to severe syndromic obesity has not already been evidenced in the molecular basis of overweight attributed to the common polygenic principles. Its potential role as risk modifier variant to provoke more severe phenotype has not yet been demonstrated. Some genetic variants of brain-derived neurotrophic factor (BDNF) have resulted in important disorders of energy balance, but it is essential to know exactly their deleterious human capacity because they play a fundamental role in the development and plasticity of the central nervous system in regulating food intake. The existence of polymorphic amino acid changes of unknown functional significance in patients carrying the haploinsufficiency of the BDNF gene could constitute an adequate model to study in depth their effects.

Bejjani A, Choi MR, Cassidy L, et al.
RB116: an RB1+ retinoblastoma cell line expressing primitive markers.
Mol Vis. 2012; 18:2805-13 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Retinoblastoma (RB), an intraocular tumor of childhood, is commonly associated with mutations in the RB1 gene. RB116 is a novel, early passage RB cell line that has not been previously characterized. In this study, we examined RB116 for the expression of RB1 and tested the hypothesis that RB116 cells would express stem cell markers as well as retinal progenitor cell markers. We compared RB116 cells with other well known RB cell lines, including Y79 and WERI-RB27.
METHODS: We evaluated expression of RB1 in RB116 cells by sequencing, multiplex ligation-dependent probe amplification, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), western immunoblot, and immunocytochemistry. Next, RB116 cells, along with Y79 and WERI-RB27 cells, were examined for expression of stem cell markers (ABCG2, Nanog, Oct3/4, ALDH1A1) and retinal progenitor markers (PAX6, CHX10) by quantitative immunocytochemistry. Immunocytochemical findings were accompanied by PCR analysis.
RESULTS: RB116 cells expressed RB1 at the mRNA and protein levels, with no mutations detected by either sequencing analysis, or gene dosage abnormalities detected by multiplex ligation-dependent probe amplification. The RB1 protein was immunoreactive in RB116 cells with an atypical perinuclear localization. RB116 cells also expressed stem cell markers, with 3%-5% of cells immunopositive for ABCG2, Oct3/4 and ALDH1A1, with at least 18% of cells immunoreactive to Nanog. These findings were confirmed by RT-PCR. Small percentages of RB116 cells also exhibited immunoreactivity to retinal progenitor markers PAX6 (9.8%) and CHX10 (1.2%). Expression of mRNAs for these markers was confirmed by qRT-PCR.
CONCLUSIONS: RB116 cells demonstrate RB1 expression accompanied by atypical perinuclear localization. RB116 cells also express primitive stem cell and retinal progenitor cell markers. Further studies on the phenotypes of both RB1-positive and RB1-negative human RB cells may be important in assessing differentiation potential of these cells, as well as designing targeted differentiation therapies.

Lin J, Teo S, Lam DH, et al.
MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.
Cell Death Dis. 2012; 3:e398 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.

Shahi MH, Rey JA, Castresana JS
The sonic hedgehog-GLI1 signaling pathway in brain tumor development.
Expert Opin Ther Targets. 2012; 16(12):1227-38 [PubMed] Related Publications
INTRODUCTION: The sonic hedgehog (Shh) pathway is a regulatory network involved in development and cancer. Proteins like Ptch, SMO, and Gli are central to the Shh pathway. Other proteins like HHIP, SUFU, Bmi-1, Cyclin D2, Plakoglobin, PAX6, Nkx2.2, and SFRP1 are not so well understood in Shh regulation as Gli-1 downstream target genes.
AREAS COVERED: In this review we try to explain the Shh pathway components and their role in development and cancer, mainly of the brain. A summary of each of the proteins is presented together with an overview of their involvement in cancer.
EXPERT OPINION: Genetic alterations of the Shh pathway have been detected in cancer stem cells, a subgroup of tumor cells implicated in the origin and maintenance of tumors, being responsible for cancer recurrence and chemotherapy resistance. Cancer stem cells constitute a novel target for biomedical researchers. Specifically, the Shh pathway is being explored as a new opportunity for targeted therapies against tumors. Therefore, a better knowledge of every of the regulators of the Shh pathway is needed.

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