Gene Summary

Gene:FOXC2; forkhead box C2
Aliases: LD, MFH1, MFH-1, FKHL14
Summary:This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the development of mesenchymal tissues. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein C2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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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 (5)

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

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

Latest Publications: FOXC2 (cancer-related)

Hadj-Ahmed M, Ghali RM, Bouaziz H, et al.
Transforming growth factor beta 1 polymorphisms and haplotypes associated with breast cancer susceptibility: A case-control study in Tunisian women.
Tumour Biol. 2019; 41(8):1010428319869096 [PubMed] Related Publications
Variable association of transforming growth factor beta 1 (TGFβ1) in breast cancer (BC) pathogenesis was documented, and the contribution of specific

Zhu B, Zhu Y, Tian J, et al.
A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk.
Mol Carcinog. 2019; 58(5):760-766 [PubMed] Related Publications
9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two-stage case-control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72-0.91) maps to the long non-coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75-0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e-QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 × 10

Went M, Sud A, Speedy H, et al.
Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.
Blood Cancer J. 2018; 9(1):1 [PubMed] Free Access to Full Article Related Publications
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R

Hamdi Y, Ben Rekaya M, Jingxuan S, et al.
A genome wide SNP genotyping study in the Tunisian population: specific reporting on a subset of common breast cancer risk loci.
BMC Cancer. 2018; 18(1):1295 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer is the most common cancer in women worldwide. Around 50% of breast cancer familial risk has been so far explained by known susceptibility alleles with variable levels of risk and prevalence. The vast majority of these breast cancer associated variations reported to date are from populations of European ancestry. In spite of its heterogeneity and genetic wealth, North-African populations have not been studied by the HapMap and the 1000Genomes projects. Thus, very little is known about the genetic architecture of these populations.
METHODS: This study aimed to investigate a subset of common breast cancer loci in the general Tunisian population and to compare their genetic composition to those of other ethnic groups. We undertook a genome-wide haplotype study by genotyping 135 Tunisian subjects using the Affymetrix 6.0-Array. We compared Tunisian allele frequencies and linkage disequilibrium patterns to those of HapMap populations and we performed a comprehensive assessment of the functional effects of several selected variants.
RESULTS: Haplotype analyses showed that at risk haplotypes on 2p24, 4q21, 6q25, 9q31, 10q26, 11p15, 11q13 and 14q32 loci are considerably frequent in the Tunisian population (> 20%). Allele frequency comparison showed that the frequency of rs13329835 is significantly different between Tunisian and all other HapMap populations. LD-blocks and Principle Component Analysis revealed that the genetic characteristics of breast cancer variants in the Tunisian, and so probably the North-African populations, are more similar to those of Europeans than Africans. Using eQTl analysis, we characterized rs9911630 as the most strongly expression-associated SNP that seems to affect the expression levels of BRCA1 and two long non coding RNAs (NBR2 and LINC008854). Additional in-silico analysis also suggested a potential functional significance of this variant.
CONCLUSIONS: We illustrated the utility of combining haplotype analysis in diverse ethnic groups with functional analysis to explore breast cancer genetic architecture in Tunisia. Results presented in this study provide the first report on a large number of common breast cancer genetic polymorphisms in the Tunisian population which may establish a baseline database to guide future association studies in North Africa.

Chen Y, Gu M, Liu C, et al.
Long noncoding RNA FOXC2-AS1 facilitates the proliferation and progression of prostate cancer via targeting miR-1253/EZH2.
Gene. 2019; 686:37-42 [PubMed] Related Publications
The vital roles of long noncoding RNAs (lncRNAs) in the cancers have been evidenced. However, there are still numerous unsolved queries for the molecular mechanism. This study tries to investigate the role of lncRNA FOXC2-AS1 in the human prostate cancer tumorigenesis. Results stated that lncRNA FOXC2-AS1 was ectopically up-regulated in prostate cancer tissue and cells. The over-expression of FOXC2-AS1 indicates the poor prognosis of prostate cancer patients. Functionally, the gain- and loss-of-functional experiments revealed that FOXC2-AS1 promoted the proliferation and tumor growth of prostate cancer cells in vitro and in vivo. Mechanically, we found that miR-1253 targeted FOXC2-AS1 at the 3'‑untranslated regions (UTR), which in turn bind the EZH2 mRNA 3-UTR. Luciferase reporter assay and rescue experiment confirmed the FOXC2-AS1/miR-1253/EZH2 pathway. In conclusion, we confirmed that lncRNA FOXC2-AS1 accelerated the tumor progression of prostate cancer cells by regulating the proliferation and tumor growth through miR-1253/EZH2 axis.

Zhang T, Choi J, Kovacs MA, et al.
Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes.
Genome Res. 2018; 28(11):1621-1635 [PubMed] Free Access to Full Article Related Publications
Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335

He Y, Xie H, Yu P, et al.
FOXC2 promotes epithelial-mesenchymal transition and cisplatin resistance of non-small cell lung cancer cells.
Cancer Chemother Pharmacol. 2018; 82(6):1049-1059 [PubMed] Related Publications
PURPOSE: Platinum-based drugs, particularly cisplatin (DDP), are used in the treatment of non-small cell lung cancer (NSCLC). However, development of drug resistance remains the major therapeutic barrier in NSCLC.
METHODS: The potential cisplatin resistance-related genes were identified from the global transcriptomes of cisplatin-resistant A549/DDP cells using microarray analysis. Gain- and loss-of-function assays were performed to analyze the effects of Forkhead Box Protein C2 (FOXC2) on the in vitro and in vivo sensitivity of NSCLC cells to cisplatin and its possible molecular mechanisms.
RESULTS: Using global transcriptome analysis, we found that FOXC2 was one of the most upregulated molecules in A549/DDP cells compared with A549 cells. We further confirmed that the expression of FOXC2 was significantly increased in cisplatin-resistant NSCLC tissues. FOXC2 knockdown significantly increased the in vitro and in vivo sensitivity of A549/DDP cells to cisplatin, whereas overexpression of FOXC2 increased cisplatin resistance in cisplatin-sensitive NSCLC cells. Moreover, we found that FOXC2 promoted cisplatin resistance by induction of epithelial-mesenchymal transition (EMT) in NSCLC cells. Furthermore, FOXC2 activated the AKT/GSK3β signaling pathway, and then increased the protein expression of EMT-related transcription factor Snail. Inhibition of AKT or knockdown of Snail reversed FOXC2-induced EMT and cisplatin resistance of NSCLC cells.
CONCLUSION: FOXC2 enhanced cisplatin resistance of NSCLC cells through activating AKT/GSK3β/Snail/EMT signaling pathway, which may be a potential novel therapeutic target for overcoming drug resistance in human NSCLCs.

Meng J, Wang S, Shen X, et al.
Polymorphism of MMP-9 gene is not associated with the risk of urinary cancers: Evidence from an updated meta-analysis.
Pathol Res Pract. 2018; 214(12):1966-1973 [PubMed] Related Publications
OBJECTIVE: Matrix metalloproteinases 9 (MMP-9) is a zinc-dependent gelatinase, which could decrease the expression of extracellular matrix proteins and influence the metastatic behavior of tumors. In order to draw a comprehensive and precise result about the relationship of MMP-9 and urinary cancers, we presented the current meta-analysis.
METHODS: We searched the PubMed, EMbase, Web of Science, CBM, CNKI and Wanfang databases, the cited references were also manually searched again, covering all the papers published until August 2018. Quality assessment was conducted using the Newcastle-Ottawa Scale. All the meta-analysis was conducted with Stata version 12.0 software to assess the strength of the association. Linkage disequilibrium (LD) analyses of gene polymorphisms and in-silico analysis of MMP-9 expression were also conducted to illustrate the relationship.
RESULTS: 17 case-control studies comprise of more than 6154 cases and 6330 controls were enrolled and analyzed. After analyzed, we found that there is no significant association between rs3918241, rs2250889, rs17576 and rs17577 of MMP-9 and urinary cancers. LD analysis uncovered a significant LD between rs3918241 and rs17577 in CEU, CHB&CHS, ESN, and JPT populations (CEU: r
CONCLUSIONS: rs3918241, rs2250889, rs17576 and rs17577 polymorphisms of MMP-9 are not associated with altered risk of urinary cancer. More studies with large sample size focused on the combined effect of two or more polymorphisms of MMP-9 are necessary in the future.

Currall BB, Chen M, Sallari RC, et al.
Loss of LDAH associated with prostate cancer and hearing loss.
Hum Mol Genet. 2018; 27(24):4194-4203 [PubMed] Article available free on PMC after 15/12/2019 Related Publications
Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the underpinnings of a constellation of phenotypes that include prostate cancer (PCa) and sensorineural hearing loss (SNHL) in a human subject. Through interrogation of the subject's de novo, germline, balanced chromosomal translocation, we first identify a correlation between his disorders and a poorly annotated gene known as lipid droplet associated hydrolase (LDAH). Using data repositories of both germline and somatic variants, we identify convergent genomic evidence that substantiates a correlation between loss of LDAH and PCa. This correlation is validated through both in vitro and in vivo models that show loss of LDAH results in increased risk of PCa and, to a lesser extent, SNHL. By leveraging convergent evidence in emerging genomic data, we hypothesize that loss of LDAH is involved in PCa and other phenotypes observed in support of a genotype-phenotype association in an n-of-one human subject.

Hua JT, Ahmed M, Guo H, et al.
Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19.
Cell. 2018; 174(3):564-575.e18 [PubMed] Related Publications
The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively. Mechanistically, the risk SNP region is bifunctional with both promoter and enhancer activity. The risk variants of rs11672691 and its LD SNP rs887391 decrease binding of transcription factors NKX3.1 and YY1 to the promoter of PCAT19-short, resulting in weaker promoter but stronger enhancer activity that subsequently activates PCAT19-long. PCAT19-long interacts with HNRNPAB to activate a subset of cell-cycle genes associated with PCa progression, thereby promoting PCa tumor growth and metastasis. Taken together, these findings reveal a risk SNP-mediated promoter-enhancer switching mechanism underlying both initiation and progression of aggressive PCa.

Li D, Song H, Mei H, et al.
Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4.
Nat Commun. 2018; 9(1):2829 [PubMed] Article available free on PMC after 15/12/2019 Related Publications
Recent studies suggest the emerging roles of armadillo (ARM) family proteins in tumor progression. However, the functions and underlying mechanisms of ARM members in tumorigenesis and aggressiveness of neuroblastoma (NB) remain to be determined. Herein, we identify armadillo repeat containing 12 (ARMC12) as an ARM member associated with NB progression. ARMC12 promotes the growth and aggressiveness of NB cell lines. Mechanistically, ARMC12 physically interacts with retinoblastoma binding protein 4 (RBBP4) to facilitate the formation and activity of polycomb repressive complex 2, resulting in transcriptional repression of tumor suppressive genes. Blocking the interaction between ARMC12 and RBBP4 by cell-penetrating inhibitory peptide activates the downstream gene expression and suppresses the tumorigenesis and aggressiveness of NB cells. Both ARMC12 and RBBP4 are upregulated in NB tissues, and are associated with unfavorable outcome of patients. These findings suggest the crucial roles of ARMC12 in tumor progression and a potential therapeutic approach for NB.

Rosenberger A, Hung RJ, Christiani DC, et al.
Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.
Int Arch Occup Environ Health. 2018; 91(8):937-950 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon.
METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes.
RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10
CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Jayson CBK, Arlt H, Fischer AW, et al.
Rab18 is not necessary for lipid droplet biogenesis or turnover in human mammary carcinoma cells.
Mol Biol Cell. 2018; 29(17):2045-2054 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Rab GTPases recruit peripheral membrane proteins and can define organelle identity. Rab18 localizes to the endoplasmic reticulum (ER) but also to lipid droplets (LDs), where it has been implicated in effector protein recruitment and in defining LD identity. Here, we studied Rab18 localization and function in a human mammary carcinoma cell line. Rab18 localized to the ER and to LD membranes on LD induction, with the latter depending on the Rab18 activation state. In cells lacking Rab18, LDs were modestly reduced in size and numbers, but we found little evidence for Rab18 function in LD formation, LD turnover on cell starvation, or the targeting of several proteins to LDs. We conclude that Rab18 is not a general, necessary component of the protein machinery involved in LD biogenesis or turnover.

Jang JE, Kim HP, Han SW, et al.
NFATC3-PLA2G15 Fusion Transcript Identified by RNA Sequencing Promotes Tumor Invasion and Proliferation in Colorectal Cancer Cell Lines.
Cancer Res Treat. 2019; 51(1):391-401 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
PURPOSE: This study was designed to identify novel fusion transcripts (FTs) and their functional significance in colorectal cancer (CRC) lines.
Materials and Methods: We performed paired-end RNA sequencing of 28 CRC cell lines. FT candidates were identified using TopHat-fusion, ChimeraScan, and FusionMap tools and further experimental validation was conducted through reverse transcription-polymerase chain reaction and Sanger sequencing. FT was depleted in human CRC line and the effects on cell proliferation, cell migration, and cell invasion were analyzed.
RESULTS: One thousand three hundred eighty FT candidates were detected through bioinformatics filtering. We selected six candidate FTs, including four inter-chromosomal and two intrachromosomal FTs and each FT was found in at least one of the 28 cell lines. Moreover, when we tested 19 pairs of CRC tumor and adjacent normal tissue samples, NFATC3-PLA2G15 FT was found in two. Knockdown of NFATC3-PLA2G15 using siRNA reduced mRNA expression of epithelial-mesenchymal transition (EMT) markers such as vimentin, twist, and fibronectin and increased mesenchymal-epithelial transition markers of E-cadherin, claudin-1, and FOXC2 in colo-320 cell line harboring NFATC3-PLA2G15 FT. The NFATC3-PLA2G15 knockdown also inhibited invasion, colony formation capacity, and cell proliferation.
CONCLUSION: These results suggest that that NFATC3-PLA2G15 FTs may contribute to tumor progression by enhancing invasion by EMT and proliferation.

Siddamalla S, Reddy TV, Govatati S, et al.
Influence of tumour suppressor gene (TP53, BRCA1 and BRCA2) polymorphisms on polycystic ovary syndrome in South Indian women.
Eur J Obstet Gynecol Reprod Biol. 2018; 227:13-18 [PubMed] Related Publications
OBJECTIVE: Polycystic Ovary Syndrome (PCOS) is a heterogeneous multifactorial endocrine metabolic disorder. In addition to hyperandrogenism, acne, hirsutism, obesity, oligoanovulation and infertility, insulin resistance is also a common feature in women of PCOS. Tumor suppressor genes (TSGs) perform essential function in the maintenance of genomic stability and regulatory pathways influencing the activity of several replication and transcription factors. The main aim of this study was to investigate the association of Single Nucleotide Polymorphisms of TP53, BRCA1and BRCA2 genes with the susceptibility to PCOS in South Indian women.
STUDY DESIGN: Present study investigated association between TP53 gene (rs1042522 G/C), BRCA1 (rs71361504 -/GTT, rs3092986 T/C) and BRCA2 (rs206118 A/G) and, SNPs and PCOS risk. Genotyping of TSGs was carried out on DNA from PCOS patients (n = 110) and controls (n = 130) of South Indian origin by polymerase chain reaction (PCR) and confirmed by sequencing analysis. The genotype frequency and allele distributions of cases and controls were analyzed using Fisher's exact test. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pair wise linkage disequilibrium (LD) were assessed by Haploview Software.
RESULTS: Significant increase in frequencies ofTP53 (rs1042522 G/C), BRCA1 (rs71361504 -/GTT, rs3092986 T/C) genotypes and alleles in patients compared to controls. In addition, the frequency of the C/T (P = 0.002) and A/C (P = 0.012) haplotype was also significantly elevated in patients. But BRCA2 (rs206118 A/G) did not show significant association with PCOS.
CONCLUSION: The TP53 and BRCA1 may constitute an inheritable risk factor for PCOS in South Indian women.

Andergassen U, Schlenk K, Jeschke U, et al.
Epithelial‑mesenchymal transition was identified as a potential marker for breast cancer aggressiveness using reverse transcription‑quantitative polymerase chain reaction.
Mol Med Rep. 2018; 18(2):1733-1739 [PubMed] Related Publications
The primary cause of breast cancer‑associated mortality is the formation of distant metastasis. During the metastatic process, single tumor cells dissolve from the primary tumor site and undergo various changes in cell adhesion and motility properties. The tumor cells invade the blood stream and travel to different sites of the body, where they may initiate outgrowth. These cells are referred to as circulating tumor cells (CTCs). The process of changing cellular properties is known as epithelial to mesenchymal transition (EMT). As a different set of genes is upregulated during EMT, such genes may serve as marker genes for the detection of CTCs based on reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Therefore, EMT‑ and breast cancer‑related genes were selected as RT‑qPCR markers. These genes were tested for performance in a model system of blood samples from healthy donors, to which a number of various breast cancer cell lines were added. The genes with optimal performance were subsequently used in RT‑qPCR with 35 breast cancer patient samples. The genes which showed the highest and most consistent increase in gene expression with the increase in the number of cancer cell line cells added were CK19, Snail, FoxC2 and Twist. Following RT‑qPCR for all patient samples, two subgroups were arranged: One group in which all genes were downregulated and the second group with at least one gene indicated an upregulation of gene expression. Comparisons were made between the tumour characteristics from these two groups. Results suggested that carcinomas of the first group exhibited a less aggressive tumor biology compared with those in the second group. The present study indicated a novel RT‑qPCR based test for tumor malignancy.

Barfield R, Feng H, Gusev A, et al.
Transcriptome-wide association studies accounting for colocalization using Egger regression.
Genet Epidemiol. 2018; 42(5):418-433 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Integrating genome-wide association (GWAS) and expression quantitative trait locus (eQTL) data into transcriptome-wide association studies (TWAS) based on predicted expression can boost power to detect novel disease loci or pinpoint the susceptibility gene at a known disease locus. However, it is often the case that multiple eQTL genes colocalize at disease loci, making the identification of the true susceptibility gene challenging, due to confounding through linkage disequilibrium (LD). To distinguish between true susceptibility genes (where the genetic effect on phenotype is mediated through expression) and colocalization due to LD, we examine an extension of the Mendelian randomization (MR) egger regression method that allows for LD while only requiring summary association data for both GWAS and eQTL. We derive the standard TWAS approach in the context of MR and show in simulations that the standard TWAS does not control type I error for causal gene identification when eQTLs have pleiotropic or LD-confounded effects on disease. In contrast, LD-aware MR-Egger (LDA MR-Egger) regression can control type I error in this case while attaining similar power as other methods in situations where these provide valid tests. However, when the direct effects of genetic variants on traits are correlated with the eQTL associations, all of the methods we examined including LDA MR-Egger regression can have inflated type I error. We illustrate these methods by integrating gene expression within a recent large-scale breast cancer GWAS to provide guidance on susceptibility gene identification.

Shimoda Y, Ubukata Y, Handa T, et al.
High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma.
BMC Cancer. 2018; 18(1):597 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC.
METHODS: The expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma.
RESULTS: A high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis.
CONCLUSION: The high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.

Agnihotri NS, Astekar M
The role of novel prognostic markers PROX1 and FOXC2 in carcinogenesis of oral squamous cell carcinoma.
J Exp Ther Oncol. 2018; 12(3):171-184 [PubMed] Related Publications
objective: Oral squamous cell carcinoma is the most common malignant tumor of the head and neck regions and accounts for more than 90% of cancers in the oral cavity. The angiogenesis, lymphangiogenesis and epithelial mesenchymal transition are known to be pivotal for tumor progression and metastasis. In the last decade, much data has been generated concerning the molecular mechanisms of angiogenesis, lymphangiogenesis and its significance in pathological conditions. The main angiogenic and lymphangiogenic factors have been identified as vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGFR-2), forkhead box (FOX) C2 while vascular endothelial growth factor C/D (VEGF-C/D), vascular endothelial growth factor receptor 3 (VEGFR-3), Prospero homeobox 1 (PROX1), LYVE-1, podoplanin, Tie/Angioprotein (Ang) 2 and EphrinB2 respectively. PROX1 is a mammalian homologue of Drosophilia homeobox protein, prospero and important for the embryonic development of many mammalian tissues. It has been suggested that it plays various tissue dependent functional roles, which reflects both oncogenic potential and a tumor suppressive role. The exact role in OSCC remains controversial. FOXC2 is a transcription factor belongs to large family of protein, forkhead box. It has been shown to be involved in cancer angiogenesis, proliferation and metastasis through its induction of epithelial-to-mesenchymal transition while its significance in OSCC remains unknown. Based on these data, this article reviews the role of novel prognostic factors PROX1 and FOXC2 in carcinogenesis of OSCC so that they might be considered as an attractive therapeutic target for both tumor associated blood vessels, lymphatic vessels and tumor cells.

Li D, Chen Y, Mei H, et al.
Ets-1 promoter-associated noncoding RNA regulates the NONO/ERG/Ets-1 axis to drive gastric cancer progression.
Oncogene. 2018; 37(35):4871-4886 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Emerging studies have indicated the essential functions of long noncoding RNAs (lncRNAs) during cancer progression. However, whether lncRNAs contribute to the upregulation of v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1), an established oncogenic protein facilitating tumor invasion and metastasis, in gastric cancer remains elusive. Herein, we identified Ets-1 promoter-associated noncoding RNA (pancEts-1) as a novel lncRNA associated with the gastric cancer progression via mining of publicly available datasets and rapid amplification of cDNA ends. RNA pull-down, RNA immunoprecipitation, in vitro binding, and RNA electrophoretic mobility shift assays indicated the binding of pancEts-1 to non-POU domain containing octamer binding (NONO) protein. Mechanistically, pancEts-1 facilitated the physical interaction between NONO and Ets related gene (ERG), resulting in increased ERG transactivation and transcription of Ets-1 associated with gastric cancer progression. In addition, pancEts-1 facilitated the growth and aggressiveness of gastric cancer cells via interacting with NONO. In gastric cancer tissues, pancEts-1, NONO, and ERG were upregulated and significantly correlated with Ets-1 levels. High levels of pancEts-1, NONO, ERG, or Ets-1 were respectively associated with poor survival of gastric cancer patients, whereas simultaneous expression of all of them (HR = 3.012, P = 0.105) was not an independent prognostic factor for predicting clinical outcome. Overall, these results demonstrate that lncRNA pancEts-1 exhibits oncogenic properties that drive the progression of gastric cancer via regulating the NONO/ERG/Ets-1 axis.

Kandori S, Kojima T, Matsuoka T, et al.
Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin.
Cancer Sci. 2018; 109(6):1865-1875 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
A hallmark of clear cell renal cell carcinoma (ccRCC) is the presence of intracellular lipid droplets (LD) and it is assumed that phosphatidic acid (PA) produced by phospholipase D (PLD) plays some role in the LD formation. However, little is known about the significance of PLD in ccRCC. In this study, we examined the expression levels of PLD in ccRCC. The classical mammalian isoforms of PLD are PLD1 and PLD2, and the levels of both mRNA were higher at the primary tumor sites than in normal kidney tissues. Similarly, both PLD were significantly abundant in tumor cells as determined by analysis using immunohistochemical staining. Importantly, a higher level of PLD was significantly associated with a higher tumor stage and grade. Because PLD2 knockdown effectively suppressed the cell proliferation and invasion of ccRCC as compared with PLD1 in vitro, we examined the effect of PLD2 in vivo. Notably, shRNA-mediated knockdown of PLD2 suppressed the growth and invasion of tumors in nude mouse xenograft models. Moreover, the higher expression of PLD2 was significantly associated with poorer prognosis in 67 patients. As for genes relating to the tumor invasion of PLD2, we found that angiogenin (ANG) was positively regulated by PLD2. In fact, the expression levels of ANG were elevated in tumor tissues as compared with normal kidney and the inhibition of ANG activity with a neutralizing antibody significantly suppressed tumor invasion. Overall, we revealed for the first time that PLD2-produced PA promoted cell invasion through the expression of ANG in ccRCC cells.

Zhou Q, Peng C, Du F, et al.
Design, synthesis and activity of BBI608 derivatives targeting on stem cells.
Eur J Med Chem. 2018; 151:39-50 [PubMed] Related Publications
STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and cancer stemness properties, can inhibit stemness gene expression and kill stemness-high cancer cells isolated from a variety of cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC

Si L, Yan X, Hao W, et al.
Licochalcone D induces apoptosis and inhibits migration and invasion in human melanoma A375 cells.
Oncol Rep. 2018; 39(5):2160-2170 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The aim of the present study was to determine the effects of Licochalcone D (LD) on the apoptosis and migration and invasion in human melanoma A375 cells. Cell proliferation was determined by sulforhodamine B assay. Apoptosis was assessed by Hoechst 33258 and Annexin V‑FITC/PI staining and JC‑1 assay. Total intracellular reactive oxygen species (ROS) was examined by DCFH‑DA. Wound healing and Transwell assays were used to detect migration and invasion of the cells. The activities of matrix metalloproteinase (MMP‑2 and MMP‑9) were assessed via gelatin zymography. Tumor growth in vivo was evaluated in C57BL/6 mice. RT‑PCR, qPCR, ELISA and western blot analysis were utilized to measure the mRNA and protein levels. Our results showed that LD inhibited the proliferation of A375 and SK‑MEL‑5 cells in a concentration‑dependent manner. After treatment with LD, A375 cells displayed obvious apoptotic characteristics, and the number of apoptotic cells was significantly increased. Pro‑apoptotic protein Bax, caspase‑9 and caspase‑3 were upregulated, while anti‑apoptotic protein Bcl‑2 was downregulated in the LD‑treated cells. Meanwhile, LD induced the loss of mitochondrial membrane potential (ΔΨm) and increased the level of ROS. ROS production was inhibited by the co‑treatment of LD and free radical scavenger N‑acetyl‑cysteine (NAC). Furthermore, LD also blocked A375 cell migration and invasion in vitro which was associated with the downregulation of MMP‑9 and MMP‑2. Finally, intragastric administration of LD suppressed tumor growth in the mouse xenograft model of murine melanoma B16F0 cells. These results suggest that LD may be a potential drug for human melanoma treatment by inhibiting proliferation, inducing apoptosis via the mitochondrial pathway and blocking cell migration and invasion.

Yang H, Chen T, Xu S, et al.
Long Noncoding RNA FOXC2-AS1 Predicts Poor Survival in Breast Cancer Patients and Promotes Cell Proliferation.
Oncol Res. 2019; 27(2):219-226 [PubMed] Related Publications
Breast cancer (BC) is the most common malignant tumor in women. Recently, long noncoding RNAs (lncRNAs) have been proposed as critical regulators in biological processes, including tumorigenesis. FOXC2-AS1, a single antisense oligonucleotide RNA transcribed from the negative strand of forkhead box protein C2 (FOXC2), has been identified as an oncogene in osteosarcoma. In the present study, we investigated the prognosis value and biological role of FOXC2-AS1 in BC. Our findings revealed that FOXC2-AS1 was significantly increased in BC tissues and cell lines, and Kaplan-Meier survival analysis indicated that a high level of FOXC2-AS1 was associated with poor prognosis of BC patients. Loss of function revealed that silenced FOXC2-AS1 significantly suppressed the proliferation ability, and flow cytometric analysis illustrated the influence of FOXC2-AS1 on cell cycle and apoptosis rate. Finally, we found that cyclin D1, cyclin D2, and cyclin D3 were all partly positively modulated by FOXC2-AS1 in BC. Collectively, FOXC2-AS1 may serve as a promising prognostic biomarker and therapeutic target for BC patients.

Springer SU, Chen CH, Rodriguez Pena MDC, et al.
Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy.
Elife. 2018; 7 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.

Jiao W, Chen Y, Song H, et al.
HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis.
Oncogene. 2018; 37(20):2728-2745 [PubMed] Related Publications
Recent studies reveal the emerging functions of enhancer RNAs (eRNAs) in gene expression. However, the roles of eRNAs in regulating the expression of heparanase (HPSE), an established endo-β-D-glucuronidase essential for cancer invasion and metastasis, still remain elusive. Herein, through comprehensive analysis of publically available FANTOM5 expression atlas and chromatin interaction dataset, we identified a super enhancer and its derived eRNA facilitating the HPSE expression (HPSE eRNA) in cancers. Gain-of-function and loss-of-function experiments indicated that HPSE eRNA facilitated the in vitro and in vivo tumorigenesis and aggressiveness of cancer cells. Mechanistically, as a p300-regulated nuclear noncoding RNA, HPSE eRNA bond to heterogeneous nuclear ribonucleoprotein U (hnRNPU) to facilitate its interaction with p300 and their enrichment on super enhancer, resulting in chromatin looping between super enhancer and HPSE promoter, p300-mediated transactivation of transcription factor early growth response 1 (EGR1), and subsequent elevation of HPSE expression. In addition, rescue studies in HPSE overexpressing or silencing cancer cells indicated that HPSE eRNA exerted oncogenic properties via driving HPSE expression. In clinical cancer tissues, HPSE eRNA was highly expressed and positively correlated with HPSE levels, and served as an independent prognostic factor for poor outcome of cancer patients. Therefore, these findings indicate that as a novel noncoding RNA, HPSE eRNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis.

O'Brien TD, Jia P, Caporaso NE, et al.
Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels.
Genome Med. 2018; 10(1):16 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype.
METHODS: We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype.
RESULTS: We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10
CONCLUSIONS: Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype.

Zheng Y, Zeng Y, Qiu R, et al.
The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.
Theranostics. 2018; 8(4):972-989 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The homeodomain transcription factor SIX3 was recently reported to be a negative regulator of the Wnt pathway and has an emerging role in cancer. However, how SIX3 contributes to tumorigenesis and metastasis is poorly understood.
METHODS: We employed affinity purification and mass spectrometry (MS) to identify the proteins physically associated with SIX3. Genome-wide analysis of the SIX3/LSD1/NuRD(MTA3) complex using a chromatin immunoprecipitation-on-chip approach identified a cohort of target genes including
RESULTS: We demonstrate that the SIX3/LSD1/NuRD(MTA3) complex inhibits carcinogenesis in breast cancer cells and suppresses metastasis in breast cancer. SIX3 expression is downregulated in various human cancers and high SIX3 is correlated with improved prognosis.
CONCLUSION: Our study revealed an important mechanistic link between the loss of function of SIX3 and tumor progression, identified a molecular basis for the opposing actions of MTA1 and MTA3, and may provide new potential prognostic indicators and targets for cancer therapy.

Ogura Y, Yabuki S, Fujibayashi S, et al.
A screening method to distinguish syndromic from sporadic spinal extradural arachnoid cyst.
J Orthop Sci. 2018; 23(3):455-458 [PubMed] Related Publications
BACKGROUND: Spinal extradural arachnoid cyst (SEDAC) is a cystic lesion that protrudes into the epidural space from a small dural defect. Early diagnosis of SEDAC is important because its expansion causes neurological damage. Two types of SEDAC, syndromic and sporadic, are present. Syndromic SEDAC is inherited as a part of lymphedema-distichiasis syndrome caused by mutations in the FOXC2 gene; however, it is often mistaken as sporadic because of low penetrance. It is not reasonable to conduct a genetic testing for all SEDAC patients and their family members. The aim of this study is to establish an effective screening method to distinguish syndromic SEDAC from sporadic SEDAC.
METHODS: We performed a retrospective review of medical records and imaging studies of 29 subjects who were diagnosed with SEDAC. Clinical features, family history and magnetic resonance imaging (MRI) were analyzed. Mutations in FOXC2 were examined by Sanger-sequencing of the entire coding region of the genes. SEDAC having a mutation in FOXC2 gene was defined with syndromic SEDAC.
RESULTS: Eleven subjects had a heterozygous mutation in FOXC2. They were all familial and hence syndromic SEDAC. Only one proband had known family history of SEDAC at diagnosis. MRI findings and physical examinations, especially eye and leg examinations, were quite useful to screen syndromic SEDAC. Physical examination often showed accompanying lymphedema and distichiasis in syndromic SEDAC. Syndromic SEDAC tended to have multiple cysts out of the thoracolumbar area.
CONCLUSIONS: We established an effective screening method based on physical examinations and MRI findings.

Bowers LW, Rossi EL, McDonell SB, et al.
Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models.
Mol Cancer Res. 2018; 16(5):869-879 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Obesity is associated with poor prognosis in triple-negative breast cancer (TNBC). Preclinical models of TNBC were used to test the hypothesis that increased leptin signaling drives obesity-associated TNBC development by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). MMTV-Wnt-1 transgenic mice, which develop spontaneous basal-like, triple-negative mammary tumors, received either a control diet (10% kcal from fat) or a diet-induced obesity regimen (DIO, 60% kcal from fat) for up to 42 weeks (

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