Gene Summary

Gene:FOXG1; forkhead box G1
Summary:This locus encodes a member of the forked-head transcription factor family. The encoded protein, which functions as a repressor, may play a role in brain development. Mutations at this locus have been associated with Rett syndrome. [provided by RefSeq, Feb 2012]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:forkhead box protein G1
Source:NCBIAccessed: 21 August, 2015


What does this gene/protein do?
Show (28)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 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.

  • Wilms Tumour
  • Nuclear Proteins
  • Forkhead Transcription Factors
  • Oncogene Proteins
  • Tumor Suppressor Proteins
  • DNA Methylation
  • Epigenetics
  • Sequence Deletion
  • CDKN1A
  • Phosphatidylinositol 3-Kinases
  • Viral Proteins
  • DNA-Binding Proteins
  • Chromosome 14
  • Neoplastic Cell Transformation
  • Transforming Growth Factor beta
  • Transcription Factors
  • Proto-Oncogene Proteins
  • Brain Tumours
  • Transcription
  • Amino Acid Sequence
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Childhood Cancer
  • Prostate Cancer
  • Promoter Regions
  • Apoptosis
  • Up-Regulation
  • Oligonucleotide Array Sequence Analysis
  • Transcriptome
  • Cancer Gene Expression Regulation
  • Immunohistochemistry
  • Gene Dosage
  • Cyclins
  • Nerve Tissue Proteins
  • Brain Tumours
  • Cell Division
  • Signal Transduction
  • Trans-Activators
  • Statistics, Nonparametric
  • Repressor Proteins
Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: FOXG1 (cancer-related)

Li F, Hao M, Feng X, et al.
Downregulated miR-33b is a novel predictor associated with disease progression and poor prognosis in multiple myeloma.
Leuk Res. 2015; 39(7):793-9 [PubMed] Related Publications
MiRNAs located at chromosome fragile sites play important roles in regulating critical genes associated with myeloma pathogenesis, disease progression and drug resistance. Our previous results have identified miR-33b (located in chromosome 17p) was one of the dysregulated miRNAs in the sera of newly diagnosed MM patients. However, little is known about its expression pattern in myeloma tumor cells and its prognostic value in MM patients. In the present study, we investigated the expression pattern of miR-33b in 58 newly diagnosed, 11 relapsed, 12 remission MM patients and 18 health donors by quantitative real-time PCR. Our results showed the expression of miR-33b was obviously down-regulated in newly diagnosed and relapsed MM patients compared to remission patients and health donors (p<0.001). Moreover, patients with del(13q), del(17p), t(4;14) and high-risk genetic abnormalities have lower expression levels of miR-33b compared to patients without those of abnormalities (p=0.032, 0.018, 0.034, 0.005). Survival analysis showed patients with miR-33b low expression had significantly shortened PFS (p=0.016) and OS (p=0.033) and might be associated with drug resistance to bortezomib-based treatment. Our data suggest that down-regulated miR-33b might be a novel predictor associated with disease progression and poor prognosis in MM.

Ge X, Wang H, Zeng H, et al.
Clinical significance of assessing Her2/neu expression in gastric cancer with dual tumor tissue paraffin blocks.
Hum Pathol. 2015; 46(6):850-7 [PubMed] Related Publications
One paraffin block is routinely used for human epidermal growth factor receptor 2 (Her2/neu) immunohistochemistry (IHC) assessment. Here, we investigated if picking 2 paraffin blocks for Her2/neu evaluation on 1 slide is an economical, efficient, and practical method, which may reduce false negativity of Her2/neu IHC assessment due to intratumoral heterogeneity. A total of 251 gastric cancer (GC) patients were divided into a cohort using 1 tumor tissue paraffin block (single-block group, n = 132) and a cohort using dual tumor tissue paraffin blocks (dual-block group, n = 119) when evaluating Her2/neu expression status by IHC. In dual-block group, we combined the results from 2 different paraffin blocks and used the higher one as the final score. The number of IHC 1+, 2+, and 3+ specimens in the single-block group was 31 (23.5%), 40 (30.3%), and 19 (14.4%), respectively. The combined final IHC score in the dual-block group of 1+, 2+, and 3+ was 26 (21.8%), 34 (28.6%), and 23 (19.3%), respectively. Inconsistent Her2/neu expression between blocks was found in 36 (30.3%) cases in the dual-block group. The pooled data in the single-block group and the dual-block group indicated that, when using dual blocks, the Her2/neu-positive (3+) rate of GC was higher compared to that in the single-block group. Our results implied that using dual paraffin blocks to assess Her2/neu expression of GC may help identify more patients with Her2/neu-positive GC who could benefit from targeted therapy, by reducing false-negative rate of Her2 status assessment. This is an efficient, economical, and practical method for Her2/neu evaluation of GC.

Dai L, Chen Y, Toole B, et al.
Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients.
Cancer Lett. 2015; 362(2):158-66 [PubMed] Article available free on PMC after 01/07/2016 Related Publications
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), malignancies arising primarily in immunocompromised patients particularly AIDS-patients, which still lack effective therapy. Hyaluronan (HA) is a large glucuronic acid and has been found closely related to multiple functions in cancer cells, although its role in viral oncogenesis remains largely unknown. Here we provide first evidence that KSHV de novo infection induces HA production from primary endothelial cells through upregulation of HA synthase gene 1 (Has1) and a multifunctional glycoprotein, CD147. Further data demonstrate that KSHV-induced HA production requires viral latent protein, LANA (in particular functional domain A) and MAPK/ERK signaling activities. In functions, HA production is necessary for KSHV/LANA-induced primary endothelial cell invasion, a hallmark feature for KS development. For clinical relevance, our data indicate that the KSHV+ group has higher levels of HA and Has1 activities in its plasma than the KSHV- group of cohort HIV-infected patients. Together, our findings provide innovative insights into the mechanisms of oncogenic virus activation of HA production and its role in virus-associated malignancy pathogenesis, which may help to develop novel therapeutic strategies by targeting HA and related signaling.

Liu Y, Xie L, Zhao J, et al.
Association between catalase gene polymorphisms and risk of chronic hepatitis B, hepatitis B virus-related liver cirrhosis and hepatocellular carcinoma in Guangxi population: a case-control study.
Medicine (Baltimore). 2015; 94(13):e702 [PubMed] Related Publications
Reactive oxygen species (ROS) play critical roles in hepatocarcinogenesis. The catalase (CAT) enzyme is involved in the repair of ROS. Therefore, we investigate the association between CAT gene polymorphisms and the risk of hepatocellular carcinoma (HCC). A total of 715 subjects were divided into 4 groups: 111 chronic hepatitis B (CHB) patients, 90 hepatitis B virus (HBV)-related liver cirrhosis (LC) patients, 266 HBV-HCC patients, and 248 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect CAT gene rs1001179, rs769217, and rs7943316 polymorphisms. Binary logistic regression analyses adjusting for sex, age, ethnicity, smoking and alcohol consumption, and body mass index suggested that subjects carrying the rs769217 T allele were at marginally increased risk of CHB, LC, and HCC, with adjusted odds ratios (ORs) of 1.51 (95% confidence interval [CI] = 1.04-2.20, P = 0.029), 1.48 (95% CI = 1.03-2.14, P = 0.035), and 1.51 (95% CI = 1.14-1.98, P = 0.004), respectively. Similarly, those individuals carrying the rs769217 TT genotype had a moderately increased risk of CHB, LC, and HCC, with adjusted ORs of 2.11 (95% CI = 1.05-4.22, P = 0.035), 2.00 (95% CI, 1.01-3.95, P = 0.047), and 1.93 (95% CI = 1.14-3.28, P = 0.015), respectively. Moreover, subjects carrying the rs769217 CT genotype and at least 1 copy of the T allele (dominant model) were 1.78 times and 1.83 times more likely to develop HCC, respectively (OR = 1.78, 95% CI = 1.16-2.73, P = 0.009 and OR = 1.83, 95% CI = 1.23-2.71, P = 0.003). This association between CAT rs769217 T alleles and HCC risk is significantly strengthened among men, nonsmokers, nondrinkers, and among individuals <50 years of age. Furthermore, we found 1 high-risk haplotype GTA for CHB (OR = 1.45, 95% CI = 1.05-2.01) and 1 protective haplotype GCA for HCC risk (OR = 0.67, 95% CI = 0.52-0.87). We did not found any significant difference in CAT rs1001179 and rs7943316 polymorphisms between controls and cases. Our findings suggest that the CAT rs769217 T allele is associated with increased risk of CHB, HBV-LC, and HBV-HCC in Guangxi population.

Meldi K, Qin T, Buchi F, et al.
Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia.
J Clin Invest. 2015; 125(5):1857-72 [PubMed] Related Publications
Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable, with few means to predict which patients will benefit. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next-generation sequencing. These DMRs were primarily localized to nonpromoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. Transcriptional analysis revealed differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34+ and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance.

Liu Y, Zhang M, Qian J, et al.
miR-134 functions as a tumor suppressor in cell proliferation and epithelial-to-mesenchymal Transition by targeting KRAS in renal cell carcinoma cells.
DNA Cell Biol. 2015; 34(6):429-36 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
Aberrant microRNAs (miRNAs) are reported to contribute to the pathogenesis of most human malignancies. The miRNA, miR-134, has been found to be downregulated in renal cell carcinoma (RCC), but its function in the disease is unknown. The aims of this study were to detect the expression of miR-134 in human RCC samples and explore its function in RCC cell lines. Real-time qualitative polymerase chain reaction (qPCR) was used to quantify miR-134 in human RCC samples. Assays for cell cycle, viability, migration, and invasion were performed to assess the phenotypic changes in RCC cells. A luciferase reporter assay was carried out to confirm whether KRAS (Kirsten rat sarcoma viral oncogene homolog) is a direct target of miR-134. Western blot was used to identify the potential signaling pathways that had an impact on RCC cell growth and alterations of markers for epithelial-mesenchymal transition (EMT), which affected metastasis by miR-134. miR-134 was found to be downregulated in RCC samples (p<0.05), while overexpression of miR-134 suppressed proliferation (p<0.05) by triggering G1/G0 cell cycle arrest (p<0.05). Forced expression of miR-134 could also inhibit migration (p<0.05) and invasion (p<0.05) by blocking EMT in RCC cell lines. KRAS was identified as a target of miR-134, and miR-134 may act as a tumor suppressor through the KRAS-related MAPK/ERK pathway other than PI3K/AKT signaling. Thus, miR-134 may function as a tumor suppressor in cell proliferation and EMT by targeting KRAS in RCC cells.

Wang L, Zhang W, Lyu S, et al.
Clinicopathologic characteristics and molecular subtypes of microinvasive carcinoma of the breast.
Tumour Biol. 2015; 36(4):2241-8 [PubMed] Related Publications
Patients with microinvasive carcinoma often have favorable prognosis, but it remains unclear whether this special type of breast cancer represents a distinct morphological entity with its own biological features and clinical behavior distinct from those of ductal carcinoma in situ (DCIS). The study is a retrospective analysis of a large patient cohort from a single institution. One hundred and thirty one microinvasive carcinoma and 451 DCIS cases were collected. ER, PR, HER2, and Ki67 were examined by immunohistochemistry in pathological sections. We assessed the clinicopathologic characteristics, molecular features, and survival status of microinvasive carcinoma and compared to those of DCIS. Microinvasive carcinoma differed from DCIS with respect to tumor size, lymph node status, and initial presentation (P < 0.05). There was a significant difference in nuclear grade among microinvasive carcinoma of different molecular subtype (P < 0.05). The clinicalpathologic features and outcomes of patients with microinvasive carcinoma were similar to those with DCIS. The 5-year OS rate for microinvasive carcinoma and DCIS patients was 99.0 and 99.2%, respectively. A combination of pathologic, clinical, and molecular factors may ultimately reveal more powerful and robust measures for disease classification than any one modality alone. Microinvasive carcinoma does not significantly predict for worse DFS or OS in comparison with patients with DCIS.

Schnell SA, Ambesi-Impiombato A, Sanchez-Martin M, et al.
Therapeutic targeting of HES1 transcriptional programs in T-ALL.
Blood. 2015; 125(18):2806-14 [PubMed] Article available free on PMC after 30/04/2016 Related Publications
Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo.

Zhao WH, Qu XF, Xing ZG, et al.
Association of rs712 polymorphism in Kras gene 3'-luntranslated region and cancer risk: a meta-analysis.
J BUON. 2015 Jan-Feb; 20(1):309-16 [PubMed] Related Publications
PURPOSE: Mutation and polymorphism of Kras oncogene are considered as candidate risk factor and drug response predictor for cancer. However, the conclusions of accumulating reports related to the relationship of rs712 of Kras gene and risk of cancer remain nuclear.
METHODS: We performed a meta-analysis including 6 eligible studies containing 1661 cases and 2139 controls to explore the role of rs712 in the risk of cancer development.
RESULTS: Meta-analysis results showed that rs712 allele T (P(H)=0.08, odds ratio/OR=1.35, 95% confidence interval/ CI=1.17-1.55) and genotype TT (P(H)=0.174, OR=2.32, 95% CI=1.60-3.37), and allele T carrier genotype (GT/TT) (P(H)=0.14, OR=1.30, 95% CI=1.10-1.55) were strongly associated with cancer in Chinese population. No evidence of association was observed between rs712 and risk of cancer in overall population.
CONCLUSION: The findings suggested that allele T, genotype TT and allele T carrier (GT/TT) of rs712 may increase susceptibility to cancer risk in Chinese population, and can be used as a genetic factor for evaluating risk of cancer.

Ye G, Qin Y, Lu X, et al.
The association of renin-angiotensin system genes with the progression of hepatocellular carcinoma.
Biochem Biophys Res Commun. 2015; 459(1):18-23 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Angiogenesis is reported to play a pivotal role in the occurrence, development and metastasis of HCC. The renin-angiotensin system (RAS) is involved in the regulation of angiogenesis. Here, based on the analysis of HCC datasets from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA), we found that there was a negative correlation between the mRNA levels of angiotensin converting enzyme 2 (ACE2) and CD34. To explore the association of RAS with the progression from fibrosis to cirrhosis to HCC, liver specimens and serum samples were collected from patients with hepatic fibrosis, cirrhosis and HCC. Relative hepatic mRNA levels of CD34 and ACE2 were determined by real-time PCR, and the serum concentrations of Angiotensin II (Ang II), Ang (1-7) and vascular endothelial growth factor (VEGF) were detected by ELISA. We found that ACE2 mRNA was gradually decreased, while CD34 mRNA was progressively increased with the increasing grade of disease severity. Concentrations of Ang II, Ang (1-7) and VEGF were higher in the sera of patients than in that of healthy volunteers. These proteins' concentrations were also progressively increased with the increasing grade of disease severity. Moreover, a positive correlation was found between VEGF and Ang II or Ang (1-7), while negative correlation was observed between mRNA levels of CD34 and ACE2. More importantly, patients with higher level of ACE2 expression had longer survival time than those with lower level of ACE2 expression. Taken together, our data suggests that the low expression of ACE2 may be a useful indicator of poor prognosis in HCC. The RAS may have a role in the progression of HCC.

Shi S, Ji S, Qin Y, et al.
Metabolic tumor burden is associated with major oncogenomic alterations and serum tumor markers in patients with resected pancreatic cancer.
Cancer Lett. 2015; 360(2):227-33 [PubMed] Related Publications
Pancreatic cancer is an aggressive and lethal disease with an overall 5-year survival rate of only 5%. Studies have demonstrated the ability of (18)F-fludrodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) to measure the metabolic tumor burden in patients with various tumors, including pancreatic cancer. In a previous study, we investigated the predictive significance of the metabolic tumor burden in terms of the metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this study, we analyzed the correlation between metabolic tumor burden and the status of the KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4 genes. Our results showed that the metabolic tumor burden was associated with oncogenomic alterations that reflected the abnormal expression of carbohydrate metabolic enzymes (GLUT1, ALDOA and FBP1). We also identified a linear correlation between serum tumor markers and the metabolic tumor burden. To estimate the metabolic tumor burden when (18)F-FDG PET/CT is not available, we used the linear regression models to establish equations for MTV and TLG using CA19-9 and CA125 as independent variables. Our results suggest that the metabolic tumor burden, as evaluated by (18)F-FDG PET/CT or estimated by serum tumor markers, may be suitable for monitoring treatment response and disease progression of pancreatic cancer. Further research is needed to better understand why pancreatic cancer patients with abnormal expressions of TP53, CDKN2A/p16, and SMAD4/DPC4 get high metabolic tumor burden.

Xiang C, Wang J, Kou X, et al.
Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer.
FASEB J. 2015; 29(5):1986-98 [PubMed] Related Publications
Inhaled xenobiotics such as tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are mainly metabolized by phase I oxidase cytochrome P450, family 2, subfamily A, polypeptide 13 (CYP2A13), phase II conjugate UDP glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17), and phase III transporter ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1), with genetic polymorphisms implicated in lung cancer. Their genetic interaction and pulmonary expression regulation are largely unknown. We analyzed joint association for CYP2A13 and ABCB1 polymorphisms in 2 independent lung cancer case populations (669 and 566 patients) and 1 common control population (749 subjects), and characterized the trans-acting function of the lung development-related transcription factor forkhead box A2 (FOXA2). We undertook FOXA2 overexpression and down-regulation in lung epithelial cell lines, analyzed functional impact on the transactivation of CYP2A13, UGT2B17, and ABCB1, and measured correlation for their expressions in lung tissues. We found a substantial reduction in cancer risk (OR 0.39; 95% CI 0.25-0.61; Pinteraction = 0.029) associated with combined genotypes for CYP2A13 R257C and a functionary regulatory variant in the cis element of ABCB1 synergistically targeted by GATA binding protein 6 and FOXA2. Genetic manipulation of FOXA2 consistently influenced its binding to and transactivation of the promoters of CYP2A13, UGT2B17, and ABCB1, whose mRNA and protein expressions were all consistently correlated with those of FOXA2 in both tumorous and normal lung tissues. We therefore establish FOXA2 as a core transcriptional modulator for pulmonary xenobiotic metabolic pathways and uncover an etiologically relevant interaction between CYP2A13 and ABCB1, furthering our understanding of expression and function of the xenobiotic metabolism system.

Qin F, Song Z, Babiceanu M, et al.
Discovery of CTCF-sensitive Cis-spliced fusion RNAs between adjacent genes in human prostate cells.
PLoS Genet. 2015; 11(2):e1005001 [PubMed] Article available free on PMC after 30/04/2016 Related Publications
Genes or their encoded products are not expected to mingle with each other unless in some disease situations. In cancer, a frequent mechanism that can produce gene fusions is chromosomal rearrangement. However, recent discoveries of RNA trans-splicing and cis-splicing between adjacent genes (cis-SAGe) support for other mechanisms in generating fusion RNAs. In our transcriptome analyses of 28 prostate normal and cancer samples, 30% fusion RNAs on average are the transcripts that contain exons belonging to same-strand neighboring genes. These fusion RNAs may be the products of cis-SAGe, which was previously thought to be rare. To validate this finding and to better understand the phenomenon, we used LNCaP, a prostate cell line as a model, and identified 16 additional cis-SAGe events by silencing transcription factor CTCF and paired-end RNA sequencing. About half of the fusions are expressed at a significant level compared to their parental genes. Silencing one of the in-frame fusions resulted in reduced cell motility. Most out-of-frame fusions are likely to function as non-coding RNAs. The majority of the 16 fusions are also detected in other prostate cell lines, as well as in the 14 clinical prostate normal and cancer pairs. By studying the features associated with these fusions, we developed a set of rules: 1) the parental genes are same-strand-neighboring genes; 2) the distance between the genes is within 30kb; 3) the 5' genes are actively transcribing; and 4) the chimeras tend to have the second-to-last exon in the 5' genes joined to the second exon in the 3' genes. We then randomly selected 20 neighboring genes in the genome, and detected four fusion events using these rules in prostate cancer and non-cancerous cells. These results suggest that splicing between neighboring gene transcripts is a rather frequent phenomenon, and it is not a feature unique to cancer cells.

Zhou C, Qin Y, Xie Z, et al.
NPTX1 is a novel epigenetic regulation gene and associated with prognosis in lung cancer.
Biochem Biophys Res Commun. 2015; 458(2):381-6 [PubMed] Related Publications
BACKGROUND: CpG island hypermethylation of gene promoters is a well-known mechanism of epigenetic regulation of tumor related-genes and is directly linked to lung carcinogenesis. Alterations in the pattern of methylation of the NPTX1 gene have not yet been studied in detail in human lung cancer.
METHODS: Methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to analyze promoter methylation status, and real-time quantitative reverse transcription-PCR (qRT-PCR) examined mRNA levels. Subsequently, we compared the methylation profile of NPTX1 in samples of neoplastic and non-neoplastic lung tissue taken from the same patients by using quantitative methylation specific PCR (QMSP).
RESULTS: CpG island hypermethylation in promoter of NPTX1 was confirmed in lung cancer cell lines. A significant increase in NPTX1 methylation was identified in lung cancer specimens compared to adjacent noncancerous tissues and that it was negatively correlated with its mRNA expression. The overall survival time among patients carrying methylated NPTX1 tumors was significantly shorter as compared to those with unmethylated NPTX1 tumors (P = 0.011). Moreover, methylation of NPTX1 gene was found to be an independent prognostic factor for poor overall survival based on multivariate analysis models (p = 0.021), as was age ≥60 years old (p = 0.012) and TNM stage (p < 0.001).
CONCLUSIONS: These results suggest that NPTX1 hypermethylation and consequent mRNA changes might be an important molecular mechanism in lung cancer. Epigenetic alterations in NPTX1 may serve as potential diagnostic and prognostic biomarkers in lung cancer.

Cong W, Liu GH, Meng QF, et al.
Toxoplasma gondii infection in cancer patients: prevalence, risk factors, genotypes and association with clinical diagnosis.
Cancer Lett. 2015; 359(2):307-13 [PubMed] Related Publications
Prevalence of human infection with Toxoplasma gondii has been increasing in China due to the increasing number of cats. However, little is known of the epidemiology of T. gondii infection in different cancer patient groups. Thus, a case-control study of 900 cancer patients and 900 controls was conducted to detect anti-T. gondii antibodies by ELISA in China. Genomic DNA was extracted from the diseased tissues of 510 patients and the T. gondii B1 gene was amplified using a semi-nested PCR. DNA samples giving positive B1 amplification were then genetically characterized using multi-locus PCR-RFLP. The prevalence of anti-T. gondii IgG in cancer patients (35.56%) was significantly higher than that in controls (17.44%). The highest T. gondii seroprevalence was detected in lung cancer patients (60.94%), followed by cervical cancer patients (50%), brain cancer patients (42.31%) and endometrial cancer patients (41.67%). Exposure with soil and consumption of raw/undercooked meat were significantly associated with T. gondii infection in cancer patients. Three T. gondii genotypes (ToxoDB#9, ToxoDB#10 and Type I variant) were identified. In conclusion, T. gondii infection is a severe problem in cancer patients and it is imperative that improved integrated measures should be conducted to prevent and control T. gondii infection in cancer patients.

Qin A, Yu Q, Gao Y, et al.
Inhibition of STAT3/cyclinD1 pathway promotes chemotherapeutic sensitivity of colorectal caner.
Biochem Biophys Res Commun. 2015; 457(4):681-7 [PubMed] Related Publications
BACKGROUND: Chemotherapeutic resistance indicated the poor prognosis of colorectal cancer.
OBJECTIVE: Our study aimed to investigate the role of STAT3/cyclinD1 pathway in the chemotherapeutic resistance of colorectal cancer.
METHODS: We firstly measured the expression of cyclinD1 in the colorectal cancer tissues using immunohistochemistry in tissue microarray. Then cell viability and apoptosis were investigated in the HT-29 cell lines dealing with recombinant lentivirus and shRNA to increase or decrease cyclinD1 expression. Furthermore, luciferase and ChIP assays were applied to investigate whether STAT3 regulated cyclinD1 expression by binding to its promoter. Finally, we determined whether inhibition of STAT3 could decrease cyclinD1 and increase the chemotherapy sensitivity.
RESULTS: CyclinD1 expression was significantly increased in the cancer cells and high level of cyclinD1 indicated the poor prognosis. Inhibition of cyclinD1 decreased the cell viability assessed by MTT and increased rate of apoptosis when exposed to 5-FU treatment while overexpression of cyclinD1 showed the reverse effect. ChIP assay showed that STAT3 directly bind to cyclinD1 promoter. Subclone of full promoter of cyclinD1 into pGL4 increased the luciferase activity while delete or mutation of any of STAT3 binding sites resulted in reductions of luciferase activity. Inhibition of STAT3 decreased cyclinD1 expression to decrease the cell viability and increase rate of apoptosis when exposed to 5-FU treatment.
CONCLUSIONS: Inhibition of STAT3/cyclinD1 pathway increased the sensitivity of colorectal cancer cell to chemotherapy.

Datar I, Tegegne H, Qin K, et al.
Genetic and epigenetic control of RKIP transcription.
Crit Rev Oncog. 2014; 19(6):417-30 [PubMed] Related Publications
Raf kinase inhibitory protein (RKIP) is known to modulate key signaling cascades and regulate normal physiological processes such as cellular proliferation, differentiation, and apoptosis. The expression of RKIP is found to be downregulated in several cancer metastases and the repressed RKIP expression can be reactivated on treatment with chemotherapeutic agents. RKIP is a proven tumor metastasis suppressor gene and investigating the mechanisms of transcriptional regulation of RKIP is therefore of immense clinical importance. In this review, we discuss the basal expression of RKIP in various tissues and the genetic aspects of the RKIP chromosomal locus including the structure of the RKIP promoter as well as gene regulatory elements such as enhancers. We also review the genetic and epigenetic modulation of RKIP transcription through EZH2, a component of the polycomb repressive complex 2 (PRC2) and sequence specific transcription factors (TFs) BACH1 and Snail. Emerging experimental evidence supports a unifying model in which both these TFs repress RKIP transcription in cancers by recruiting the EZH2 containing repressive complex to the proximal RKIP promoter. Finally, we review the known mechanisms employed by different types of chemotherapeutic agents to activate RKIP expression in cancer cells.

Zhang Q, Tang Q, Qin D, et al.
Role of microRNA 30a targeting insulin receptor substrate 2 in colorectal tumorigenesis.
Mol Cell Biol. 2015; 35(6):988-1000 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
MicroRNAs (miRNAs) are dysregulated in many types of malignant diseases, including colorectal cancer. miRNA 30a (miR-30a) is a member of the miR-30 family and has been implicated in many types of cancers. In this study, we determined the expression of miR-30a in human colon cancer tissues and cell lines. miR-30a was found to be significantly downregulated in both the tissues and cell lines. Furthermore, overexpression of miR-30a inhibited, while silencing of miR-30a promoted, cell proliferation, migration, and invasion in vitro. Consistently, stable overexpression of miR-30a suppressed the growth of colon cancer cell xenografts in vivo. Moreover, bioinformatic algorithms and luciferase reporter assays revealed that insulin receptor substrate 2 (IRS2) is a direct target of miR-30a. Further functional studies suggested that repression of IRS2 by miR-30a partially mediated the tumor suppressor effect of miR-30a. In addition, miR-30a inhibited constitutive phosphorylation of Akt by targeting IRS2. Additionally, clinicopathological analysis indicated that miR-30a has an inverse correlation with the staging in patients with colon cancer. Taken together, our study provides the first evidence that miR-30a suppressed colon cancer cell growth through inhibition of IRS2. Thus, miR-30a might serve as a promising therapeutic strategy for colon cancer treatment.

Wan F, Qin X, Zhang G, et al.
Oxidized low-density lipoprotein is associated with advanced-stage prostate cancer.
Tumour Biol. 2015; 36(5):3573-82 [PubMed] Related Publications
Clinical and epidemiological data suggest coronary artery disease shares etiology with prostate cancer (PCa). The aim of this work was to assess the effects of several serum markers reported in cardiovascular disease on PCa. Serum markers (oxidized low-density lipoprotein [ox-LDL], apolipoprotein [apo] B100, and apoB48) in peripheral blood samples from 50 patients from Fudan University Shanghai Cancer Center (FUSCC) with localized or lymph node metastatic PCa were investigated in this study. Twenty-five samples from normal individuals were set as controls. We first conducted enzyme-linked immunosorbent assay analysis to select candidate markers that were significantly different between these patients and controls. Then, the clinical relevance between OLR1 (the ox-LDL receptor) expression and PCa was analyzed in The Cancer Genome Atlas (TCGA) cohort. We also investigated the function of ox-LDL in PCa cell lines in vitro. Phosphorylation protein chips were used to analyze cell signaling pathways in ox-LDL-treated PC-3 cells. The ox-LDL level was found to be significantly correlated with N stage of prostate cancer. OLR1 expression was correlated with lymph node metastasis in the TCGA cohort. In vitro, ox-LDL stimulated the proliferation, migration, and invasion of LNCaP and PC-3 in a dose-dependent manner. The results of phosphoprotein microarray illustrated that ox-LDL could influence multiple signaling pathways of PC-3. Activation of proliferation promoting signaling pathways (including β-catenin, cMyc, NF-κB, STAT1, STAT3) as well as apoptosis-associating signaling pathways (including p27, caspase-3) demonstrated that ox-LDL had complicated effects on prostate cancer. Increased serum ox-LDL level and OLR1 expression may indicate advanced-stage PCa and lymph node metastasis. Moreover, ox-LDL could stimulate PCa proliferation, migration, and invasion in vitro.

Yang W, Yoshigoe K, Qin X, et al.
Identification of genes and pathways involved in kidney renal clear cell carcinoma.
BMC Bioinformatics. 2014; 15 Suppl 17:S2 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is one of fatal genitourinary diseases and accounts for most malignant kidney tumours. KIRC has been shown resistance to radiotherapy and chemotherapy. Like many types of cancers, there is no curative treatment for metastatic KIRC. Using advanced sequencing technologies, The Cancer Genome Atlas (TCGA) project of NIH/NCI-NHGRI has produced large-scale sequencing data, which provide unprecedented opportunities to reveal new molecular mechanisms of cancer. We combined differentially expressed genes, pathways and network analyses to gain new insights into the underlying molecular mechanisms of the disease development.
RESULTS: Followed by the experimental design for obtaining significant genes and pathways, comprehensive analysis of 537 KIRC patients' sequencing data provided by TCGA was performed. Differentially expressed genes were obtained from the RNA-Seq data. Pathway and network analyses were performed. We identified 186 differentially expressed genes with significant p-value and large fold changes (P < 0.01, |log(FC)| > 5). The study not only confirmed a number of identified differentially expressed genes in literature reports, but also provided new findings. We performed hierarchical clustering analysis utilizing the whole genome-wide gene expressions and differentially expressed genes that were identified in this study. We revealed distinct groups of differentially expressed genes that can aid to the identification of subtypes of the cancer. The hierarchical clustering analysis based on gene expression profile and differentially expressed genes suggested four subtypes of the cancer. We found enriched distinct Gene Ontology (GO) terms associated with these groups of genes. Based on these findings, we built a support vector machine based supervised-learning classifier to predict unknown samples, and the classifier achieved high accuracy and robust classification results. In addition, we identified a number of pathways (P < 0.04) that were significantly influenced by the disease. We found that some of the identified pathways have been implicated in cancers from literatures, while others have not been reported in the cancer before. The network analysis leads to the identification of significantly disrupted pathways and associated genes involved in the disease development. Furthermore, this study can provide a viable alternative in identifying effective drug targets.
CONCLUSIONS: Our study identified a set of differentially expressed genes and pathways in kidney renal clear cell carcinoma, and represents a comprehensive computational approach to analysis large-scale next-generation sequencing data. The pathway and network analyses suggested that information from distinctly expressed genes can be utilized in the identification of aberrant upstream regulators. Identification of distinctly expressed genes and altered pathways are important in effective biomarker identification for early cancer diagnosis and treatment planning. Combining differentially expressed genes with pathway and network analyses using intelligent computational approaches provide an unprecedented opportunity to identify upstream disease causal genes and effective drug targets.

Yang JY, Dunker A, Liu JS, et al.
Advances in translational bioinformatics facilitate revealing the landscape of complex disease mechanisms.
BMC Bioinformatics. 2014; 15 Suppl 17:I1 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Advances of high-throughput technologies have rapidly produced more and more data from DNAs and RNAs to proteins, especially large volumes of genome-scale data. However, connection of the genomic information to cellular functions and biological behaviours relies on the development of effective approaches at higher systems level. In particular, advances in RNA-Seq technology has helped the studies of transcriptome, RNA expressed from the genome, while systems biology on the other hand provides more comprehensive pictures, from which genes and proteins actively interact to lead to cellular behaviours and physiological phenotypes. As biological interactions mediate many biological processes that are essential for cellular function or disease development, it is important to systematically identify genomic information including genetic mutations from GWAS (genome-wide association study), differentially expressed genes, bidirectional promoters, intrinsic disordered proteins (IDP) and protein interactions to gain deep insights into the underlying mechanisms of gene regulations and networks. Furthermore, bidirectional promoters can co-regulate many biological pathways, where the roles of bidirectional promoters can be studied systematically for identifying co-regulating genes at interactive network level. Combining information from different but related studies can ultimately help revealing the landscape of molecular mechanisms underlying complex diseases such as cancer.

Waight JD, Takai S, Marelli B, et al.
Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans.
J Immunol. 2015; 194(3):878-82 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
CD4(+) regulatory T cells (Tregs) are critical for maintaining self-tolerance and function to prevent autoimmune disease. High densities of intratumoral Tregs are generally associated with poor patient prognosis, a correlation attributed to their broad immune-suppressive features. Two major populations of Tregs have been defined, thymically derived natural Tregs (nTregs) and peripherally induced Tregs (iTregs). However, the relative contribution of nTregs versus iTregs to the intratumoral Treg compartment remains controversial. Demarcating the proportion of nTregs versus iTregs has important implications in the design of therapeutic strategies to overcome their antagonistic effects on antitumor immune responses. We used epigenetic, phenotypic, and functional parameters to evaluate the composition of nTregs versus iTregs isolated from mouse tumor models and primary human tumors. Our findings failed to find evidence for extensive intratumoral iTreg induction. Rather, we identified a population of Foxp3-stable nTregs in tumors from mice and humans.

Xu K, Song X, Chen Z, et al.
XRCC2 promotes colorectal cancer cell growth, regulates cell cycle progression, and apoptosis.
Medicine (Baltimore). 2014; 93(28):e294 [PubMed] Related Publications
X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in homologous recombination DNA repair. According to the theory of synthetic lethality, XRCC2-deficient cells are more sensitive to PARP1 inhibitors compared to XRCC2-expressing cells. We investigated XRCC2 expression and function in colorectal cancer (CRC), and the characteristics of sensitivity to PARP1 inhibitor in CRC cells with different XRCC2 levels. We enrolled 153 patients with CRC who had undergone surgery in this study. XRCC2 expression was assessed using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2 expression were constructed. Following treatment with the PARP1 inhibitor olaparib, the viability of cells with different XRCC2 levels was determined; cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell lymphoma-2 (Bcl-2) protein expression was measured by Western blotting. The positive rates of XRCC2 in primary CRC tissue were significantly higher than that in the matched adjacent noncancerous tissue, and XRCC2 expression status in primary CRC was related to tumor site, Dukes' stage, and tumor-nodes-metastasis (TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2 expression was greater. High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2 expression cells are more sensitive to olaparib, which inhibits their viability.

Liu JB, Dai CM, Su XY, et al.
Gene microarray assessment of multiple genes and signal pathways involved in androgen-dependent prostate cancer becoming androgen independent.
Asian Pac J Cancer Prev. 2014; 15(22):9791-5 [PubMed] Related Publications
To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-β signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.

Liu T, Qin W, Hou L, Huang Y
MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway.
Tumour Biol. 2015; 36(3):1881-93 [PubMed] Related Publications
The mechanism underlying the development of human ovarian cancer is poorly understood. The liver kinase protein, LKB1, is hypothesized to play a pivotal role in tumor cell proliferation and invasion capacity through regulation of p53 and p21/WAF1 expression. Previous studies suggest LKB1 may, in turn, be regulated by microRNA-17. Here, we examined the role of miR-17 in the expression of LKB1 and the downstream effects on proliferation and invasion capacity of normal ovarian cancer cells (OCCs) and ovarian stem cells. In this study, both the mRNA and protein expression levels of LKB1, p53, and p21 decreased in OCCs following transfection with a miR-17 expression plasmid. MiR-17 expression affected cell cycle regulation and stimulated the proliferation and invasion capacity of OCCs in vitro. ChIP assays indicated that the binding efficiency of p53 to the p21/WAF1 gene promoter was much lower in miR-17 transfected OCCs than in OCCs transfected with a mutated miR-17. Co-immunoprecipitation and western blotting showed significantly lower levels of p53 and p53 Ser15-pho in the miR-17 transfected OCCs as compared to the mutant miR-17 transfected OCCs. Xenograft experiments confirmed that suppression of tumor growth in vivo occurred in the absence of functional miR-17. These findings suggest that mature miR-17 expression may have an important role in the pathogenesis of human ovarian tumors through its interference with the LKB1-p53-p21/WAF1 pathway expression by epigenetic modification. These findings are of potential importance in the identification of novel therapeutic targets in human ovarian cancer.

Yang QY, Li JH, Wang QY, et al.
MTA1 promotes cell proliferation via DNA damage repair in epithelial ovarian cancer.
Genet Mol Res. 2014; 13(4):10269-78 [PubMed] Related Publications
We examined whether metastasis-associated gene 1 (MTA1) promotes cell proliferation via DNA damage repair in ovarian cancer. MTA1 was successfully down-regulated using small interfering RNA in the epithelial ovarian cancer cell lines SKOV-3 and OVCAR-3. Cell growth was evaluated through MTT and colony formation assays. Fluorescence-activated cell sorting analysis was used to evaluate the distribution of cells in the cell cycle, and cytotoxicity assays were performed to study cell sensitivity to cisplatin. A neutral comet assay was used to measure levels of ionizing radiation-induced DNA damage in SKOV-3 cells, and Western blot analyses were carried out to examine the expression of key proteins involved in DNA damage repair pathways. MTA1 knockdown markedly inhibited cell growth and led to S phase cell cycle arrest. In addition, MTA1 depletion conferred sensitivity of ovarian cancer cells to cisplatin. Moreover, MTA1 depletion increased the level of ionizing radiation-induced DNA damage and caused irreparable damage, which was illustrated by a remarkable increase and persistent existence of a comet tail as well as protein expression levels of γH2AX, pRPA, and pChk1, all of which play critical roles in DNA repair. Thus, MTA1 promotes the proliferation of epithelial ovarian cancer cells by enhancing DNA repair.

Wang HF, Yang H, Hu LB, et al.
 Effect of siRNA targeting EZH2 on cell viability and apoptosis of bladder cancer T24 cells.
Genet Mol Res. 2014; 13(4):9939-50 [PubMed] Related Publications
We investigated the effect of siRNA targeting enhancer of EZH2 on cell proliferation, invasion, migration, and apoptosis of human bladder cancer T24 cells. An siRNA-expressing plasmid targeting the EZH2 gene was transfected into T24 cells. Quantitative polymerase chain reaction and Western blot analysis were used to detect EZH2 expression at the mRNA and protein levels, respectively. Proliferation, invasion, and migration of T24 cells were examined in vivo using MTT, wound healing, and transwell chamber migration assays, respectively. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometric analysis was performed to determine cell apoptosis levels. Expression of EZH2 in T24 cells was suppressed at the mRNA and protein levels. Following transfection for 48 h, growth was inhibited by 37.9%, which was markedly lower than that in the negative control group (P < 0.05). Following a wound-healing assay for 24 h, transfected cell migration distance was 1.37 ± 0.12, which was markedly less than the horizontal migration distance of negative control group cells (P < 0.01). In addition, the cell invasion ability of EZH2- siRNA group cells decreased by 67% compared with negative control group cells (P < 0.01). Following transfection for 48 h, early- and late-stage apoptosis rates for T24 cells were 22.8 and 3.60%, respectively, which were higher than in the negative control group (P < 0.01). EZH2 gene silencing effectively suppressed the proliferation, invasion, and migration abilities of human bladder cancer cells, promoting apoptosis.

Dai J, Wang JY, Yang LL, et al.
Correlation of Forkhead Box c2 with subtypes and invasive ability of invasive breast cancer.
J Huazhong Univ Sci Technolog Med Sci. 2014; 34(6):896-901 [PubMed] Related Publications
Forkhead Box c2 (FOXC2) is a member of forkhead/winged-helix family of transcription factors. The relationship between FOXC2 and invasive breast cancers, including basal-like breast cancer (BLBC, a subtype of breast cancer), remains to be elucidated. In this study, immunohistochemistry was used to detect the expression of FOXC2 in samples from 103 cases of invasive breast cancers and 15 cases of normal mammary glands. The relationship between FOXC2 and clinical parameters of invasive breast cancers such as patient's age, tumor size, lymph node metastasis, tumor grade, the expression of ER, PR, HER-2 and p53, and Ki-67 labeling index (LI) was evaluated. The expression of FOXC2 was detected in parent MCF7 cells, MCF cells transfected with FOXC2 expression vectors and MDA-MB-435 cells by immunohistochemistry and Western blotting. Transwell assay was used to determine the invasive ability of these cells. The results showed that FOXC2 was strongly expressed in basal epithelial cells in normal mammary glands and weakly expressed or even not expressed in glandular epithelial cells. The majority of invasive breast cancers (71.8%, 74/103) had negative or weak expression of FOXC2. However, FOXC2 was strongly expressed in 60.7% of BLBCs. Moreover, FOXC2 was related with tumor grade, p53 expression, ki-67 LI and lymph nodes metastasis. It was expressed in FOXC2-transfected MCF cells and MDA-MB-435 cells but not in parent MCF cells. Transwell assay revealed that MCF cells transfected with FOXC2 expression vectors were more aggressive than the parent MCF cells, suggesting a positive correlation between FOXC2 and the invasion of breast cancer. It was concluded that there is a significant association between FOXC2 and the metastasis of invasive breast cancer. FOXC2 may be used as a new marker for the diagnosis and prognosis prediction of different subtypes of invasive breast cancers.

Zhou Z, Guo Y, Liu Y, et al.
Methylation-mediated silencing of Dlg5 facilitates bladder cancer metastasis.
Exp Cell Res. 2015; 331(2):399-407 [PubMed] Related Publications
UNLABELLED: Dlg5 (Discs large homolog 5), a member of the membrane-associated guanylate kinase adaptor family of scaffolding proteins, has been shown to participate in cancer progression. However, little is known about whether abnormal expression of Dlg5 facilitates bladder cancer metastasis. In the current study we initiated a study analyzing Dlg5 expression and its roles in human bladder cancer metastasis. The expression of Dlg5 is decreased in most bladder cancer tissues compared with adjacent normal tissues, and Dlg5 expression is further downregulated in patients with muscle-invasive tumors. DNA methylation analysis showed a methylation of Dlg5 gene in bladder cancer cell lines and in bladder cancer tumors, especially in muscle-invasive tumors. Hypermethylation of Dlg5 in bladder tumors is tightly correlated with silencing of Dlg5 expression, which is further functionally validated by demethylation analysis in bladder cancer cell lines. Knockdown of Dlg5 increases cancer cell invasion in vitro and promotes cancer metastasis in vivo. Of clinical significance, Kaplan-Meier analysis showed that downregulation of Dlg5 is significantly associated with reduced overall survival in patients with bladder cancer.
CONCLUSION: These data suggest that inhibition of Dlg5 by DNA hypermethylation contributes to provoke invasive phenotypes in bladder tumor.

Song J, Ge Z, Yang X, et al.
Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin.
Cancer Lett. 2015; 356(2 Pt B):713-20 [PubMed] Related Publications
Extracellular pH of solid tumor is generally acidic due to excessive glycolysis and poor perfusion. But whether acidic tumor microenvironment influenced the stromal cells infiltrating in tumor remains unknown. As the predominant progenitor of stromal cells in liver, the number of activated hepatic stellate cells (HSCs) was found positively correlated to the acidification level in the tumor tissues of HCC patients in our study. Whereas, in vitro acidic culture condition and in vivo co-implanting xenograft model were adopted to study the response of HSCs and its influence on HCC progression. HSCs were activated under acidic culture condition depending on the phosphorylation of cellular signal-regulated kinase (ERK). Acidity-activated HSCs promoted HCC metastasis in vitro and in vivo. Osteopontin (OPN) excretion from HSCs was increased under acidic condition and proved to promote the migration of HCC cells. Furthermore, the expression level of OPN was significantly associated with myofibroblasts and the combination of α-SMA with OPN was a powerful predictor for poor prognosis of HCC patients. Activation of HSCs in acidic tumor microenvironment represents a novel mechanism for HCC metastasis and provides a potential therapeutic strategy for HCC.

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