Gene Summary

Gene:PITX2; paired like homeodomain 2
Aliases: RS, RGS, ARP1, Brx1, IDG2, IGDS, IHG2, PTX2, RIEG, ASGD4, IGDS2, IRID2, Otlx2, RIEG1
Summary:This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:pituitary homeobox 2
Source:NCBIAccessed: 16 March, 2017


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

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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

  • Base Sequence
  • Messenger RNA
  • Signal Transduction
  • Chromosome 4
  • Cancer Gene Expression Regulation
  • Adenocarcinoma
  • Prostatectomy
  • Cancer Screening
  • Transcription Factors
  • Neoplasm Proteins
  • Thyroid Cancer
  • Wnt Proteins
  • Gene Expression
  • Breast Cancer
  • Polymerase Chain Reaction
  • Neoplasm Invasiveness
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Prostate Cancer
  • Genetic Markers
  • Neoplasm Recurrence, Local
  • Gene Expression Profiling
  • Molecular Sequence Data
  • Epigenetics
  • DNA Methylation
  • Promoter Regions
  • Cancer DNA
  • Reproducibility of Results
  • Homeodomain Proteins
  • Risk Factors
  • Cell Proliferation
  • Ovarian Cancer
  • CpG Islands
  • Biomarkers, Tumor
  • Randomized Controlled Trials
  • Oligonucleotide Array Sequence Analysis
  • Staging
  • Cyclin D2
  • Cell Differentiation
  • Tamoxifen
Tag cloud generated 16 March, 2017 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: PITX2 (cancer-related)

Mezzomo LC, Pesce FG, Marçal JM, et al.
Decreased TAp63 and ΔNp63 mRNA Levels in Most Human Pituitary Adenomas Are Correlated with Notch3/Jagged1 Relative Expression.
Endocr Pathol. 2017; 28(1):13-21 [PubMed] Related Publications
Despite recent advances in molecular genetics, the pituitary adenoma initiation, development, progress, and the molecular basis of their unique features are still poorly understood. In this sense, it is proposed that stem cell could be involved in pituitary adenoma tumorigenesis. It is suggested that TP63 has important functions in stem cells, and it may have interplay of TP63 and Notch and its ligand Jagged in this process. This study aimed to evaluate the distinct expression of TP63 isoforms (TAp63 and ΔNp63), as well as its correlation with Notch3 receptor and its ligand Jagged1 in human pituitary adenomas at the messenger RNA (mRNA) level. We included 77 pituitary adenoma tumor samples from patients who underwent surgical resection. The expression levels of TP63 isoforms (TAp63 and ΔNp63) and Notch3 and its ligand Jagged1 were evaluated by qRT-PCR using isoform-specific primers. We also evaluated proliferation index immunohistochemically using KI-67 antibody. The expression levels were associated with clinical outcomes, as age, gender, tumor size, and tumor subtype. In summary, we found that mRNA expression of both TP63 isoforms decreased in pituitary adenomas compared with normal pituitary control. On the other hand, there was an increase of relative Notch3 and Jagged1 mRNA expression in the majority of examined samples. The mRNA expression of three genes evaluated was correlated and statistically significantly. There was no significant association between gene expression and the analyzed clinical data. The current study has provided the first time evidence that Tap63 and ΔNp63 isoforms are underexpressed in most pituitary adenomas. These results are correlated with Notch3 and its ligand Jagged1 overexpression, corroborating previous studies pointing its antagonistic interactions.

Gao XH, Li J, Liu Y, et al.
ZNF148 modulates TOP2A expression and cell proliferation via ceRNA regulatory mechanism in colorectal cancer.
Medicine (Baltimore). 2017; 96(1):e5845 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Competing endogenous RNA (ceRNA) regulation is a novel hypothesized mechanism that states RNA molecules share common target microRNAs (miRNAs) and may competitively combine into the same miRNA pool.
METHODS: Zinc finger protein 148 (ZNF148) and TOP2A expression were analyzed in 742 colorectal cancer (CRC) tissues using immunohistochemistry (IHC). ZNF148 mRNA, TOP2A mRNA, miR101, miR144, miR335, and miR365 expression were estimated in 53 fresh frozen CRC tissues by reverse transcription polymerase chain reaction. Mechanisms underpinning ceRNA were examined using bioinformatics, correlation analysis, RNA interference, gene over-expression, and luciferase assays.
RESULTS: Protein levels of ZNF148 and TOP2A detected by IHC positively correlated (Spearman correlation coefficient [rs] = 0.431, P < 0.001); mRNA levels of ZNF148 and TOP2A also positively correlated (r = 0.591, P < 0.001). Bioinformatics analysis demonstrated that ZNF148 and TOP2A mRNA had 13 common target miRNAs, including miR101, miR144, miR335, and miR365. Correlation analysis demonstrated that levels of ZNF148 mRNA were negatively associated with levels of miR144, miR335, and miR365. Knockdown and overexpression tests showed that ZNF148 mRNA and TOP2A mRNA regulated each other in HCT116 cells, respectively, but not in Dicer-deficient HCT116 cells. Luciferase assays demonstrated that ZNF148 and TOP2A regulated each other through 3'UTR. Overexpression of ZNF148 mRNA and TOP2A mRNA caused significant downregulation of miR101, miR144, miR335, and miR365 in the HCT116 cells. We also found that knockdown of ZNF148 and TOP2A significantly promoted cell growth, and overexpression of ZNF148 and TOP2A inhibited cell proliferation, which was abrogated in Dicer-deficient HCT116 cells.
CONCLUSION: ZNF148 and TOP2A regulate each other through ceRNA regulatory mechanism in CRC, which has biological effects on cell proliferation.

Yang L, Liu Z, Yuan X, et al.
Random Subspace Aggregation for Cancer Prediction with Gene Expression Profiles.
Biomed Res Int. 2016; 2016:4596326 [PubMed] Free Access to Full Article Related Publications
Background. Precisely predicting cancer is crucial for cancer treatment. Gene expression profiles make it possible to analyze patterns between genes and cancers on the genome-wide scale. Gene expression data analysis, however, is confronted with enormous challenges for its characteristics, such as high dimensionality, small sample size, and low Signal-to-Noise Ratio. Results. This paper proposes a method, termed RS_SVM, to predict gene expression profiles via aggregating SVM trained on random subspaces. After choosing gene features through statistical analysis, RS_SVM randomly selects feature subsets to yield random subspaces and training SVM classifiers accordingly and then aggregates SVM classifiers to capture the advantage of ensemble learning. Experiments on eight real gene expression datasets are performed to validate the RS_SVM method. Experimental results show that RS_SVM achieved better classification accuracy and generalization performance in contrast with single SVM, K-nearest neighbor, decision tree, Bagging, AdaBoost, and the state-of-the-art methods. Experiments also explored the effect of subspace size on prediction performance. Conclusions. The proposed RS_SVM method yielded superior performance in analyzing gene expression profiles, which demonstrates that RS_SVM provides a good channel for such biological data.

Dragoj M, Milosevic Z, Bankovic J, et al.
Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma.
Cell Oncol (Dordr). 2017; 40(1):47-62 [PubMed] Related Publications
BACKGROUND: Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells.
METHODS: qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLC patients and the human NSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment.
RESULTS: We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G2/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion.
CONCLUSIONS: From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.

Yan L, Zhan C, Wang S, et al.
Genetic analysis of radiation-specific biomarkers in sinonasal squamous cell carcinomas.
Tumour Biol. 2016; 37(9):12001-12009 [PubMed] Related Publications
The aim of this study was to investigate the differences in the gene expression profiles of radiation-sensitive (RS) and radiation-resistant (RR) sinonasal squamous cell carcinoma (SNSCC) and to identify prognostic markers for the radiation reaction of SNSCC. We first examined the differentially expressed genes (DEGs) in RS and RR SNSCC tissues by analyzing clinical samples with GeneChip Human Transcriptome Array 2.0 (HTA 2.0).To understand the functional significance of the molecular changes, we examined the DEGs with Gene Ontology (GO) and pathway analyses to identify the core genes. The expression of several core genes (CCND2, COL5A2, GADD45B, and THBS2) was confirmed with reverse transcription quantitative PCR (RT-qPCR) in a larger series of tissues. We identified 208 DEGs, of which 76 were upregulated and 132 downregulated in the RS tissues relative to the RR tissues. The DEGs were mainly involved in the regulation of cell proliferation, the NF-kappaB signaling pathway, the cell adhesion molecule signaling pathway, and the extracellular matrix-receptor interaction signaling pathway. RT-qPCR confirmed that the CCND2, COL5A2, GADD45B, and THBS2 genes were significantly differentially expressed in the RS and RR tissues, consistent with the GeneChip data. These results extend our understanding of the molecular mechanisms underlying the sensitivity of SNSCC to radiation. The DEGs are involved in the differential response to radiation therapy and the dysregulated core genes identified in this study can be used to predict radiation sensitivity in SNSCC.

Sun L, Xu JC, Wang W, Yin Y
Locally linear embedding and neighborhood rough set-based gene selection for gene expression data classification.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Cancer subtype recognition and feature selection are important problems in the diagnosis and treatment of tumors. Here, we propose a novel gene selection approach applied to gene expression data classification. First, two classical feature reduction methods including locally linear embedding (LLE) and rough set (RS) are summarized. The advantages and disadvantages of these algorithms were analyzed and an optimized model for tumor gene selection was developed based on LLE and neighborhood RS (NRS). Bhattacharyya distance was introduced to delete irrelevant genes, pair-wise redundant analysis was performed to remove strongly correlated genes, and the wavelet soft threshold was determined to eliminate noise in the gene datasets. Next, prior optimized search processing was carried out. A new approach combining dimension reduction of LLE and feature reduction of NRS (LLE-NRS) was developed for selecting gene subsets, and then an open source software Weka was applied to distinguish different tumor types and verify the cross-validation classification accuracy of our proposed method. The experimental results demonstrated that the classification performance of the proposed LLE-NRS for selecting gene subset outperforms those of other related models in terms of accuracy, and our proposed approach is feasible and effective in the field of high-dimensional tumor classification.

Kammerer S, Jahn SW, Winter E, et al.
Critical evaluation of KCNJ3 gene product detection in human breast cancer: mRNA in situ hybridisation is superior to immunohistochemistry.
J Clin Pathol. 2016; 69(12):1116-1121 [PubMed] Free Access to Full Article Related Publications
Increased expression levels of KCNJ3 have been correlated with lymph node metastases and poor prognosis in patients with breast cancer, suggesting a prognostic role of KCNJ3 We aimed to establish protocols for the detection of KCNJ3 in formalin-fixed, paraffin-embedded (FFPE) breast cancer tissue. Several antibodies were tested for sensitivity and specificity by western blot, followed by optimisation of the immunohistochemistry (IHC) procedure and establishment of KCNJ3 mRNA in situ hybridisation (ISH). Methods were validated by processing 15 FFPE breast cancer samples for which microarray data were available. Spearman's rank correlation analysis resulted in borderline significant correlation for IHC versus ISH (rS: 0.625; p<0.05) and IHC versus microarray (rS: 0.668; p<0.01), but in significant correlation for ISH versus microarray (rS: 0.861; p<0.001). The ISH method was superior to IHC, regarding robustness, sensitivity and specificity and will aid to further study expression levels of KCNJ3 in both malignant and physiological conditions.

Kulcheski FR, Christoff AP, Margis R
Circular RNAs are miRNA sponges and can be used as a new class of biomarker.
J Biotechnol. 2016; 238:42-51 [PubMed] Related Publications
Circular RNAs (circRNAs) are a class of non-coding RNAs (ncRNAs) that are involved in transcriptional and posttranscriptional gene expression regulation. The development of deep sequencing of ribosomal RNA (rRNA)-depleted RNA libraries, associated with improved computational tools, has provided the identification of several new circRNAs in all sorts of organisms, from protists, plants and fungi to animals. Recently, it was discovered that endogenous circRNAs can work as microRNA (miRNA) sponges. This means that the circRNAs bind to miRNAs and consequently repress their function, providing a new model of action for this class of ncRNA, as well as indicating another mechanism that regulates miRNA activity. As miRNAs control a large set of biological processes, circRNA sponge activity will also affect these pathways. Several studies have associated miRNA sponges with human diseases, including osteoarthritis, diabetes, neurodegenerative pathologies and several types of cancer. Additionally, high stability, abundance and tissue-specific expression patterns make circRNA sponges very attractive for clinical research. Herein, we review the biogenesis, properties and function of endogenous circRNA sponges, with a special focus on those related to human cancer. A list of web tools available for the study of circRNAs is also given. Additionally, we discuss the possibility of using circRNAs as molecular markers for the diagnosis of diseases.

Soran A, Bhargava R, Johnson R, et al.
The impact of Oncotype DX® recurrence score of paraffin-embedded core biopsy tissues in predicting response to neoadjuvant chemotherapy in women with breast cancer.
Breast Dis. 2016; 36(2-3):65-71 [PubMed] Related Publications
BACKGROUND: Oncotype DX® test is beneficial in predicting recurrence free survival in estrogen receptor positive (ER+) breast cancer. Ability of the assay to predict response to neoadjuvant chemotherapy (NCT) is less well-studied.
OBJECTIVE: We hypothesize a positive association between the Oncotype DX® recurrence score (RS) and the percentage tumor response (%TR) after NCT.
METHODS: Pre-therapy RS was measured on core biopsies from 60 patients with ER+, HER2- invasive breast cancer (IBC) who then received NCT. Pre-therapy tumor size was measured using imaging. %TR, partial response (PR; >50%), pathologic complete response (pCR) and breast conserving surgery (BCS) rates were measured.
RESULTS: Median RS was 20 (2-69). Median %TR was 42 (0-97)%. PR was observed in 43% of patients. There was no association between %TR and pre-NCT tumor size, age, Nottingham score or nodal status (p > 0.05). No statistically significant association with %TR was seen with RS as a categorical or continuous variable (p = 0.21 and 0.7, respectively). Response to NCT improved as ER (p = 0.02) by RT-PCR decreased. Lower ER expression by IHC correlated with response (p = 0.03).
CONCLUSIONS: In patients with ER+ IBC receiving NCT, RS did not predict response to NCT using %TR. The benefit of the assay prior to NCT requires further study.

Bur H, Haapasaari KM, Turpeenniemi-Hujanen T, et al.
Strong KDM4B and KDM4D Expression Associates with Radioresistance and Aggressive Phenotype in Classical Hodgkin Lymphoma.
Anticancer Res. 2016; 36(9):4677-83 [PubMed] Related Publications
BACKGROUND: Epigenetic regulators, including Jumonji domain 2 (JMJD2/KDM4) proteins are involved in post-translational modification of histone demethylation and have a major role in carcinogenesis of many solid tumors.
MATERIALS AND METHODS: We assessed immunohistochemically the expression of lysine (K)-specific demethylase 4 (KDM4)A, KDM4B and KDM4D in tumors from 91 patients of adriamycin, bleomycin, vinblastine, darcabazine (ABVD)-treated classical Hodgkin lymphoma.
RESULTS: Strong cytoplasmic KDM4B expression in the reactive cellular infiltrate and also in Reed-Sternberg (RS) cells predicted poor relapse-free survival (RFS) (p=0.020 and p=0.022, respectively) in patients with limited-stage disease. Strong KDM4B expression in RS cells was also related to B-symptoms (p=0.007) and advanced stage (p=0.024). Strong KDM4D expression in the cytoplasm of RS cells was also associated with poor RFS in limited-stage patients RFS (p=0.043) and, most significantly, in patients receiving involved-field radiotherapy (p=0.007).
CONCLUSION: KDM4B and KDM4D expression may associate with an aggressive subtype of classical Hodgkin lymphoma and be linked with radioresistance.

Gong C, Tan W, Chen K, et al.
Prognostic Value of a BCSC-associated MicroRNA Signature in Hormone Receptor-Positive HER2-Negative Breast Cancer.
EBioMedicine. 2016; 11:199-209 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Breast cancer patients with high proportion of cancer stem cells (BCSCs) have unfavorable clinical outcomes. MicroRNAs (miRNAs) regulate key features of BCSCs. We hypothesized that a biology-driven model based on BCSC-associated miRNAs could predict prognosis for the most common subtype, hormone receptor (HR)-positive, HER2-negative breast cancer patients.
PATIENTS AND METHODS: After screening candidate miRNAs based on literature review and a pilot study, we built a miRNA-based classifier using LASSO Cox regression method in the training group (n=202) and validated its prognostic accuracy in an internal (n=101) and two external validation groups (n=308).
RESULTS: In this multicenter study, a 10-miRNA classifier incorporating miR-21, miR-30c, miR-181a, miR-181c, miR-125b, miR-7, miR-200a, miR-135b, miR-22 and miR-200c was developed to predict distant relapse free survival (DRFS). With this classifier, HR+HER2- patients were scored and classified into high-risk and low-risk disease recurrence, which was significantly associated with 5-year DRFS of the patients. Moreover, this classifier outperformed traditional clinicopathological risk factors, IHC4 scoring and 21-gene Recurrence Score (RS). The patients with high-risk recurrence determined by this classifier benefit more from chemotherapy.
CONCLUSIONS: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This model may facilitate personalized therapy-decision making for HR+HER2- individuals.

Cha PH, Choi KY
Simultaneous destabilization of β-catenin and Ras via targeting of the axin-RGS domain as a potential therapeutic strategy for colorectal cancer.
BMB Rep. 2016; 49(9):455-6 [PubMed] Free Access to Full Article Related Publications
Mutations of APC and KRAS are frequently observed in human colorectal cancers (CRCs) and the Wnt/β-catenin and Ras pathways are consequently activated in a significant proportion of CRC patients. Mutations in these two genes are also known to synergistically induce progression of CRCs. Through a series of studies, we have demonstrated that inhibition of the Wnt/β-catenin signaling pathway negatively regulates Ras stability, therefore, Ras abundance is increased together with β-catenin in both mice and human CRCs harboring adenomatous polyposis coli (APC) mutations. In a recent study, we identified KY1220, a small molecule that simultaneously degrades β-catenin and Ras by inhibition of the Wnt/β-catenin pathway, and obtained its derivative KYA1797K, which has improved activity and solubility. We found that KYA1797K binds the RGS domain of axin and enhances the binding affinity of β-catenin or Ras with the β-catenin destruction complex components, leading to simultaneous destabilization of β-catenin and Ras via GSK3β activation. By using both in vitro and in vivo studies, we showed that KYA1797K suppressed the growth of CRCs harboring APC and KRAS mutations through destabilization of β-catenin and Ras. Therefore, our findings indicate that the simultaneous destabilization of β-catenin and Ras via targeting axin may serve as an effective strategy for inhibition of CRCs. [BMB Reports 2016; 49(9): 455-456].

Marjanovic I, Kostic J, Stanic B, et al.
Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease.
Tumour Biol. 2016; 37(10):13391-13401 [PubMed] Related Publications
The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.

Halifu Y, Liang JQ, Zeng XW, et al.
Wnt1 and SFRP1 as potential prognostic factors and therapeutic targets in cutaneous squamous cell carcinoma.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
The Wnt signaling pathway plays a key role in insurgence and progression of many different forms of cancer. Some crucial components of the Wnt pathway have been proposed to be novel targets for cancer therapy. To date, the Wnt signaling pathway has not been studied in cutaneous squamous cell carcinoma (CSCC). This study was designed to investigate the expression of Wnt1 and SFRP1 from the Wnt pathway in CSCC. Tissue samples were obtained from 35 patients with CSCC and 30 controls admitted to the Xinjiang Uygur Autonomous Region People's Hospital at Urumchi City, China. Gene and protein expressions of Wnt1 and SFRP1 were quantified by immunohistochemistry and western blotting. Wnt1 expression was significantly higher (P < 0.05) in CSCC samples than in normal skin cells of the control subjects; in contrast, SFRP1 expression was significantly lower in CSCC tissues than that in tissues of control subjects (P < 0.05). Moreover, Wnt1 expression (P < 0.05) was found to be correlated with histopathological differentiation in CSCC, and negatively correlated with SFRP1 expression in CSCC (rs = -0.473, P = 0.015). Therefore, we concluded that Wnt1 and SFRP1 play important roles in the development of CSCC and could be potent markers for diagnosis, prevention, and therapy of CSCC.

Qiu X, Huang Y, Zhou Y, Zheng F
Aberrant methylation of TRIM58 in hepatocellular carcinoma and its potential clinical implication.
Oncol Rep. 2016; 36(2):811-8 [PubMed] Related Publications
TRIM58 (tripartite motif containing 58) has been reported as a novel methylated gene in hepatocellular carcinoma (HCC) by methylation microarrays. However, its associations with mRNA expression and clinicopathological characteristics have not been evaluated. In this study, we explored the potential clinical implications of TRIM58 methylation in HCC. We analyzed the methylation level of TRIM58 in 181 HCC tissues, 172 matched adjacent non-tumor tissues and 13 normal liver tissues using methylation-sensitive restriction enzyme based quantitative PCR and bisulfite genomic sequencing. Further, the mRNA expression level of TRIM58 was measured in 46 paired HCC and adjacent non-tumor tissues by quantitative real-time PCR. Moreover, the relationship between TRIM58 methylation and mRNA expression, the clinicopathological features, as well as prognostic value were evaluated. The results showed that TRIM58 methylation was significantly higher in HCC tissues compared with adjacent non-tumor tissues and normal liver tissues (both p<0.0001). Using 10% as the cut-off value, hypermethylation of TRIM58 was specific in HCC tissues (28.18%, 51/181), with a tendency to correlate with unfavorable disease-free survival (p=0.047). Moreover, TRIM58 expression was significantly decreased in HCC tissues compared with adjacent non-tumor tissues (p<0.0001), and showed a negative association with DNA methylation (p=0.015, rs= -0.260). Our data indicate that TRIM58 methylation is a common event in HCC and may contribute to downregulation of its mRNA expression. Furthermore, hypermethylation of TRIM58 tends to be associated with worse DFS after hepatectomy. However, the potential clinical application of TRIM58 need to be further investigated.

Haider M, Ji B, Haselgrübler T, et al.
A microfluidic multiwell chip for enzyme-free detection of mRNA from few cells.
Biosens Bioelectron. 2016; 86:20-6 [PubMed] Related Publications
Isogenic cell populations possess heterogeneous gene expression patterns. Most methods for mRNA expression analysis start with the reverse transcription of mRNA into cDNA, a process that can introduce strong signal variations not related to the actual mRNA levels. Miniaturized lab-on-a-chip systems offer properties - e.g. low sample dilution, low contamination - that enable new reaction schemes for molecular analyses. To enable transcription-free mRNA expression analysis of few single cells, a one-step cell lysis, target labelling and hybridisation approach as well as a corresponding passive multiwell chip with a volume of 25.5 nL/well were developed. The method enabled the parallel analysis of up to 96 samples and 6 target genes per sample. Preceding light microscopy of the living cells allowed correlating mRNA levels and cell number. As a proof-of-principle, the pancreatic cancer cell line Panc-1 was investigated for expression heterogeneity of a reference gene plus 5 genes reported to be overexpressed in cancer stem cells (CSCs). A good correlation (r(51)=0.739, p<0.001; rs(51)=0.744, p<0.001) between the cell number per well and the number of detected reference gene mRNA confirmed the proper function of the device. Moreover, a heterogeneous expression of the CSC-associated target genes was found which matched well with reports on the presence of CSCs in the Panc-1 cell line.

Lee SH, Ha S, An HJ, et al.
Association between partial-volume corrected SUVmax and Oncotype DX recurrence score in early-stage, ER-positive/HER2-negative invasive breast cancer.
Eur J Nucl Med Mol Imaging. 2016; 43(9):1574-84 [PubMed] Related Publications
PURPOSE: Oncotype DX, a 21-gene expression assay, provides a recurrence score (RS) which predicts prognosis and the benefit from adjuvant chemotherapy in patients with early-stage, estrogen receptor-positive (ER-positive), and human epidermal growth factor receptor 2-negative (HER2-negative) invasive breast cancer. However, Oncotype DX tests are expensive and not readily available in all institutions. The purpose of this study was to investigate whether metabolic parameters on (18)F-FDG PET/CT are associated with the Oncotype DX RS and whether (18)F-FDG PET/CT can be used to predict the Oncotype DX RS.
METHODS: The study group comprised 38 women with stage I/II, ER-positive/HER2-negative invasive breast cancer who underwent pretreatment (18)F-FDG PET/CT and Oncotype DX testing. On PET/CT, maximum (SUVmax) and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis were measured. Partial volume-corrected SUVmax (PVC-SUVmax) determined using the recovery coefficient method was also evaluated. Oncotype DX RS (0 - 100) was categorized as low (<18), intermediate (18 - 30), or high (≥31). The associations between metabolic parameters and RS were analyzed. Multivariate logistic regression was used to identify significant independent predictors of low versus intermediate-to-high RS.
RESULTS: Of the 38 patients, 22 (58 %) had a low RS, 13 (34 %) had an intermediate RS, and 3 (8 %) had a high RS. In the analysis with 38 index tumors, PVC-SUVmax was higher in tumors in patients with intermediate-to-high RS than in those with low RS (5.68 vs. 4.06; P = 0.067, marginally significant). High PVC-SUVmax (≥4.96) was significantly associated with intermediate-to-high RS (odds ratio, OR, 10.556; P = 0.004) in univariate analysis. In multivariate analysis with clinicopathologic factors, PVC-SUVmax ≥4.96 (OR 8.459; P = 0.013) was a significant independent predictor of intermediate-to-high RS.
CONCLUSIONS: High PVC-SUVmax on (18)F-FDG PET/CT was significantly associated with an intermediate-to-high Oncotype DX RS. PVC metabolic parameters on (18)F-FDG PET/CT can be used to predict the Oncotype DX RS in patients with early-stage, ER-positive/HER2-negative breast cancer.

Luan ZM, Zhang H, Qu XL
Prediction efficiency of PITX2 DNA methylation for prostate cancer survival.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
This study determined the level of PITX2 methylation in prostate cancer and benign tissues and its relationship with the postoperative survival rate. Forty-four patients with prostate cancer who underwent radical prostatectomy and 43 patients with benign prostatic hyperplasia were selected. DNA was extracted from the tissues and PITX2 methylation status was quantitatively analyzed by using the EpiTect MethyLight method. The median follow-up time of the patients was 63 months and was used to analyze the relationship between PITX2 methylation status with tumor stage and survival rates. Median PITX2 gene expression in benign tissues was 1.46, which was higher than that of tumor tissues with a median of 0.01 (P < 0.001). The median methylation in the controls was less than 0.001%, while the median methylation in the test group was 23.3% (P = 0.000). The number of patients with low methylation level in T2 stage was 15, which was more than that in T3 and T4 stages (8 patients); while the number of patients with high methylation levels in T2 stage was 6, which was less than that in T3 and T4 stages (15 patients) (P = 0.035). The PITX2 gene expression level in prostate cancer tissues was lower than that in benign tissues. A higher degree of PITX2 DNA methylation was associated with higher tumor stage and lower survival rates. PITX2 DNA methylation presents a good predictive value for prostate cancer survival.

Farzaneh F, Noghabaei G, Barouti E, et al.
Analysis of CYP17, CYP19 and CYP1A1 Gene Polymorphisms in Iranian Women with Breast Cancer.
Asian Pac J Cancer Prev. 2016; 17(S3):23-6 [PubMed] Related Publications
Breast cancer (BC) is the most common cancer and the second cause of mortality in women all around the world. It is caused by several factors including genetic determinants, so that both genetic susceptibility factors and environmental factors are involved in the etiology. Significance of genes functioning in steroid hormone synthesis and metabolism are well established in breast cancer susceptibility. In this study, 134 women with BC and 135 normal controls were analyzed for their genotypes for the polymorphisms, rs743572, rs10046 and rs4646903, resided in CYP17, CYP19 and CYP1A1 genes, respectively. Significant differences in distributions of allele and genotype frequencies were found for the rs10046 polymorphism in CYP19 (p-value=0.01, OR (CI 95%) =1.59 (1.1-2.3), p-value=0.04, OR (CI 95%) =1.7 (1.1-2.5) respectively). For rs743,572 and rs 4646903 polymorphisms, no significant associations were observed. A significant association was observed between the rs10046 polymorphism of the CYP19gene and breast cancer in Iranian patients. Due to inconsistent previous results, more studies in different populations with larger sample sizes are indicated.

Todorovic Balint M, Jelicic J, Mihaljevic B, et al.
Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.
Int J Mol Sci. 2016; 17(5) [PubMed] Free Access to Full Article Related Publications
The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

Su Z, Li G, Liu C, et al.
Ionizing radiation promotes advanced malignant traits in nasopharyngeal carcinoma via activation of epithelial-mesenchymal transition and the cancer stem cell phenotype.
Oncol Rep. 2016; 36(1):72-8 [PubMed] Free Access to Full Article Related Publications
Post-irradiation residual mass and recurrence always suggest a worse prognosis for nasopharyngeal carcinoma (NPC). Our study aimed to investigate the malignant behaviors of post-irradiation residual NPC cells, to identify the potential underlying mechanisms and to search for appropriate bio-targets to overcome this malignancy. Two NPC cell lines were firstly exposed to 60 Gy irradiation, and residual cells were collected. In our previous study, colony formation assay detected the radioresistance of these cells. Here, the CCK-8 assay examined the cell sensitivity to paclitaxel and cisplatin. Wound-healing and Transwell assays were performed to investigate cell motility and invasion capabilities. Inverted phase-contrast microscopy was used to observe and photograph the morphology of cells. Expression levels of epithelial-mesenchymal transition (EMT)-related proteins were detected by western blot assay in NPC cells and tissues. The mRNA levels of cancer stem cell (CSC)-related genes were detected via qRT-PCR. The results revealed that residual NPC cells exhibited enhanced radioresistance and cross-resistance to paclitaxel and cisplatin. Higher capacities of invasion and migration were also observed. An elongated morphology with pseudopodia formation and broadening in the intercellular space was observed in the residual cells. Downregulation of E-cadherin and upregulation of vimentin were detected in the residual NPC cells and tissues. CSC-related Lgr5 and c-myc were significantly upregulated in the CNE-2-Rs and 6-10B-Rs radioresistance cells. Higher proportions of Lgr5+ cells were observed in radioresistant cells via immunofluorescent staining and flow cytometry. In conclusion, our study demonstrated that residual NPC cells had an advanced malignant transition and presented with both EMT and a CSC phenotype. This provides a possible clue and treatment strategy for advanced and residual NPC.

Evans CN, Brewer NT, Vadaparampil ST, et al.
Impact of genomic testing and patient-reported outcomes on receipt of adjuvant chemotherapy.
Breast Cancer Res Treat. 2016; 156(3):549-55 [PubMed] Article available free on PMC after 08/04/2017 Related Publications
Practice guidelines incorporate genomic tumor profiling, using results such as the Oncotype DX Recurrence Score (RS), to refine recurrence risk estimates for the large proportion of breast cancer patients with early-stage, estrogen receptor-positive disease. We sought to understand the impact of receiving genomic recurrence risk estimates on breast cancer patients' well-being and the impact of these patient-reported outcomes on receipt of adjuvant chemotherapy. Participants were 193 women (mean age 57) newly diagnosed with early-stage breast cancer. Women were interviewed before and 2-3 weeks after receiving the RS result between 2011 and 2015. We assessed subsequent receipt of chemotherapy from chart review. After receiving their RS, perceived pros (t = 4.27, P < .001) and cons (t = 8.54, P < .001) of chemotherapy increased from pre-test to post-test, while perceived risk of breast cancer recurrence decreased (t = 2.90, P = .004). Women with high RS tumors were more likely to receive chemotherapy than women with low RS tumors (88 vs. 5 %, OR 0.01, 0.00-0.02, P < .001). Higher distress (OR 2.19, 95 % CI 1.05-4.57, P < .05) and lower perceived cons of chemotherapy (OR 0.50, 95 % CI 0.26-0.97, P < .05) also predicted receipt of chemotherapy. Distressed patients who saw few downsides of chemotherapy received this treatment. Clinicians should consider these factors when discussing chemotherapy with breast cancer patients.

Ahlers KE, Chakravarti B, Fisher RA
RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer.
AAPS J. 2016; 18(3):560-72 [PubMed] Article available free on PMC after 22/03/2017 Related Publications
Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gαi/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

Hsiao LT, Wang HY, Yang CF, et al.
Human Cytokine Genetic Variants Associated With HBsAg Reverse Seroconversion in Rituximab-Treated Non-Hodgkin Lymphoma Patients.
Medicine (Baltimore). 2016; 95(11):e3064 [PubMed] Article available free on PMC after 22/03/2017 Related Publications
Hepatitis B virus (HBV) reactivation has been noted in HBV surface antigen (HBsAg)-seronegative patients with CD20 B-cell non-Hodgkin lymphoma (NHL) undergoing rituximab treatment. Clinically, hepatitis flares are usually associated with the reappearance of HBsAg (reverse seroconversion of HBsAg, HBV-RS). It is unclear whether human genetic factors are related to rituximab-associated HBV reactivation. Unvaccinated HBsAg-seronegative adults (n = 104) with CD20 NHL who had received rituximab-containing therapy without anti-HBV prophylaxis were enrolled. Eighty-nine candidate single nucleotide polymorphisms (SNPs) of 49 human cytokine genes were chosen and were analyzed using the iPLEX technique. Competing risk regression was used to identify the factors associated with HBV-RS. Participants had a median age of 66.1 years and 56.7% were male (n = 59). The anti-HBs and anti-HBc positivity rates were 82.4% and 94.1%, respectively, among patients for whom data were available (approximately 81%). A mean of 7.14 cycles of rituximab therapy were administered, and a total of 14 (13.4%) patients developed HBV-RS. Nine SNPs showed significant differences in frequency between patients with or without HBV-RS: CD40 rs1883832, IL4 rs2243248 and rs2243263, IL13 rs1295686, IL18 rs243908, IL20 rs1518108, and TNFSF13B rs12428930 and rs12583006. Multivariate analysis showed that ≥6 cycles of rituximab therapy, IL18 rs243908, and the IL4 haplotype rs2243248∼rs2243263 were independently associated with HBV-RS. The IL4 haplotype rs2243248∼rs2243263 was significantly associated with HBV-RS regardless of anti-HBs status. Polymorphisms in human cytokine genes impact the risk of rituximab-associated HBV-RS.

Beckenkamp A, Davies S, Willig JB, Buffon A
DPPIV/CD26: a tumor suppressor or a marker of malignancy?
Tumour Biol. 2016; 37(6):7059-73 [PubMed] Related Publications
Dipeptidyl peptidase IV (DPPIV/CD26) is a multifunctional protein with intrinsic peptidase activity that inactivates or degrades some bioactive peptides. It is the main cellular binding protein for ecto-adenosine deaminase and interacts with extracellular matrix proteins, besides participating in different signaling pathways. Due to these multiple functions, DPPIV/CD26 has been shown to be closely related to the tumor process. It has been reported that the progression of certain types of cancer is accompanied by a decrease in DPPIV/CD26 expression, and studies have shown that the malignant phenotype can be reverted when DPPIV/CD26 expression is induced in these cancer cells, characterizing this protein as a tumor suppressor. On the other hand, DPPIV/CD26 was described as a protein associated with invasion and metastatic spread, characterizing it as a marker of malignancy. Thus, this review explores the roles of DPPIV/CD26 expression in tumor progression in different types of cancer and demonstrates the importance of this protein as a promising therapeutic target and tumor biomarker.

Hartkopf AD, Wallwiener M, Kommoss S, et al.
Detection of disseminated tumor cells from the bone marrow of patients with early breast cancer is associated with high 21-gene recurrence score.
Breast Cancer Res Treat. 2016; 156(1):91-5 [PubMed] Related Publications
High 21-gene recurrence score (RS) is associated with an impaired prognosis in patients with HR-positive/HER2-negative early breast cancer (EBC) and predictive of response to adjuvant chemotherapy. Detection of disseminated tumor cells (DTCs) in the bone marrow is a surrogate of minimal residual disease and of prognostic value. The aim of this study was to compare DTC detection with the 21-gene RS. DTCs were identified in bone marrow aspirates of HR-positive/HER2-negative EBC patients by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology at primary surgery. The 21-gene RS was assessed in paraffin-embedded tumor tissue samples using Oncotype DX (Genomic Health). A total of 114 patients were included in this study. DTCs were detected in 13 of these (11 %). Of the women with a low RS (<18), 5/75 (7 %) were DTC positive. Of the women with an intermediate/high RS (≥18), 8/39 (21 %) were DTC positive (p = 0.03, Chi-squared test). The median RS in DTC-negative patients was significantly lower as compared to DTC-positive patients (15 vs. 20, p = 0.04, Mann-Whitney U test). In conclusion, detection of DTCs in patients with EBC is associated with high 21-gene recurrence score. These findings are meaningful for further basic research that aims to investigate the biological mechanism of tumor cell spread and cancer progression and may have prognostic and/or predictive clinical implications that should be evaluated in future clinical trials.

Zambra FM, Biolchi V, de Cerqueira CC, et al.
Immunogenetics of prostate cancer and benign hyperplasia--the potential use of an HLA-G variant as a tag SNP for prostate cancer risk.
HLA. 2016; 87(2):79-88 [PubMed] Related Publications
Human leukocyte antigen G (HLA-G) is an immunomodulatory molecule with important roles both physiologically as well as an escape mechanism of cancer cells. In this study, we evaluated the impact of eight polymorphisms at the 3' untranslated region (3'UTR) of the HLA-G gene in the development of prostate cancer (PCa) and benign prostatic hyperplasia (BPH). A total of 468 DNA samples of Brazilian men predominantly Euro-descendant with PCa (N = 187), BPH (N = 152) and healthy control individuals (N = 129) were evaluated. The HLA-G 3'UTR region was amplified by polymerase chain reaction (PCR), sequenced and genotyped to identify the 14 bp insertion/deletion (rs371194629), +3003T/C (rs1707), +3010C/G (rs1710), +3027A/C (rs17179101), +3035C/T (rs17179108), +3142G/C (rs1063320), +3187A/G (rs9380142) and +3196C/G (rs1610696) polymorphisms. Regression logistic and chi-square tests were performed to verify the influence of single nucleotide polymorphisms (SNPs) in PCa and/or BPH susceptibility, as well as in PCa progression (clinicopathological status). Our data showed the UTR-4 haplotype as a risk factor to PCa in comparison with control [odds ratio (OR) 2.35, 95% confidence interval (CI) 1.39-3.96, P adjusted = 0.003) and BPH groups (OR 1.82, 95% CI 1.15-2.86, P adjusted = 0.030). Further, the 'non-14bp Ins_ + 3142G_+3187A' haplotype (OR 1.56, 95% CI 1.10-2.20, P adjusted = 0.036), the +3003CT genotype (OR 4.44, 95% CI 1.33-4.50, P adjusted = 0.032) and the +3003C allele (OR 2.33, 95% CI 1.38-3.92, P adjusted = 0.016) also conferred susceptibility to PCa. Our data suggest an important influence of HLA-G 3'UTR polymorphisms in PCa susceptibility and support the use of the +3003 variant as a tag SNP for PCa risk.

Vujovic S, Vujosevic S, Kavaric S, et al.
Cancerous leptomeningitis and familial congenital hypopituitarism.
Endocrine. 2016; 52(2):231-5 [PubMed] Related Publications
People are at higher risk of cancer as they get older or have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Earlier population and case control studies reported that upper quartile of circulating IGF-I is associated with a higher risk of developing cancer suggesting possible involvement of the growth hormone (GH)/IGF system in initiation or progression of cancer. Since GH therapy increases IGF-1 levels, there have been concerns that GH therapy in hypopituitarism might increase the risk of cancer. We report a 42-year-old female patient who presented with subacute onset of symptoms of meningitis and with the absence of fever which resulted in death 70 days after the onset of symptoms. The patient together with her younger brother was diagnosed at the age of 5 years with familial congenital hypopituitarism, due to homozygous mutation c.150delA in PROP1 gene. Due to evolving hypopituitarism, she was replaced with thyroxine (from age 5), hydrocortisone (from age 13), GH (from age 13 until 17), and sex steroids in adolescence and adulthood. Her consanguineous family has a prominent history of malignant diseases. Six close relatives had malignant disease including her late maternal aunt with breast cancer. BRCA 1 and BRCA 2 mutational analysis in the patient's mother was negative. Histology after autopsy disclosed advanced ovarian cancer with multiple metastases to the brain, leptomeninges, lungs, heart, and adrenals. Low circulating IGF-1 did not seem to protect this patient from cancer initiation and progression in the context of strong family history of malignancies.

de Oliveira VA, da Motta LL, De Bastiani MA, et al.
In vitro evaluation of antitumoral efficacy of catalase in combination with traditional chemotherapeutic drugs against human lung adenocarcinoma cells.
Tumour Biol. 2016; 37(8):10775-84 [PubMed] Related Publications
Lung cancer is the most lethal cancer-related disease worldwide. Since survival rates remain poor, there is an urgent need for more effective therapies that could increase the overall survival of lung cancer patients. Lung tumors exhibit increased levels of oxidative markers with altered levels of antioxidant defenses, and previous studies demonstrated that the overexpression of the antioxidant enzyme catalase (CAT) might control tumor proliferation and aggressiveness. Herein, we evaluated the effect of CAT treatment on the sensitivity of A549 human lung adenocarcinoma cells toward various anticancer treatments, aiming to establish the best drug combination for further therapeutic management of this disease. Exponentially growing A549 cells were treated with CAT alone or in combination with chemotherapeutic drugs (cisplatin, 5-fluorouracil, paclitaxel, daunorubicin, and hydroxyurea). CalcuSyn(®) software was used to assess CAT/drug interactions (synergism or antagonism). Growth inhibition, NFκB activation status, and redox parameters were also evaluated in CAT-treated A549 cells. CAT treatment caused a cytostatic effect, decreased NFκB activation, and modulated the redox parameters evaluated. CAT treatment exhibited a synergistic effect among most of the anticancer drugs tested, which is significantly correlated with an increased H2O2 production. Moreover, CAT combination caused an antagonism in paclitaxel anticancer effect. These data suggest that combining CAT (or CAT analogs) with traditional chemotherapeutic drugs, especially cisplatin, is a promising therapeutic strategy for the treatment of lung cancer.

Yun BH, Chon SJ, Choi YS, et al.
Pathophysiology of Endometriosis: Role of High Mobility Group Box-1 and Toll-Like Receptor 4 Developing Inflammation in Endometrium.
PLoS One. 2016; 11(2):e0148165 [PubMed] Article available free on PMC after 22/03/2017 Related Publications
Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner. Treatment with a TLR4 antagonist and an NF-κB inhibitor resulted in suppression of rHMGB-1-induced HESC proliferation (P<0.05). Levels of IL-6 were significantly decreased following treatment with an NF-κB inhibitor (P<0.05). Our results support the development of altered, pathological endometrium resulted from oxidative stress in normal endometrium. These findings may provide important insights into the changes in endometrium linking the development and progression of endometriosis.

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