Gene Summary

Gene:GUSB; glucuronidase beta
Aliases: BG, MPS7
Summary:This gene encodes a hydrolase that degrades glycosaminoglycans, including heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme forms a homotetramer that is localized to the lysosome. Mutations in this gene result in mucopolysaccharidosis type VII. Alternative splicing results in multiple transcript variants. There are many pseudogenes of this locus in the human genome.[provided by RefSeq, May 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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

Latest Publications: GUSB (cancer-related)

Zhu XL, Ren LF, Wang HP, et al.
Plasma microRNAs as potential new biomarkers for early detection of early gastric cancer.
World J Gastroenterol. 2019; 25(13):1580-1591 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Early gastric cancer (EGC), compared with advanced gastric cancer (AGC), has a higher 5-year survival rate. However, due to the lack of typical symptoms and the difficulty in diagnosing EGC, no effective biomarkers exist for the detection of EGC, and gastroscopy is the only detection method.
AIM: To provide new biomarkers with high specificity and sensitivity through analyzed the differentially expressed microRNAs (miRNAs) in EGC and AGC and compared them with those in benign gastritis (BG).
METHODS: We examined the differentially expressed miRNAs in the plasma of 30 patients with EGC, AGC, and BG by miRNA chip analysis. Then, we analyzed and selected the significantly different miRNAs using bioinformatics. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) confirmed the relative transcription level of these miRNAs in another 122 patients, including patients with EGC, AGC,
RESULTS: Among the expression profiles of the miRNA chips in the three groups in the discovery set, of 117 aberrantly expressed miRNAs, 30 confirmed target prediction, whereas 14 were included as potential miRNAs. The RT-qPCR results showed that 14 potential miRNAs expression profiles in the two groups exhibited no differences in terms of
CONCLUSION: The differentially expressed circulatory plasma miR-425-5p, miR-1180-3p, miR-122-5p, miR-24-3p and miR-4632-5p can be regarded as a new potential biomarker panel for the diagnosis of EGC. The prediction and early diagnosis of EGC can be considerably facilitated by combining gastroscopy with the use of these miRNA biomarkers, thereby optimizing the strategy for effective detection of EGC. Nevertheless, larger-scale human experiments are still required to confirm our findings.

Hu T, Linghu K, Huang S, et al.
Flaxseed extract induces apoptosis in human breast cancer MCF-7 cells.
Food Chem Toxicol. 2019; 127:188-196 [PubMed] Related Publications
Significant evidence indicated that flaxseed (Linum usitatissimum) possesses various positive health aspects such as reducing the risk of cancer and cardiovascular diseases. The fatty acids are considered to be responsible for these benefits of flaxseed. Herein, the in vitro effects of flaxseed extract on the growth and apoptosis of human breast cancer MCF-7 cells were investigated. The MCF-7 cells treated with flaxseed extract showed a dose-dependent decrease in cell viability. The flaxseed extract induced reactive oxygen species and the flow cytometric analysis demonstrated that flaxseed fatty acids triggered apoptosis of MCF-7 cells, which was also shown by the loss of mitochondrial membrane potential and caspase cascade reaction. Thus, the flaxseed extract regulated the growth of MCF-7 cells and induced apoptosis. Eventually, the flaxseed could be used as a dietary supplement to prevent breast cancer.

Ruoß M, Damm G, Vosough M, et al.
Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards 'normal' liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.

Haralambiev L, Wien L, Gelbrich N, et al.
Effects of Cold Atmospheric Plasma on the Expression of Chemokines, Growth Factors, TNF Superfamily Members, Interleukins, and Cytokines in Human Osteosarcoma Cells.
Anticancer Res. 2019; 39(1):151-157 [PubMed] Related Publications
BACKGROUND/AIM: Therapeutic options for osteosarcoma (OS) are still limited. Cold atmospheric plasma (CAP) leads to inhibition of tumor growth and metastasis, but underlying mechanisms are not fully understood. The aim of this study was to investigate CAP-induced changes in cytokine expression in OS cells.
MATERIALS AND METHODS: OS cell lines (U2-OS, MNNG/HOS) were treated with CAP and administered to an RT2 Profiler PCR Array (Qiagen, Hilden, Germany) detecting 84 chemokines, growth factors, TNF superfamily members, interleukins, and cytokines.
RESULTS: The analyses showed that 15 factors (C5, CCL5, CNTF, CSF1, CSF3, CXCL1, IL-1A, IL-1B, IL-18, IL-22, IL23A, MSTN, NODAL, TGFβ2, THPO) were induced, but only one factor (VEGFA) was suppressed after CAP treatment.
CONCLUSION: No extensive systemic cell response with presumably far-reaching consequences for neighboring cells was detectable after CAP treatment. Since the antitumoral effect of CAP on OS cells has already been demonstrated, intraoperative treatment with CAP represents a promising and systemic safe option for the therapy of OS.

METCAM/MUC18 Decreases the Malignant Propensity of Human Ovarian Carcinoma Cells.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling pathways and to regulate general behaviors of cells. We and other two groups previously suggested that METCAM/MUC18 probably be utilized as a biomarker for predicting the malignant tendency of clinical ovarian carcinomas, since METAM/MUC18 expression appears to associate with the carcinoma at advanced stages. It has been further postulated to promote the malignant tendency of the carcinoma. However, our recent research results appear to support the conclusion that the above positive correlation is fortuitous; actually METCAM/MUC18 acts as a tumor and metastasis suppressor for the ovarian carcinoma cells. We also suggest possible mechanisms in the METCAM/MUC18-mediated early tumor development and metastasis of ovarian carcinoma. Moreover, we propose to employ recombinant METCAM/MUC18 proteins and other derived products as therapeutic agents to treat the ovarian cancer patients by decreasing the malignant potential of ovarian carcinoma.

Lemma S, Avnet S, Meade MJ, et al.
Validation of Suitable Housekeeping Genes for the Normalization of mRNA Expression for Studying Tumor Acidosis.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Similar to other types of cancer, acidification of tumor microenvironment is an important feature of osteosarcoma, and a major source of cellular stress that triggers cancer aggressiveness, drug resistance, and progression. Among the different effects of low extracellular pH on tumor cells, we have recently found that short-term exposure to acidosis strongly affects gene expression. This alteration might also occur for the most commonly used housekeeping genes (HKG), thereby causing erroneous interpretation of RT-qPCR data. On this basis, by using osteosarcoma cells cultured at different pH values, we aimed to identify the ideal HKG to be considered in studies on tumor-associated acidosis. We verified the stability of 15 commonly used HKG through five algorithms (NormFinder, geNorm, BestKeeper, ΔCT, coefficient of variation) and found that no universal HKG is suitable, since at least four HKG are necessary for proper normalization. Furthermore, according to the acceptable range of values,

Marjanovic Vicentic J, Drakulic D, Garcia I, et al.
SOX3 can promote the malignant behavior of glioblastoma cells.
Cell Oncol (Dordr). 2019; 42(1):41-54 [PubMed] Related Publications
PURPOSE: Glioblastoma is the most common and lethal adult brain tumor. Despite current therapeutic strategies, including surgery, radiation and chemotherapy, the median survival of glioblastoma patients is 15 months. The development of this tumor depends on a sub-population of glioblastoma stem cells governing tumor propagation and therapy resistance. SOX3 plays a role in both normal neural development and carcinogenesis. However, little is known about its role in glioblastoma. Thus, the aim of this work was to elucidate the role of SOX3 in glioblastoma.
METHODS: SOX3 expression was assessed using real-time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry. MTT, immunocytochemistry and Transwell assays were used to evaluate the effects of exogenous SOX3 overexpression on the viability, proliferation, migration and invasion of glioblastoma cells, respectively. The expression of Hedgehog signaling pathway components and autophagy markers was assessed using RT-qPCR and Western blot analyses, respectively.
RESULTS: Higher levels of SOX3 expression were detected in a subset of primary glioblastoma samples compared to those in non-tumoral brain tissues. Exogenous overexpression of this gene was found to increase the proliferation, viability, migration and invasion of glioblastoma cells. We also found that SOX3 up-regulation was accompanied by an enhanced activity of the Hedgehog signaling pathway and by suppression of autophagy in glioblastoma cells. Additionally, we found that SOX3 expression was elevated in patient-derived glioblastoma stem cells, as well as in oncospheres derived from glioblastoma cell lines, compared to their differentiated counterparts, implying that SOX3 expression is associated with the undifferentiated state of glioblastoma cells.
CONCLUSION: From our data we conclude that SOX3 can promote the malignant behavior of glioblastoma cells.

Banko AV, Lazarevic IB, Karalic DZ, et al.
The sequence analysis of Epstein-Barr virus EBNA1 gene: could viral screening markers for nasopharyngeal carcinoma be identified?
Med Microbiol Immunol. 2019; 208(1):81-88 [PubMed] Related Publications
Epstein-Barr virus (EBV) has been identified as a group 1 carcinogenic agent, particularly for nasopharyngeal carcinoma (NPC). The sequence diversity of EBV nuclear antigen 1 (EBNA1) reflects region-restricted polymorphisms, which may be associated with the development of certain malignancies. The aims of the present study were to evaluate EBV EBNA1 gene polymorphisms circulating in NPC, infectious mononucleosis, and isolates from patients with transplanted organs to determine if EBNA1 sequence specificities are useful as viral biomarkers for NPC. Forty biopsies of undifferentiated carcinoma of nasopharyngeal type (UCNT), 31 plasma samples from patients with mononucleosis syndrome, and 16 plasma samples from patients after renal transplantation were tested in this study. The EBNA1 gene was amplified by nested PCR. Further investigation included sequencing, phylogenetic, and statistical evaluations. Eighty-seven sequences were identified as one of the four EBNA1 subtypes, P-Ala, P-Thr, V-Val, and V-Ala, with further classification into ten subvariants. Of these, P-Thr-sv-1 and P-Thr-sv-3 have never been identified in Europe, while V-Val-sv-1 was newly discovered. Statistical analysis revealed significant differences in the distribution of EBNA1 P-Thr subvariants between the three groups of patients, with noticeable clustering of P-Thr-sv-5 in NPC isolates (p < 0.001). EBV EBNA1 showed no sequence specificity in primary infection. This research revealed a newly discovered EBNA1 subvariant. Importantly, EBNA1 P-Thr-sv-5 showed carcinoma-specific EBNA1 variability. Thus, identification of this subvariant should be considered as a viral screening marker for NPC or UCNT.

Durinikova E, Kozovska Z, Poturnajova M, et al.
ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells.
BMC Cancer. 2018; 18(1):848 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Efficiency of colorectal carcinoma treatment by chemotherapy is diminished as the resistance develops over time in patients. The same holds true for 5-fluorouracil, the drug used in first line chemotherapy of colorectal carcinoma.
METHODS: Chemoresistant derivative of HT-29 cells was prepared by long-term culturing in increasing concentration of 5-fluorouracil. Cells were characterized by viability assays, flow cytometry, gene expression arrays and kinetic imaging. Immunomagnetic separation was used for isolation of subpopulations positive for cancer stem cells-related surface markers. Aldehyde dehydrogenase expression was attenuated by siRNA. In vivo studies were performed on SCID/bg mice.
RESULTS: The prepared chemoresistant cell line labeled as HT-29/EGFP/FUR is assigned with different morphology, decreased proliferation rate and 135-fold increased IC
CONCLUSION: Our study demonstrated that acquired chemoresistance goes along with metastatic and migratory phenotype and can be accompanied with increased activity of aldehyde dehydrogenase. We describe here the valuable model to study molecular link between resistance to chemotherapy and metastatic dissemination.

Chen S, He H, Wang Y, et al.
Poor prognosis of nucleophosmin overexpression in solid tumors: a meta-analysis.
BMC Cancer. 2018; 18(1):838 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nucleophosmin is a non-ribosomal nucleolar phosphoprotein that is found primarily in the nucleolus region of cell nucleus, plays multiple important roles in tumor processes. Accumulated previous studies have reported a potential value of NPM acted as a biomarker for prognosis in various solid tumors, but the results were more inconsistency. We performed this meta-analysis to precisely evaluate the prognostic significance of NPM in solid tumors.
METHODS: Clinical data were collected from a comprehensive literature search in PubMed, Web of Science, Embase, and China National Knowledge Infrastructure databases (up to October, 2017). A total of 11 studied with 997 patients were used to assess the association of NPM expression and patients' overall survival (OS). The hazard ratio (HR) or odds ratio (OR) with its 95% confidence intervals (CI) were calculated to estimate the effect.
RESULTS: The pooled results indicated that higher expression of NPM was observably correlated with poor OS in solid tumor (HR = 1.85, 95% CI: 1.44-2.38, P < 0.001). Furthermore, high expression of NPM was associated with some phenotypes of tumor aggressiveness, such as tumor stage (4 studies, III/IV vs. I/II, OR = 5.21, 95% CI: 2.72-9.56, P < 0.001), differentiation grade (poor vs. well/moderate, OR = 1.82, 95% CI: 1.01-3.27, P = 0.046).
CONCLUSION: This meta-analysis indicated that NPM may act as a valuable prognosis biomarker and a potential therapeutic target in human solid tumors.

Irimie AI, Braicu C, Cojocneanu R, et al.
Differential Effect of Smoking on Gene Expression in Head and Neck Cancer Patients.
Int J Environ Res Public Health. 2018; 15(7) [PubMed] Free Access to Full Article Related Publications
Smoking is a well-known behavior that has an important negative impact on human health, and is considered to be a significant factor related to the development and progression of head and neck squamous cell carcinomas (HNSCCs). Use of high-dimensional datasets to discern novel HNSCC driver genes related to smoking represents an important challenge. The Cancer Genome Atlas (TCGA) analysis was performed in three co-existing groups of HNSCC in order to assess whether gene expression landscape is affected by tobacco smoking, having quit, or non-smoking status. We identified a set of differentially expressed genes that discriminate between smokers and non-smokers or based on human papilloma virus (HPV)16 status, or the co-occurrence of these two exposome components in HNSCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways classification shows that most of the genes are specific to cellular metabolism, emphasizing metabolic detoxification pathways, metabolism of chemical carcinogenesis, or drug metabolism. In the case of HPV16-positive patients it has been demonstrated that the altered genes are related to cellular adhesion and inflammation. The correlation between smoking and the survival rate was not statistically significant. This emphasizes the importance of the complex environmental exposure and genetic factors in order to establish prevention assays and personalized care system for HNSCC, with the potential for being extended to other cancer types.

Janik ME, Szwed S, Grzmil P, et al.
RT-qPCR analysis of human melanoma progression-related genes - A novel workflow for selection and validation of candidate reference genes.
Int J Biochem Cell Biol. 2018; 101:12-18 [PubMed] Related Publications
The objective of this study was to identify a normalizer or combination of normalizers for quantitative evaluation of the expression of a target gene of interest during melanoma progression. Adult melanocytes, uveal primary melanoma cells and cutaneous primary and metastatic melanoma cells were used to construct a panel of 14 experimental models reflecting cancer promotion and progression. Hypoxanthine phosphoribosyltransferase 1 (HPRT1), glucuronidase beta (GUSB), ribosomal protein S23 (RPS23), phosphoglycerate kinase 1 (PGK1) and small nuclear ribonucleoprotein progression. Adult melanocytes, uveal primary melanoma cells and cutaneous primary and metastatic melanoma cells were used to construct a panel of 14 experimental models reflecting cancer promotion and progression. Hypoxanthine phosphoribosyltransferase 1 (HPRT1), glucuronidase beta (GUSB), ribosomal protein S23 (RPS23), phosphoglycerate kinase 1 (PGK1) and small nuclear ribonucleoprotein polypeptide A (SRNPA) were chosen as candidate housekeeping genes. NormFinder software was used to identify the best reference gene or pair of reference genes from five candidate housekeeping genes, on the basis of expression stability in a given experimental model. The suitability of references was validated by normalizing the transcriptional activities of E-cadherin (CDH1), N-cadherin (CDH2) and endoplasmic reticulum aminopeptidase 1 (ERAP1) target genes. It has been shown that the relative expression of CDH2 and ERAP1 target genes in a given cell line may vary between experimental models, leading to biological misinterpretation. In view of this, we devised a strategy for improved selection of the best stable reference and for obtaining biologically consistent results. This strategy avoided experimental model- and normalizer-dependent conclusions concerning the relative expression of target gene, in the examined cell lines.

Rinaldetti S, Pfirrmann M, Manz K, et al.
Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial.
Clin Lymphoma Myeloma Leuk. 2018; 18(4):266-271 [PubMed] Related Publications
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated.
MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated.
RESULTS: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (‰) was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.5‰ (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (≤4.5‰; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%).
CONCLUSION: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation.

Irimie AI, Ciocan C, Gulei D, et al.
Current Insights into Oral Cancer Epigenetics.
Int J Mol Sci. 2018; 19(3) [PubMed] Free Access to Full Article Related Publications
Epigenetic modifications have emerged into one of the cancer hallmarks, replacing the concept of malignant pathologies as being solely genetic-based conditions. The epigenetic landscape is responsible for normal development but also for the heterogeneity among tissues in terms of gene expression patterns. Dysregulation in these mechanisms has been associated with disease stage, and increased attention is now granted to cancer in order to take advantage of these modifications in terms of novel therapeutic strategies or diagnosis/prognosis tools. Oral cancer has also been subjected to epigenetic analysis with numerous studies revealing that the development and progression of this malignancy are partially induced by an altered epigenetic substrate together with genetic alterations and prolonged exposure to environmental risk factors. The present review summarizes the most important epigenetic modifications associated with oral cancer and also their potential to be used as new therapeutic targets.

Eljabo N, Nikolic N, Carkic J, et al.
Genetic and epigenetic alterations in the tumour, tumour margins, and normal buccal mucosa of patients with oral cancer.
Int J Oral Maxillofac Surg. 2018; 47(8):976-982 [PubMed] Related Publications
Despite adequate surgical resection, oral squamous cell carcinoma (OSCC) shows a high rate of recurrence and metastasis, which could be explained by the presence of molecular alterations in seemingly normal tumour margins and the entire oral mucosa. The aims of this study were (1) to assess the presence of gene amplification (c-Myc and HER2) and promoter methylation (p14 and p16) in the tumours, tumour margins, and unaffected oral mucosa of 40 OSCC patients, and (2) to evaluate the possibility of using these alterations as prognostic markers. c-Myc and HER2 genes were quantified by means of real-time PCR (qPCR), and p14 and p16 methylation status was determined by methylation-specific PCR (MSP PCR). All tissues examined exhibited molecular alterations in various proportions. Tumour tissues, as expected, showed the highest prevalence of alterations, while oral mucosa showed the lowest. Multiple alterations (co-alterations) in tumours and tumour margins were significantly more frequent than in unaffected oral mucosa (P<0.001 and P=0.027, respectively). HER2 amplification in margin tissue (P<0.001) and swabs (P=0.013), as well as the existence of three co-alterations in margins (P=0.001) and macroscopically unaffected oral mucosa (P<0.001) were correlated with shorter disease-specific survival.

Dang W, Li T, Li B, et al.
A bifunctional scaffold with CuFeSe
Biomaterials. 2018; 160:92-106 [PubMed] Related Publications
Bone tumor is one of major challenging issues clinically. After surgical intervention, a few bone tumor cells still remain around bone defects and then proliferate over days. Fabrication of specific biomaterials with dual functions of bone tumor therapy and bone regeneration is of great significance. In order to achieve this aim, we managed to prepare bioactive glass (BG) scaffolds functionalized by the CuFeSe

Lu JW, Yang F, Ke QF, et al.
Magnetic nanoparticles modified-porous scaffolds for bone regeneration and photothermal therapy against tumors.
Nanomedicine. 2018; 14(3):811-822 [PubMed] Related Publications
For effectively treating tumor related-bone defects, design and fabrication of multifunctional biomaterials still remain a great challenge. Herein, we firstly fabricated magnetic SrFe

Majumder M, Dunn L, Liu L, et al.
COX-2 induces oncogenic micro RNA miR655 in human breast cancer.
Sci Rep. 2018; 8(1):327 [PubMed] Free Access to Full Article Related Publications
We show that Cyclooxygenase-2 over-expression induces an oncogenic microRNA miR655 in human breast cancer cells by activation of EP4. MiR655 expression positively correlated with COX-2 in genetically disparate breast cancer cell lines and increased in all cell lines when grown as spheroids, implicating its link with stem-like cells (SLCs). Ectopic miR655 over-expression in MCF7 and SKBR3 cells resulted in increased proliferation, migration, invasion, spheroid formation and Epithelial to Masenchymal transition (EMT). Conversely, knocking down miR655 in aggressive MCF7-COX2 and SKBR3-COX2 cells reverted these phenotypes. MCF7-miR655 cells displayed upregulated NOTCH/WNT genes; both pathway inhibitors abrogated miR655-induced spheroid formation, linking miR655 with SLC-related pathways. MiR655 expression was dependent on EP4 activity and EP4 downstream signaling pathways PI3K/AKT, ERK and NF-kB and led to TGFβ resistance for Smad3 phosphorylation. Tail vein injection of MCF7-miR655 and SKBR3-miR655 cells in NOD/SCID/GUSB-null mice revealed increased lung colony growth and micrometastases to liver and spleen. MiR655 expression was significantly high in human breast tumors (n = 105) compared to non-tumor tissues (n = 20) and associated with reduced patient survival. Thus miR655 could serve as a prognostic breast cancer biomarker.

Irimie AI, Braicu C, Sonea L, et al.
A Looking-Glass of Non-coding RNAs in oral cancer.
Int J Mol Sci. 2017; 18(12) [PubMed] Free Access to Full Article Related Publications
Oral cancer is a multifactorial pathology and is characterized by the lack of efficient treatment and accurate diagnostic tools. This is mainly due the late diagnosis; therefore, reliable biomarkers for the timely detection of the disease and patient stratification are required. Non-coding RNAs (ncRNAs) are key elements in the physiological and pathological processes of various cancers, which is also reflected in oral cancer development and progression. A better understanding of their role could give a more thorough perspective on the future treatment options for this cancer type. This review offers a glimpse into the ncRNA involvement in oral cancer, which can help the medical community tap into the world of ncRNAs and lay the ground for more powerful diagnostic, prognostic and treatment tools for oral cancer that will ultimately help build a brighter future for these patients.

Wallner C, Drysch M, Becerikli M, et al.
Interaction with the GDF8/11 pathway reveals treatment options for adenocarcinoma of the breast.
Breast. 2018; 37:134-141 [PubMed] Related Publications
Breast adenocarcinoma continues to be the most frequently diagnosed tumor entity. Despite established therapy options, mortality for breast cancer remains to be as high as 40,000 patients in the US annually. Thus, a need to develop a patient-oriented, targeted therapy exists. In this study, we investigated the interaction of breast adenocarcinoma with the ubiquitously present protein Follistatin and subsequently the GDF8/11 pathway. We analyzed primary histological samples from adenocarcinoma patients for expression of Follistatin and GDF8/11. Furthermore, expression levels of Follistatin and GDF8/11 in MCF7 were compared with MCF10a cells. From the resulting data, GDF8 and Follistatin were used as chemotherapeutic agents in MCF7 cells and their migratory, proliferative behavior and viability were measured. From the experiments, we were able to detect a significantly increased expression of Follistatin and GDF8/11 in the low malignant breast adenocarcinoma (G1) as compared to benign breast fibroadenoma. Interestingly, a decrease was demonstrated in higher grade malignancies. These findings were accompanied by the clinical observation that increased expression of Follistatin and GDF8 is associated with a higher overall survival rate of breasts cancer patients. Substitution of GDF8 and Follistatin reduces the viability of the MCF7 cells and disrupts the migrative and proliferative potential. In summary, MCF7 cells show high chemosensitivity to Follistatin and especially GDF8 and both proteins might serve as targets to improve systemic treatment in breast cancer. In contrast to most established chemotherapy regimens Follistatin and GDF8 show no cytotoxicity to other organs.

Nikolic N, Carkic J, Ilic Dimitrijevic I, et al.
P14 methylation: an epigenetic signature of salivary gland mucoepidermoid carcinoma in the Serbian population.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 125(1):52-58 [PubMed] Related Publications
OBJECTIVE: To investigate the prevalence of p16
STUDY DESIGN: DNA extracted from 35 formalin-fixed and paraffin-embedded MEC samples and 10 normal salivary gland (NSG) tissue samples was analyzed for the presence of promoter hypermethylation using methylation-specific polymerase chain reaction testing.
RESULTS: The percentages of gene hypermethylation in MECs versus NSGs were the following: p14: 100% versus 20% (P<.001); p16: 60% versus 20% (P = .035); hTERT: 54.3% versus 20% (P = .078); and TP53: 31.4% versus 30% (P = .981). Multiple sites were found to be methylated in 86% of MECs compared with 10% in NSGs (P< .001). TP53 and hTERT were more often methylated in lower clinical stages (P = .033 and P = .005, respectively).
CONCLUSIONS: Hypermethylation of p14 appears to be an important event in the development of mucoepidermoid carcinoma. High frequency of gene hypermethylation and high incidence of methylation at multiple sites point to the importance of epigenetic phenomena in the pathogenesis of MECs, although with modest impact on clinical parameters.

Gelbrich N, Ahrend H, Kaul A, et al.
Different Cytokine and Chemokine Expression Patterns in Malignant Compared to Those in Nonmalignant Renal Cells.
Anal Cell Pathol (Amst). 2017; 2017:7190546 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Cytokines and chemokines are widely involved in cancer cell progression and thus represent promising candidate factors for new biomarkers.
METHODS: Four renal cell cancer (RCC) cell lines (Caki-1, 786-O, RCC4, and A498) and a nonmalignant renal cell line (RC-124) were examined with respect to their proliferation. The cytokine and chemokine expression pattern was examined by a DNA array (Human Cytokines & Chemokines RT
RESULTS: Caki-1 and 786-O cells exhibited significantly increased proliferation rates, whereas RCC4 and A498 cells demonstrated attenuated proliferation, compared to nonmalignant RC-124 cells. Expression analysis revealed 52 cytokines and chemokines primarily involved in proliferation and inflammation and differentially expressed not only in malignant and nonmalignant renal cells but also in the four RCC cell lines.
CONCLUSION: This is the first study examining the expression of 84 cytokines and chemokines in four RCC cell lines compared to that in a nonmalignant renal cell line. VEGFA, NODAL, and BMP6 correlated with RCC cell line proliferation and, thus, may represent putative clinical biomarkers for RCC progression as well as for RCC diagnosis and prognosis.

Petrelli F, Tomasello G, Barni S, et al.
Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature.
Breast Cancer Res Treat. 2017; 166(2):339-349 [PubMed] Related Publications
PURPOSE: HER2 gene is a member of the epidermal growth factor receptor (EGFR) family. Across different malignancies, aberrations of HER2 gene commonly correspond to gain-of-function alterations leading to increased receptor signaling.
METHODS: We have reviewed the literature currently available on HER2 mutations in human breast cancer (BC) evaluating type and frequency of such mutations. The primary objective was to determine the frequency and the number of patients with HER2-mut in the series analyzed. The secondary objectives were to assess characteristics of mutated cases (ER and HER2 status and stage of disease, type of mutations, and finally the clinical outcome if reported).
RESULTS: We retrieved 31 published papers, and the pooled rate of HER2 mutations across 12,905 BC patients was calculated. Overall, the frequency of HER2 mutations was 2.7% with most involving the intracellular domain. About 4% of patients were finally mutated. The predictive role was not described. Only 30% of these patients were simultaneously HER2 positive and 63% were ER positive.
CONCLUSION: We have found that the prevalence of HER2 mutations is about 3%. These genic alterations are independently associated with HER2 amplification status, occurring in both ER-positive/HER2-negative diseases or HER2-enriched cancers. Ongoing trials are investigating small molecules tyrosine kinase inhibitors in patients harboring these mutations.

Dragoj M, Bankovic J, Sereti E, et al.
Anti-invasive effects of CXCR4 and FAK inhibitors in non-small cell lung carcinomas with mutually inactivated p53 and PTEN tumor suppressors.
Invest New Drugs. 2017; 35(6):718-732 [PubMed] Related Publications
Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. At the time of diagnosis, a large percentage of NSCLC patients have already developed metastasis, responsible for extremely high mortality rates. CXCR4 receptor and focal adhesion kinase (FAK) are known to regulate such invasive cancer behavior. Their expression is downregulated by p53 and PTEN tumor suppressors which are commonly co-inactivated in NSCLC patients and contribute to metastasis. Therefore, targeting CXCR4 or FAK seems to be a promising strategy in suppressing metastatic spread of p53/PTEN deficient NSCLCs. In this study, we first examined the invasive characteristics of NSCLC cells with suppressed p53 and PTEN activity using wound healing, gelatin degradation and invasion assays. Further, changes in the expression of CXCR4 and FAK were evaluated by RT-qPCR and Western Blot analysis. Finally, we tested the ability of CXCR4 and FAK inhibitors (WZ811 and PF-573228, respectively) to suppress the migratory and invasive potential of p53/PTEN deficient NSCLC cells, in vitro and in vivo using metastatic models of human NSCLC. Our results showed that cells with mutually inactive p53 and PTEN have significantly increased invasive potential associated with hyperactivation of CXCR4 and FAK signaling pathways. Treatments with WZ811 and PF-573228 inhibitors significantly reduced migratory and invasive capacity in vitro and showed a trend of improved survival in vivo. Accordingly, we demonstrated that p53/PTEN deficient NSCLCs have extremely invasive phenotype and provided a rationale for the use of CXCR4 or FAK inhibitors for the suppression of NSCLC dissemination.

Gümbel D, Gelbrich N, Napp M, et al.
Peroxiredoxin Expression of Human Osteosarcoma Cells Is Influenced by Cold Atmospheric Plasma Treatment.
Anticancer Res. 2017; 37(3):1031-1038 [PubMed] Related Publications
BACKGROUND/AIM: To evaluate the potential involvement of redox-specific signalling pathways in cold atmospheric plasma (CAP)-induced apoptosis on human osteosarcoma cells.
MATERIALS AND METHODS: Osteosarcoma cell lines were treated with CAP with or without antioxidative agents and seeded in cell culture plates. Cell proliferation was determined by counting viable cells. Carrier gas-treated cells served as control. Peroxiredoxin (PRX) 1-3 expression and secretion were assessed.
RESULTS: CAP treatment exhibited strongly attenuated proliferation rates. This effect was significantly attenuated by the addition of N-acetylcysteine (NAC). CAP-treated cells exhibited an increase of PRX 1 and 2 10 sec after treatment. The ratio of oxidized to reduced PRX1 and PRX2 was significantly altered with increasing cellular concentration of the oxidized dimer.
CONCLUSION: Antioxidant supplementation with NAC increases proliferation of CAP-treated osteosarcoma cells, implicating an involvement of redox signalling. Activation of PRX1 and -2 indicate CAP affects redox homeostasis.

Iyer G, Wang AR, Brennan SR, et al.
Identification of stable housekeeping genes in response to ionizing radiation in cancer research.
Sci Rep. 2017; 7:43763 [PubMed] Free Access to Full Article Related Publications
Housekeeping genes (HKGs) are essential for basic maintenance of a variety of cellular processes. They ideally maintain uniform expression independent of experimental conditions. However, the effects of ionizing radiation (IR) on HKG expression is unclear. Statistical algorithms, geNorm and Normfinder were used for estimating the stability of HKGs as raw quantification cycle (Cq) values were not a reliable factor for normalization. Head and neck, non-small lung and pancreas cells were exposed to 2, 4 and 6 Gy IR doses and expression of fourteen HKGs was measured at 5 min to 48 h post-irradiation within a given tissue. Paired and single cell line analyses under these experimental conditions identified TATA-Box Binding Protein (TBP) and Importin 8 (IPO8) to be stable in non-small cell lung cancer. In addition to these two genes, Ubiquitin C (UBC) in head and neck cancer and Transferrin receptor (TFRC) and β-Glucuronidase (GUSB) in pancreatic cancer were identified to be stable as well. In summary we present a resource for top ranked five stable HKGs and their transcriptional behavior in commonly used cancer model cell lines and suggest the use of multiple HKGs under radiation treatment conditions is a reliable metric for quantifying gene expression.

Zeljic K, Supic G, Magic Z
New insights into vitamin D anticancer properties: focus on miRNA modulation.
Mol Genet Genomics. 2017; 292(3):511-524 [PubMed] Related Publications
Vitamin D anticancer properties are well known and have been demonstrated in many in vitro and in vivo studies. Mechanistic insights have given an explanation on how vitamin D exerts antineoplastic functions, which are mainly conducted via the canonical vitamin D receptor (VDR)-vitamin D response elements (VDRE) pathway. Numerous findings indicate that dietary components, including vitamin D, could exert chemopreventive effects through alterations of microRNA (miRNA) expression. As miRNAs have important roles in regulating diverse and vital cellular processes, it has been speculated that vitamin D's non-classical effects, including anticancer effects, could be mediated through alterations of miRNA expression level. The current review focuses on up-to-date experimental data on modulation of miRNA expression by vitamin D treatment in cancer, obtained in a cell culture system, animal models and human cohorts. Reported findings in the review show that vitamin D modulates expression of numerous and diverse miRNAs specific for cancer types. Even in its early phases, with many questions remaining to be answered, dissecting the molecular pathways of vitamin D miRNA modulation is an emerging area of science. The complete unraveling of vitamin D molecular mechanisms will emphasize the vitamin D dietary component as a potential chemopreventive agent in cancer and personalized nutrition.

Marjanovic I, Karan-Djurasevic T, Ugrin M, et al.
Use of Wilms Tumor 1 Gene Expression as a Reliable Marker for Prognosis and Minimal Residual Disease Monitoring in Acute Myeloid Leukemia With Normal Karyotype Patients.
Clin Lymphoma Myeloma Leuk. 2017; 17(5):312-319 [PubMed] Related Publications
BACKGROUND: Acute myeloid leukemia with normal karyotype (AML-NK) represents the largest group of AML patients classified with an intermediate prognosis. A constant need exists to introduce new molecular markers for more precise risk stratification and for minimal residual disease (MRD) monitoring.
PATIENTS AND METHODS: Quantitative assessment of Wilms tumor 1 (WT1) gene transcripts was performed using real-time polymerase chain reaction. The bone marrow samples were collected at the diagnosis from 104 AML-NK patients and from 34 of these patients during follow-up or disease relapse.
RESULTS: We found that overexpression of the WT1 gene (WT1
CONCLUSION: WT1 expression status represents a good molecular marker of prognosis, response to treatment, and MRD monitoring. Above all, the usage of the WT1 expression level as an additional marker for more precise risk stratification of AML-NK patients could lead to more adapted, personalized treatment protocols.

Todorova K, Metodiev MV, Metodieva G, et al.
Micro-RNA-204 Participates in TMPRSS2/ERG Regulation and Androgen Receptor Reprogramming in Prostate Cancer.
Horm Cancer. 2017; 8(1):28-48 [PubMed] Related Publications
Cancer progression is driven by genome instability incurred rearrangements such as transmembrane protease, serine 2 (TMPRSS2)/v-ets erythroblastosis virus E26 oncogene (ERG) that could possibly turn some of the tumor suppressor micro-RNAs into pro-oncogenic ones. Previously, we found dualistic miR-204 effects, acting either as a tumor suppressor or as an oncomiR in ERG fusion-dependent manner. Here, we provided further evidence for an important role of miR-204 for TMPRSS2/ERG and androgen receptor (AR) signaling modulation and fine tuning that prevents TMPRSS2/ERG overexpression in prostate cancer. Based on proximity-based ligation assay, we designed a novel method for detection of TMPRSS2/ERG protein products. We found that miR-204 is TMPRSS2/ERG oncofusion negative regulator, and this was mediated by DNA methylation of TMPRSS2 promoter. Transcriptional factors runt-related transcription factor 2 (RUNX2) and ETS proto-oncogene 1 (ETS1) were positive regulators of TMPRSS2/ERG expression and promoter hypo-methylation. Clustering of patients' sera for fusion protein, transcript expression, and wild-type ERG transcript isoforms, demonstrated not all patients harboring fusion transcripts had fusion protein products, and only few fusion positive ones exhibited increased wild-type ERG transcripts. miR-204 upregulated AR through direct promoter hypo-methylation, potentiated by the presence of ERG fusion and RUNX2 and ETS1. Proteomics studies provided evidence that miR-204 has dualistic role in AR cancer-related reprogramming, promoting prostate cancer-related androgen-responsive genes and AR target genes, as well as AR co-regulatory molecules. miR-204 methylation regulation was supported by changes in molecules responsible for chromatin remodeling, DNA methylation, and its regulation. In summary, miR-204 is a mild regulator of the AR function during the phase of preserved AR sensitivity as the latter one is required for ERG-fusion translocation.

Song W, Zhang WH, Zhang H, et al.
Validation of housekeeping genes for the normalization of RT-qPCR expression studies in oral squamous cell carcinoma cell line treated by 5 kinds of chemotherapy drugs.
Cell Mol Biol (Noisy-le-grand). 2016; 62(13):29-34 [PubMed] Related Publications
Reverse transcription quantitative polymerase chain reaction (RT-qPCR) has become a frequently used strategy in gene expression studies. The relative quantification method is an important and commonly used method for the evaluation of RT-qPCR data. The key of this method is to identify an applicable internal control gene because the usage of different internal control genes may lead to distinct conclusions. Herein, we report the validation of 12 common housekeeping genes for RT-qPCR for gene expression analysis in the Oral squamous cell carcinoma (OSCC) cell line (KB and Tca-8113) treated by 5 kinds of Chemotherapy Drugs. The gene expression stability and applicability of the 12 housekeeping gene candidates were determined using the geNorm, NormFinder, and BestKeeper software programs. Comprehensive analyzing the results of the three software, ALAS1/GAPDH, ALAS1 and GUSB were suggested to be the most stable candidate genes for the study of both KB and Tca-8113 cell line together, KB cell line, and Tca-8113 cell line, respectively. This study provides useful information to normalize gene expression accurately for the investigation of target gene profiling in cell lines of OSCC. Further clarification of tumor molecular expression markers with our recommended housekeeping genes may improve the accuracy of diagnosis and estimation of prognostic factors as well as provide novel personalized treatments for OSCC patients.

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