Levels In Malignant Tissues Research Articles

Association of overexpression of TNF receptor superfamily members (CD40, BAFFR, LTβR and RANK) with favorable prognosis in patients with colorectal adenocarcinoma.

e15516 Background: Numerous studies by our and other groups have highlighted the implication of NF-κB in colorectal cancer (CRC) through the deterioration of classical and alternative pathway signaling. The alternative pathway of NF-κB can be activated by members of TNF superfamily, such as lymphotoxin β (LTβ), tumor necrosis factor ligand superfamily member 5 (CD40L), B-cell activation factor (BAFF) and receptor activator of NF-κB ligand (RANKL). We have previously shown that alternative pathway of NF-κΒ is deteriorated in CRC. In the present study, we investigated the clinical significance of the aforementioned receptors in patients with CRC as well as their relation with effector transcription factors NF-κB2 and RELB. Methods: Gene expression of CD40, BAFFR, LT β R, RANK, NF- κ B2 and RELB, quantified by using real-time qRT-PCT and specific primers and probes, was assessed in 97 cancerous and 61 paired non-neoplastic tumor-adjacent formalin-fixed paraffin-embedded (FFPE) tissue specimens from CRC patients who were surgically managed in the University Hospital of Patras, Greece. Concurrently, we assessed protein expression of the same molecules by immunohistochemistry in the same cohort of patients. Both, mRNA and protein levels of the receptors were analyzed in association with clinicopathological parameters and clinical outcome of the patients in terms of time to disease progression. Results: Cytoplasmic expression of all molecules was higher in cancer compared to tumor-adjacent epithelial cells ( p= 0.047 for CD40, p= 0.007 for BAFFR, p< 0.001 for LTβR and p= 0.003 for RANK) and in stromal cells ( p< 0.001 for all molecules), while the reverse pattern (lower in neoplastic epithelial cells) was observed for nuclear expression ( p< 0.001 for all molecules). Similarly, mRNA levels of LTβR and RANK were higher in cancer compared to adjacent non-neoplastic tissues ( p= 0.019 and p= 0.037, respectively). Notably, patients with high mRNA levels of all studied receptors had significantly longer time to disease progression ( p= 0.026 for CD40, p= 0.023 for BAFFR, p= 0.027 for LTβR and p= 0.038 for RANK). In addition, mRNA levels of BAFFR, LTβR and RANK levels were higher in ulcerative tumors compared to polypoid tumors ( p= 0.002, p= 0.005 and p= 0.011, respectively). RELB mRNA levels were positively correlated with mRNA levels of CD40, BAFFR and LTβR in cancerous ( p< 0.001 for all molecules) and non-cancerous tissues (p < 0.001 for all molecules). Surprisingly, NF-κB2 mRNA levels were positively correlated with BAFFR and LTβR mRNA levels in malignant tissues, while in non-malignant tissues were positively correlated with all receptors’ mRNA levels ( p< 0.001 for all molecules). Conclusions: This study suggests a prognostic value for CD40, BAFFR, LTβR and RANK expression in patients with CRC and further supports the role of the alternative pathway of NF-κB in CRC.

SID: a new carbohydrate blood group system based on a well-characterized but still mysterious antigen of great pathophysiologic interest.

The high-prevalence blood group antigen, Sda, had been puzzling blood bankers and transfusionists for at least a decade when it was reported in 1967. The characteristic mix of agglutinates and free red blood cells (RBCs), caused by anti-Sda, is seen with the RBCs from 90 percent of individuals of European descent. However, only 2-4 percent of individuals are truly Sd(a-) and may produce anti-Sda. The antibodies, generally considered insignificant, may cause hemolytic transfusion reactions with high-expressing Sd(a+) RBCs (e.g., the unusual Cad phenotype, which can also be polyagglutinable). The Sda glycan, GalNAcβ1-4(NeuAcα2-3)Gal-R, is produced in the gastrointestinal and urinary systems, while its origin on RBCs is more controversial. According to current theory, Sda is likely to be passively adsorbed in low amounts, except in Cad individuals, where it has been found on erythroid proteins and at higher levels. The long-standing hypothesis that B4GALNT2 encodes the Sda synthase was confirmed in 2019, since homozygosity for a variant allele with rs7224888:C produces a non-functional enzyme associated with most cases of the Sd(a-) phenotype. Thereby, the SID blood group system was acknowledged as number 038 by the International Society of Blood Transfusion. Although the genetic background of Sd(a-) was settled, questions remain. The genetic background of the Cad phenotype has not yet been determined, and the source of the RBC-carried Sda is unknown. Furthermore, the interest of Sda stretches beyond transfusion medicine. Some tantalizing examples are lowered antigen levels in malignant tissue compared with normal tissue and interference with infectious agents like Escherichia coli, influenza virus, and malaria parasites.

The lncRNA GATA3-AS1/miR-495-3p/CENPU axis predicts poor prognosis of breast cancer via the PLK1 signaling pathway

The function of centromere protein U (CENPU) gene in breast cancer has not been well understood. Therefore, we explored the expression profiles of CENPU gene in breast carcinoma to better understand the functions of this gene, as well as the relationship between CENPU expression and the prognosis of breast carcinoma patients. Our results indicate that CENPU was expressed at significantly higher levels in cancerous tissues than in normal tissues. Furthermore, CENPU expression correlated significantly with many clinicopathological characteristics of breast cancer. In addition, we discovered that high levels of CENPU expression predicted poor prognosis in patients with breast cancer. Functional investigation revealed that 180 genes exhibited co-expression with CENPU. Functional annotation indicated that 17 of these genes were involved in the PLK1 signaling pathway, with most of them (16/17) being expressed at significantly higher levels in malignant tissues compared with normal controls and correlating with a poor prognosis. Subsequently, we found that four miRNAs, namely hsa-miR-543, hsa-miR-495-3p, hsa-miR-485-3p, and hsa-miR-337-3p, could be regarded as potential CENPU expression regulators. Then, five lncRNAs were predicted to potentially bind to the four miRNAs. Combination of the results from expression, survival, correlation analysis and functional experiments analysis demonstrated the link between lncRNA GATA3-AS1/miR-495-3p/CENPU axis and prognosis of breast cancer. In conclusion, CENPU could be involved in cell cycle progression through PLK1 signaling pathway.

Hypoxanthine Phosphoribosyl Transferase 1 Is Upregulated, Predicts Clinical Outcome and Controls Gene Expression in Breast Cancer.

Hypoxanthine phosphoribosyl transferase 1 (HPRT1) is traditionally believed to be a housekeeping gene; however, recent reports suggest that it is upregulated in several cancers and is associated with clinical outcomes. HPRT1 is located on chromosome X and encodes the HPRT enzyme, which functions in recycling nucleotides to supply for DNA and RNA synthesis in actively dividing cells. Here, we used transcriptomic analyses to interrogate its expression across all known cancer types and elucidated its role in regulating gene expression in breast cancer. We observed elevated HPRT1 RNA levels in malignant tissues when compared to normal controls, indicating its potential as a diagnostic and prognostic marker. Further, in breast cancer, the subtype-specific analysis showed that its expression was highest in basal and triple-negative breast cancer, and HPRT1 knockdown in breast cancer cells suggested that HPRT1 positively regulates genes related to cancer pathways. Collectively, our results essentially highlight the importance of and change the way in which HPRT1’s function is studied in biology, warranting careful examination of its role in cancer.

A Clinicopathological Analysis of S100A14 Expression in Colorectal Cancer.

The calcium-binding protein S100A14 is involved in processes related to tumorigenesis and tumor propagation, such as proliferation, apoptosis, motility and invasiveness. Our aim was to investigate its role in colorectal cancer. One hundred and seven patients (65 men and 42 women) were included in this study. They had been diagnosed with colorectal cancer and undergone complete resection of their primary tumor. Tissue samples from archival blocks of their normal and malignant colorectal tissues were used for immunohistochemical assessment of S100A14 expression. S100A14 levels were evaluated using image analysis and associated with various clinicopathological parameters and prognosis. S100A14 expression was reduced in malignant tissues when compared to normal intestinal mucosa in cases of T3-T4 tumors (p=0.017). Moreover, as far as S100A14 levels in malignant tissues are concerned, they were lower in T3-T4 tumors (p=0.001), N2 disease (p=0.034) and M1 disease (p=0.019). Finally, very high S100A14 production (>75th percentile) was associated with shorter disease-specific (HR=3.584, p=0.045) and relapse-free survival (HR=4.527, p=0.007) in multivariate survival analysis. S100A14 expression is decreased in advanced colorectal cancer. However, cases with very high S100A14 levels have a worse survival.

Survivin in Insulin-Like Growth Factor-Induced Resistance to Lapatinib in Head and Neck Squamous Carcinoma Cells

Epidermal growth factor receptor (EGFR) inhibitors have limited efficacy in head and neck squamous cell carcinoma (HNSCC) due to various resistance mechanisms, such as activation of the insulin-like growth factor-1 receptor (IGF1R), which initiates pro-survival signaling. Survivin, a member of the inhibitor of apoptosis proteins family, is expressed at relatively high levels in malignant tissues and plays a role in cell division. Expression of survivin in tumors has been shown to correlate with poor prognosis due to chemotherapy resistance and anti-apoptotic behavior. We previously demonstrated that activation of the IGF1R reduces sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) via reduced apoptosis suggesting a role of survivin in this process. This study evaluates the role of survivin in IGF1R-mediated lapatinib resistance. Using HNSCC cell lines FaDu and SCC25, survivin expression increased and lapatinib sensitivity decreased with IGF1R activation. Further, these effects were reversed by the survivin inhibitor YM-155. Conversely, survivin expression and lapatinib sensitivity were unchanged with IGF1R activation in UNC10 cells. YM-155 enhanced the inhibitory effect of lapatinib on UNC10 cells, regardless of activation of the IGF1R. These results demonstrate that enhanced survivin expression correlates with IGF1R-mediated lapatinib resistance in HNSCC cells and suggest that regulation of survivin expression may be a key mechanistic element in IGF1R-based therapeutic resistance. Combinatorial treatment with survivin antagonists and EGFR-TKIs warrants further investigation.

Expression of Glycosyltransferases; ST3GAL1, FUT3, FUT5, and FUT6 Transcripts in Oral Cancer

Oral carcinogenesis process is frequently accompanied by alterations in glycosylation, regulated by sialyltransferase (ST) and fucosyltransferase (FUT) enzymes. The study aimed to assess ST3GAL1, FUT3, FUT5, and FUT6 mRNA expression by semi-quantitative reverse transcriptase PCR in 50 oral cancer and 50 adjacent normal tissues. The results indicated increased ST3GAL1 mRNA levels in malignant tissues as compared to adjacent normal tissues. A significant decrease in FUT3 and FUT5 transcripts was observed in malignant tissues as compared to adjacent normal tissues. Survival analysis of FUT3 transcript levels depicted significant lower survival with values above cutoff. The levels of ST3GAL1 and FUT6 were found to be higher in metastatic tissues as compared to the non-metastatic tissues and were also higher in advanced disease as compared to the early disease. The results indicated potential clinical utility of ST3GAL1, FUT3, FUT5, and FUT6 transcript levels in oral cancer pathogenesis.

Utility of micro-ribonucleic acid profile for predicting recurrence of rectal cancer

BackgroundIn early-stage rectal cancer, the surgeon must decide between the high morbidity of radical surgery and the high recurrence rates of local excision. A prognostic marker could improve patient selection and lower recurrence rates. Micro-ribonucleic acids (miRNAs), small RNAs that often inhibit tumor suppressors, have shown prognostic potential in colorectal cancer. We hypothesized that high miRNA levels in malignant tissue from early-stage rectal cancer patients could predict recurrence after local excision. Materials and methodsWe identified 17 early-stage rectal cancer patients treated with local excision between 1990 and 2005, four of whom had recurrences. Total RNA was extracted from benign and malignant tissue and used in quantitative real-time reverse transcriptase polymerase chain reaction to probe for miR-20a, miR-21, miR-106a, miR-181b, and miR-203. MiRNA data were evaluated for association with recurrence using univariate analysis with Wilcoxon rank sum test. ResultsMalignant tissue in both patients who had recurrences and patients who did not have recurrences had equivalently high levels of miRNA. However, the benign tissue of patients who recurred contained significantly higher levels of all five miRNAs when compared with the benign tissue of nonrecurrent patients despite having no histological differences. ConclusionsThis is the first study to show that high miRNA levels of histologically benign tissue obtained from the surgical margin of locally excised rectal cancers can predict recurrence. The malignant miRNA levels did not have predictive value. Further investigation of miRNAs is needed to explore their potential for a more accurate prognosis of rectal cancer.

Utility of MiRNA Profile for Predicting Recurrence of Rectal Cancer

Background In early-stage rectal cancer, the surgeon must decide between the high morbidity of radical surgery and the high recurrence rates of local excision. A prognostic marker could improve patient selection and lower recurrence rates. MicroRNAs (miRNAs), small RNAs that often inhibit tumor suppressors, have shown prognostic potential in colorectal cancer. We hypothesized that high miRNA levels in malignant tissue from early-stage rectal cancer patients could predict recurrence after local excision.

Differential expression of gp200-MR6 molecule in benign hyperplasia and down-regulation in invasive carcinoma of the breast.

In this study, we used immunohistochemical and biochemical analysis to show that gp200-MR6, a 200 kDa molecule that is functionally associated with the human interleukin 4 (IL-4) receptor complex, is expressed at high levels on normal breast epithelial tissues, at lower levels on in situ carcinomas, and that the expression is lost in the invasive carcinoma of the breast. Furthermore, a preliminary study showed that benign epithelial hyperplasia of the breast expresses the gp200-MR6 heterogeneously. Two populations of cells have been observed: MR6 positive and MR6 negative. Interestingly, MR6-positive cells were observed to have different morphology from those that were MR6 negative; the nuclei of the former were larger and rounded in shape, whereas the nuclei of the latter were relatively small and oval in shape. In sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting, monoclonal antibody MR6 detects the same molecular weight molecule in both normal and transformed tissue, indicating that the molecule is not a product of a truncated gene. The intensity of the gp200-MR6 bands correlates with the immunohistochemical data, indicating that the molecule is expressed at high levels in normal tissue and at lower levels in malignant tissue. These results suggest that analysis of gp200-MR6 expression may be useful in tumour grading and prognostic evaluation in breast cancer. Moreover, the molecule may be involved early in the process of tumorigenesis of the breast, in which a loss or a down-regulation of gp200-MR6 could contribute towards tumour development and progression via an effect on cell growth and differentiation.

Transforming growth factor alpha and epidermal growth factor levels in bladder cancer and their relationship to epidermal growth factor receptor.

We have examined levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in neoplastic and non-neoplastic bladder tissue using a standard radioimmunoassay technique. Tumour samples had much higher TGF-alpha levels compared with EGF and TGF-alpha levels in malignant tissue were significantly higher than in benign bladder samples. There was, in addition, a difference in mean EGF levels from 'normal' bladder samples from non-tumour bearing areas of bladder in patients with bladder cancer compared with 'normal' bladder tissue obtained at the time of organ retrieval surgery. Levels of EGF and TGF-alpha did not correlate with levels of EGF receptor (EGFR) as determined by a radioligand binding method but levels of TGF-alpha > 10 ng gm-1 of tumour tissue did correlate with EGFR positivity defined using immunohistochemistry. These data suggest that TGF-alpha is the likely ligand for EGFR in bladder tumours.

PROTEASES ASSOCIATED WITH GYNECOLOGICAL TUMORS

Proteases are involved in the invasion and metastasis of tumours by destruction of the basal membrane and connective tissue. As levels in malignant tissue have both prognostic and therapeutic implications, we examined 318 frozen samples from malignant tumours and comparable non-malignant tissue looking for urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) levels with ELISA, as well as cathepsin D with RIA. Oestrogen receptor (ER) levels, progesterone receptor (PrgR) levels and epidermal growth factor receptors (EGFR) were measured by biochemical methods at the same time. Significantly raised levels of uPA, PAI-1 and cathepsin D were found in malignant tissue, with PAI-1 particularly high in carcinoma of the cervix. Significantly raised tPA levels were found in breast cancer tissue with a more favourable clinical prognosis, with a positive correlation between tPA and ER. No correlation could be shown between uPA, PAI-1 and cathepsin D with other prognostic factors for breast cancer. It could be that routine, uncomplicated estimation of tumour-associated proteases such as uPA, tPA, PAI-1 and cathepsin D will provide an independent prognostic marker for therapeutic decisions with regard to gynaecological tumours and breast cancer.

Endogenous levels and dynamics of estrogen sulfates--physiological and pathological roles of estrone sulfate and estradiol 17-sulfate

Plasma ethinylestradiol increases 47.6% when taken with ascorbic acid because of competition in producing sulfate conjugation. Thus the role of sulfates may be important. Serum and urinary estrone sulfate (E1-S) in pregnancy and non-pregnancy were analyzed. Its serum peak during the menstrual cycle was 2.67 +/- 0.37 ng/ml (mean +/- SE) and about ten times that of estradiol-17 beta. E1-S showed lower levels in malignant tissues of breast cancer and endometrial cancer. Increased sulfatase activity in the malignant tissue hydrolyzes E1-S to E1, which may develop the tumors. Serum estradiol 17-sulfate (E2-17-S) in pregnancy was first measured. As E2-17-S decreased, lipid peroxides increased. E2-17-S is converted to 2-OH or 4-OH E2-17-S, which act as lipid peroxide scavengers. Pregnancy-induced hypertension showed lower levels of E2-17-S. In vitro study using the human endothelial cell of the aorta, E2-17-S and 2-OH E2-17-S strongly suppressed lipid peroxidation, which precedes atherosclerotic change.