Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases.

Neoplastic lesions typically express specific carbohydrate antigens on glycolipids, mucins, and other glycoproteins. Such antigens are often under epigenetic control and are subject to reversion and loss upon therapeutic selective pressure. We report here that two of the most common tumor-associated carbohydrate antigens, Tn and sialyl Tn (STn), result from somatic mutations in the gene Cosmc that encodes a molecular chaperone required for formation of the active T-synthase. Diverse neoplastic lesions, including colon cancer and melanoma-derived cells lines, expressed both Tn and STn antigen due to loss-of-function mutations in Cosmc. In addition, two human cervical cancer specimens that showed expression of the Tn/STn antigens were also found to have mutations in Cosmc and loss of heterozygosity for the cross-linked Cosmc locus. This is the first example of somatic mutations in multiple types of cancers that cause global alterations in cell surface carbohydrate antigen expression.

https://cancerres.aacrjournals.org/content/canres/68/6/1636.full.pdf

Human Tumor Antigens Tn and Sialyl Tn Arise from Mutations in Cosmc

Glycosylation changes that occur in cancer often lead to the expression of tumour-associated carbohydrate antigens. In breast cancer, these antigens are usually associated with a poor prognosis and a reduced overall survival. Cellular models have shown the implication of these antigens in cell adhesion, migration, proliferation and tumour growth. The present review summarizes our current knowledge of glycosylation changes (structures, biosynthesis and occurrence) in breast cancer cell lines and primary tumours, and the consequences on disease progression and aggressiveness. The therapeutic strategies attempted to target tumour-associated carbohydrate antigens in breast cancer are also discussed.

/pdf/tumour-associated-carbohydrate-antigens-in-breast-cancer-3g3g3xcylt.pdf

Tumour-associated carbohydrate antigens in breast cancer

Germin and germin-like proteins (GLPs) are encoded by a family of genes found in all plants. They are part of the cupin superfamily of biochemically diverse proteins, a superfamily that has a conserved tertiary structure, though with limited similarity in primary sequence. The subgroups of GLPs have different enzyme functions that include the two hydrogen peroxide-generating enzymes, oxalate oxidase (OxO) and superoxide dismutase. This review summarizes the sequence and structural details of GLPs and also discusses their evolutionary progression, particularly their amplification in gene number during the evolution of the land plants. In terms of function, the GLPs are known to be differentially expressed during specific periods of plant growth and development, a pattern of evolutionary subfunctionalization. They are also implicated in the response of plants to biotic (viruses, bacteria, mycorrhizae, fungi, insects, nematodes, and parasitic plants) and abiotic (salt, heat/cold, drought, nutrient, and metal) stress. Most detailed data come from studies of fungal pathogenesis in cereals. This involvement with the protection of plants from environmental stress of various types has led to numerous plant breeding studies that have found links between GLPs and QTLs for disease and stress resistance. In addition the OxO enzyme has considerable commercial significance, based principally on its use in the medical diagnosis of oxalate concentration in plasma and urine. Finally, this review provides information on the nutritional importance of these proteins in the human diet, as several members are known to be allergenic, a feature related to their thermal stability and evolutionary connection to the seed storage proteins, also members of the cupin superfamily.

/pdf/germin-and-germin-like-proteins-evolution-structure-and-3m2s90wi1l.pdf

Germin and Germin-like Proteins: Evolution, Structure, and Function

Mucins are the most abundant high molecular weight glycoproteins in mucus. Their nature and glycosylation content dictates the biochemical and biophysical properties of viscoelastic secretions, pointing out an important role in diverse biological functions, such as differentiation, cell adhesions, immune responses, and cell signaling. Mucins are expressed in tubular organs by specialized epithelial cells in the body. Their aberrant expression is well documented in a variety of inflammatory or malignant diseases. From a prognosis point of view, their expression and alterations in glycosylation are associated with the development and progression of malignant diseases. Therefore, mucins can be used as valuable markers to distinguish between normal and disease conditions. Indeed, this alteration in glycosylation patterns generates several epitopes in the oligosaccharide side chains that can be used as diagnostic and/or prognostic markers. Furthermore, these characteristic tumor-associated epitopes are extensively used as appropriate immunotargets of malignant epithelial cells. Therefore, in an effort to detect and treat cancer at the earliest stage possible, mucins are analyzed as potential markers of disease for diagnosis, progression, and for therapeutic purposes. In this review, we focused on the current status of the distribution of mucins in normal and pathologic conditions and their clinical use both in cancer diagnosis and therapeutics treatments.

/pdf/current-status-of-mucins-in-the-diagnosis-and-therapy-of-5c9nxlxcdz.pdf

Current status of mucins in the diagnosis and therapy of cancer

There are indications that obesity and hyperuricemia may influence the formation and composition of urinary stones. The aim of our study was to determine the effect of obesity and hyperuricemia on the urinary lithogenic risk profile in a large cohort of pediatric patients. The study population comprised 478 children with urolithiasis and 517 healthy children (reference group). We studied the effects of obesity on the lithogenic profile by dividing the patients with urolithiasis into two groups based on body mass index Z-score (patients who were overweight/obese vs. those with normal weight for age) and comparing the two groups. To study the effect of hyperuricemia on the lithogenic profile, we divided the patients with urolithiasis into two groups based on the presence or not of hyperuricemia (110 patients with urolithiasis accompanied by hyperuricemia vs. 368 patients with urolithiasis and normal serum uric acid levels) and compared the groups. Among the children and adolescents with urolithiasis and hyperuricemia, there was a significantly lower excretion of crystallization inhibitors (citrates, magnesium). We also found significantly negative correlations between serum uric acid levels and the urine citrate/creatinine ratio (citrate/cr.; r = −0.30, p < 0.01), as well as the magnesium/cr. ratio (Mg/cr.; r = −0.33, p < 0.01). There was no statistically significant differences in the urinary excretion of oxalates, citrates, calcium, phosphorus, magnesium and uric acid between children with urolithiasis who were either overweight or obese and children with urolithiasis who had a normal body weight. In our pediatric patient cohort, hyperuricemia was associated with a decrease in the excretion of crystallization inhibitors in the urine, but the clinical relevance of this observation needs to be confirmed in future studies. Obesity and overweight had no direct influence on the lithogenic risk profile in the urinary stone formers in our study, but there was an indication that higher serum uric acid may be associated with impairment in renal function, which in turn could influence the excretion of lithogenic parameters.

/pdf/does-obesity-or-hyperuricemia-influence-lithogenic-risk-3hn3harzlj.pdf

Does obesity or hyperuricemia influence lithogenic risk profile in children with urolithiasis

The effects of N- and O-glycosylation inhibitors on the expression of membrane proteins (MUC1 and some integrins) were evaluated in human endometrial (Ishikawa) and breast (MCF-7) cancer cells. Subconfluent cells were treated with 1-3 mg% concentration of tunicamycin and 2-10 mM of benzyl-N-acetyl-alpha-galactosaminide for 1-2 days, and used for flow cytometry, immunohistochemical staining, adhesion test and Western blotting. Benzyl-N-acetyl-alpha-galactosaminide inhibits MUC1 expression on the surface of breast more than endometrial cancer cells. Tunicamycin reduces MUC1 concentration on the cellular surface more than benzylglycoside, and greatly reduces glycosylation of glycoproteins, causing an increase in cell adhesion in both types of cancer cells. The expression of alpha2beta1 integrins on the surface of these cells was weak and decreased after treatment with inhibitors. Two different glycoforms of MUC1 proteins in endometrial cells and three in breast cancer cells were expressed and their molecular weights were reduced after treatment with glycosylation inhibitors. It was confirmed with lectin detection of carbohydrate epitopes (Tn and T) in MUC1 proteins. These observations show that glycosylation inhibitors altered the N- and O-glycan patterns in a sufficient manner, and positively modified the biological features of cancer cells.

/pdf/the-influence-of-n-and-o-glycosylation-inhibitors-on-the-3trdxs730l.pdf

The influence of N- and O-glycosylation inhibitors on the glycosylation profile of cellular membrane proteins and adhesive properties of carcinoma cell lines.

Polymorphic epithelial mucin MUC1 is expressed by most epithelial cancers, although free natural MUC1 antibodies are present in the circulation of healthy subjects as well as in that of cancer patients. The role of MUC1 mucin molecules in cancer cells of endometrium is not precisely known. The results reported here demonstrate that MUC1 biosynthesis in human endometrial adenocarcinoma cells (Ishikawa line) is stimulated by estradiol hormone and inhibited by tamoxifen, which was measured by [(14)C]threonine or [(3)H]glucosamine incorporation into MUC1 protein. Tamoxifen applied in combination with estradiol also inhibited this process, but pre-incubation of cells with estradiol resulted in a decrease in the inhibitory effect of tamoxifen. Electroblotting and reactions with antibodies against MUC1 core protein epitopes confirmed the presence of MUC1 in cell lysates and culture media of Ishikawa cells. Reactions with lectins showed the presence of oligosaccharide structures demonstrating antigen-T activity and the presence of sialic acid residues. The results confirm that there is downregulation of MUC1 expression in cancer culture cells treated with selective estrogen receptor modulators, which may be essential for reducing the migration of cancer cells and the metastatic properties of tumor cells.

Biosynthesis of MUC1 mucin in human endometrial adenocarcinoma is modulated by estradiol and tamoxifen.

Aim

There is conflicting evidence about the role of obesity in paediatric nephrolithiasis. This Polish study explored the influence of nutritional status and lipid disturbances on urinary lithogenic factors and the risk of kidney stone formation in children and adolescents from three to 18 years of age.



Methods

We carried out serum lipid profile evaluations and 24-h urine chemistry analyses on 493 overweight/obese paediatric participants (mean age 13 years) without nephrolithiasis and 492 healthy normal weight sex and age-matched controls.



Results

A third (33%) of the study group had blood lipid disturbances, with more acidic urine, lower urinary citrate excretion and a higher fraction of ionised calcium and higher Bonn Risk Index than the controls. The participants' body mass index standard deviation score (BMI Z-score) was positively correlated with urinary oxalate and uric acid and negatively correlated with citrate excretion. Total cholesterol, low-density lipoprotein cholesterol and triglycerides correlated negatively with citraturia, while high-density lipoprotein cholesterol correlated positively.



Conclusion

The main factor that predisposed overweight and obese children to kidney stones was hypocitraturia. Urinary citrate excretion was related to both BMI Z-scores and all lipid fraction abnormalities. However, hypercholesterolaemia and particularly low-density lipoprotein hypercholesterolaemia seemed to play a major role.

Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones.

Oxalate homeostasis is a derivative of absorption and transportation in the digestive system and renal/intestinal excretion of oxalate. The objective of this cross-sectional study was to determine normative values of plasma oxalate in relation to age, gender, and body size. A group of 1,260 healthy Caucasian children and adolescents aged 3 months to 18 years [mean ± standard deviation (SD) 10.5 ± 4.3] was studied. Each 1-year group comprised 70 subjects. Oxalate levels were assessed in blood plasma samples obtained from fasted individuals using the precipitation–enzymatic method with oxalate oxidase. Median oxalate levels in healthy infants was 3.20 µmol/L (5th–95th percentiles: 1.56–5.58) and was higher compared with older children [2.50 µmol/L (5th–95th percentiles: 0.95–5.74); p < 0.01]. No differences were found in plasma oxalate levels between boys and girls. There were no associations between plasma oxalate levels and anthropometric traits. In the healthy population aged 1–18 years, plasma oxalate concentration is independent of age, gender, and body size. Infants demonstrate higher plasma oxalate levels compared with older children, which suggests possible immature mechanisms of renal excretion. This study appears to be the first extensive report providing normative data for plasma oxalate in children and adolescents.

Halina Porowska

Papers

Does obesity or hyperuricemia influence lithogenic risk profile in children with urolithiasis

The influence of N- and O-glycosylation inhibitors on the glycosylation profile of cellular membrane proteins and adhesive properties of carcinoma cell lines.

Biosynthesis of MUC1 mucin in human endometrial adenocarcinoma is modulated by estradiol and tamoxifen.

Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones.

Reference values of plasma oxalate in children and adolescents.