Abstract
Posttranslational modifications are dynamic enzymatic-mediated processes, regulated in time and space, associated with cancer development. We aimed to evaluate the significance of posttranslational modifications in the pathogenesis of clear cell renal cell carcinoma. The authors developed a prospective, observational study during a period of three years and included 55 patients with localized renal cell carcinoma and 30 heathy subjects. Glycosylation, nitration and carbonylation, thiol-disulfide homeostasis, methylation, phosphorylation and proteolytic cleavage were evaluated in the serum of the evaluated subjects in the present study. Our results showed some characteristics for early ccRCC: high production of cytokines, substrate hypersialylation, induced nitrosative and carbonylic stress, arginine hypermethylation, thiol/disulfide homeostasis (TDH) alteration, the regulatory role of soluble receptors (sRAGE—soluble receptor for advanced glycation end products, sIL-6R—soluble receptor for Interleukin 6) in RAGE and IL-6 signaling, the modulatory effect of TK1—thymidine kinase 1 and TuM2-PK—tumoral pyruvate-kinase 2 in controlling the level of phosphometabolites in neoplastic cells. These data could be the initial point for development of a panel of biomarkers such as total sialic acid, orosomucoids, nitrotyrosine, carbonylic metabolites, Asymmetric Dimethylarginines (ADMA), Symmetric Dimethylarginines (SDMA), and thiol-disulfide equilibrium for early diagnosis of ccRCC. Moreover, they could be considered a specific disease posttranslational modification signature which underlines the transition from early to advanced stages in this neoplasia, and of a therapeutic target in kidney oncogenesis.
Highlights
Genetic and epigenetic alterations are considered primary steps in cancer development, while posttranslational modifications (PTMs) play an important role in cancer progression and dissemination
Protein glycosylation, evaluated by serum levels of sialic acid and orosomucoids, was statistically significantly higher in the renal cell carcinoma group compared with the control group (Table 1)
The present study showed that serum levels of IL-6 and IL-8 determined in patients with early Clear cell renal cell carcinoma (ccRCC) were higher compared to the control
Summary
Genetic and epigenetic alterations are considered primary steps in cancer development, while posttranslational modifications (PTMs) play an important role in cancer progression and dissemination. Posttranslational changes are dynamic enzymatic-mediated processes, regulated in time and space. Glycosylation is a complex process, mediated by glycosyltransferases, which consists of covalent binding of hydrocarbonate to lipids or proteins. Glycobiology showed congenital alterations of glycosylation in autoimmune diseases, in diabetes, and in glomerulopathies [3]. Some studies showed aberrant glycosylation in patients with renal cell carcinoma (RCC) and alterations of N-glycosylation according to the stage of the disease [5]. Other studies analyzed the glycosylation of proteins involved in lipids transport and different metabolic processes (folate receptor 1—FOLR1; low density lipoprotein-related protein 2—LRP2; phospholipid phosphatase—PLPP; cathepsin D—CATD), in immune processes (CD97, CD63, CD276, anti-helicobacter pylori, alpha-1antitripsine phenotype, prostaglandin D2 synthetase) [5,6,7,8,9,10,11]
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