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Molecular Mechanisms of Relationship Between Blood Plasma Beta-Globulins and Protein Markers of Renal and Bladder Cancer

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Molecular Mechanisms of Relationship Between Blood Plasma Beta-Globulins and Protein Markers of Renal and Bladder Cancer BioNanoSci. (2015) 5:84–90 DOI 10.1007/s12668-015-0165-x Molecular Mechanisms of Relationship Between Blood Plasma Beta-globulins and Protein Markers of Renal and Bladder Cancer E. I. Erlykina & L. M. Obukhova & A. B. Yazykova & V. F. Rossokhin & T. N. Gorshkova & V. P. Frantsuzova Published online: 14 March 2015 # Springer Science+Business Media New York 2015 Abstract The aim of the investigation was to enhance the CD1b). Analysis of the relationship between individual blood screening diagnosis of epithelial tissue malignant tumors, the plasma β-globulin proteins and identified tissue markers molecular relationship between blood plasma protein fractions, showed the greatest number of protein-protein interactions for and carcinogenesis tissue markers in renal and bladder cancer. proteins with reduced level in malignant tumors: transferrin had Blood plasma of 87 cancer patients, not previously subjected to 11-interactor proteins, as well as angiostatin had only 4. The antitumor treatment, and 9 patients with psoriasis was studied. involvement of protein markers interacting with individual pro- Blood plasma of 52 healthy people was used as control. Bio- teins of blood plasma β-globulin fractions in the signaling path- chemical parameters were evaluated on the analyzer BKoneLab ways that regulate apoptosis and cell proliferation was shown. 20 / 20i^ (Finland). Statistical analysis was performed using the Changes in the content of β-globulins of blood plasma in ma- software Statistica 6.0. Network construction of protein-protein lignant tumors of epithelial tissues, including renal and epithe- interactions was performed by means of Cytoscape software, lial cancer are suggested to be considered as specific pathogenic using databases STRING, BioGrid, SwissPro. It has been criteria and serve as an additional diagnostic feature. shown that in patients with malignant tumors of epithelial tis- sues, compared to the control group (healthy people), albumin and β-globulins levels were significantly reduced and α1- Keywords Epithelial malignant tumors . β-globulins . globulin and γ-globulins were increased. Comparison of pro- Tissue oncomarkers . Protein-protein interactions tein fractions in cancer and psoriasis patients showed the most expressed differences for β-globulin fraction; their level was increased in psoriasis, and, conversely, decreased in cancer, 1 Introduction with a significant reduction, starting from the early stages of cancer. Tissue markers common to renal and bladder cancer It is well known that cancer is one of the most commonly diag- were discovered, and they were, dynamin 2 (DNM2), tyrosine nosed diseases in developed countries. Elevated frequency of this 3-monooxygenase/tryptophan 5-monooxygenase activation disease is postulated to be of great importance all over the world protein, gamma polypeptide (YWHAG), plasminogen receptor, [1]. Сancer is known to be the leading cause of death [2, 3]. C-terminal lysine transmembrane protein (PLGRKT), cytoplas- According to the World Cancer Report 2014, kidney cancer mic FMR1 interacting protein 2 (CYFIP2), glutamate dehydro- is noted to be the ninth most common cancer in men and the genase 1(GLUD1), and antigen-presenting proteins (CD1a, fourteenth most common in women in 2012 [4]. Incidence and mortality rates have been increasing in many countries [5, 6]. : : * : E. I. Erlykina L.: M. Obukhova A. B. Yazykova ( ) According to epidemiological data, rising incidence of renal V. F. Rossokhin V. P. Frantsuzova cell cancer in the USA has so far been discovered [7–9]. Sev- Nizhny Novgorod State Medical Academy, Minin and Pozharsky eral European regions show particularly high rates of kidney Square, 10/1, Nizhny Novgorod, Russian Federation 603005, Russia e-mail: [email protected] cancer incidence also [10]. With approximately115,000 new cases diagnosed in Europe in 2012, cancer of the kidney, renal T. N. Gorshkova pelvis, and ureter (international Classification of Diseases B ^ FBUZ Volga Regional Medical Center of the Federal ([ICD]-10 code C64-66) combined is the seventh most com- Medical-Biological Agency of Russia, Nizhniy Novgorod, Nizhnevolzhskaya naberezhnaya, 2, Nizhniy Novgorod 603001, mon cancer and accounts for 3.3 % of all new cancer cases Russia diagnosed [10, 11]. BioNanoSci. (2015) 5:84–90 85 Renal cancer mortality is slowly decreasing now due to early The aim of the investigation was to study changes in blood detection and improved treatment, but there are still many uncer- plasma protein fractions and reveal of molecular link between tain points in diagnostics [12]. At present, for the preliminary those fractions and known tissue markers in renal and bladder diagnosis of malignancy, known tumor markers in the blood plas- cancer. ma or other biological fluids are increasingly identified [13]. Tu- mor markers or oncomarkers are complex substances which are defined in significantly higher concentrations in malignantly 2 Experimental Details (Materials and Methods) transformed cells, compared to normal cells, or produced by the body in response to the presence of malignant cells, and thus The objects of our study were 87 blood plasma samples from found in blood and/or urine of cancer patients [14]. However, untreated cancer patients, and among them, there were 60 men all these methods have several drawbacks. Various dysfunctions (45–75 years old) and 27 women (34–73 years old). Analysis of human liver and kidneys can cause falsely elevated levels of of patient distribution by diagnosis and stages showed the tumor markers. Prostate-specific antigen (PSA) false high levels following: renal cancer in 22 patients (25 %), bladder cancer can be temporarily detected after palpation of the prostate, uro- in 13 (15 %), prostate cancer in 15 (17 %), ovarian cancer in 4 logic manipulation, prolonged retention of urine or in smokers. (4.5 %), larynx cancer in 6 (7 %), colorectal cancer in 15 Also, there is a dependence of some oncomarker content on the (17 %), uterine carcinoma in 4 (4.5 %), pancreatic cancer in patients’ age. Taking into consideration low sensitivity of this 4 (4.5 %), and gallbladder cancer in 4 (4.5 %) patients corre- method in reveal of carcinogenesis early stages, there are doubts spondingly. After the surgical intervention, histological exam- about suitability of certain tumor markers detection as a screening ination of tumor material was performed by immunohisto- investigation technique [15]. Thus, in breast malignant tumors, chemistry. Stage I was established in 21 % of patients, stage elevated levels of oncomarker CA 15–3 are found in 9 % for II in 16 %, stage III in 41 %, and stage IV in 22 %. Compar- stage I, in 19 % of cases for stage, 38 % for stage , and ison group consisted of nine patients with psoriasis, and 75 % for stage V. Elevated levels of this marker are found in among them, there were three men (43–58 years old) and six 5–6 % of healthy women. In this way, using this marker, it is women (38–61 years old), as the pathogenesis of this disease possible to identify the tumor only in 76 patients out of 400, and is associated with activation of cell proliferation. As the con- establish one productive research out of 66 futile. Deficient effec- trol samples, blood plasma from 52 practically healthy per- tiveness of tumor marker analysis for screening detection of ma- sons (20 males (24 to 74 years) and 32 females (25–68 years)) lignancies conditions necessity to find other diagnostic criteria. was applied. Biochemical parameters were evaluated on the Contrariwise, changes in biochemical parameters of blood plasma analyzer BKoneLab 20 / 20i^ (Finland). Statistical analysis are often quite early sensitive diagnostic criteria in various patho- was performed using the software Statistica 6.0. Network con- logical conditions. It has been shown that substances with in- struction of protein-protein interactions was performed by creased content directly in malignant tissue and almost not detect- means of Cytoscape software, using databases STRING, able in blood are of the greatest diagnostic value [15]. BioGrid, SwissProt. Table 1 The comparative analysis of protein fractions in the blood plasma in patients with malignant tumors of epithelial tissues and psoriasis Groups of investigation Albumins, % α1-globulins, % α2-globulins % β-globulins, % γ-globulins, % Healthy people (control group) 59.50±0.56 3.83±0.17 9.48±0.34 11.78±0.16 14.99±0.52 Psoriasis 50.44±1.12*▲ 5.78±0.39*▲ 9.31±0.54 13.36±0.26*▲ 18.42±0.74* p=0.0001 p=0.0002 p=0.774 p=0.008 p=0.009 ▲p=0.017 ▲p=0.008 ▲p=0.821 ▲p=0.008 ▲p=0.801 Cancer patients I stage 57.26 4.32±0.41 8.71±0.51 11.04±0.16* 18.19±1.37* ±1.55 p=0.148 p=0.207 p=0.008 p=0.011 p=0.244 II stage 58.71±2.00 3.62±0.48 9.95±0.79 11.33±0.21* 16.35±1.94 p=0.594 p=0.597 p=0.533 p=0.037 p=0.339 III stage 55.78±1.23* 4.38±0.28 9.21±0.50 11.32±0.24* 18.20±0.77* p=0.021 p=0.026* p=0.306 p=0.041 p=0.006 IV stage 52.03±4.21 4.67±0.39 9.18±0.62 11.29±0.28* 19.23±1.47* p=0.007* p=0.017* p=0.212 p=0.032 p=0.001 *Mann-WhitneyU-test ▲ Kolmogorov-Smirnov test 86 BioNanoSci. (2015) 5:84–90 3 Results and Discussion α1-globulins (p=0.021) and γ-globulins (p=0.001) were in- creased (Table 1). When carrying out statistical data manipulation, significant When performing comparison of patient groups with dif- differences in the level of blood plasma protein fractions by ferent epithelial tissue tumor localization by variance analysis, gender were not found (p>0.05); so these received data were statistically significant differences were not detected combined.
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