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Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma

  • Xiao Li Zhang EMAIL logo , Zheng Zhi Wu , Yun Xu , Ji Guo Wang , Yong Qiang Wang , Mei Qun Cao and Chang Hao Wang
Published/Copyright: August 3, 2020
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Open Chemistry
From the journal Open Chemistry Volume 18 Issue 1

Abstract

Early diagnosis is a key to improve the prognosis of renal cell carcinoma (RCC); however, reliable RCC biomarkers are lacking in clinical practice. In this study, we used isobaric tags for relative and absolute quantification-based mass spectrometry to identify salivary proteins as biomarkers for the diagnosis of RCC. The objective of this study is to discover biomarkers from saliva by utilizing high-throughput quantitative proteomics approaches. Saliva proteins from 124 RCC patients and healthy individuals were identified and quantified. RCC putative biomarkers were verified by real-time polymerase chain reaction or enzyme-linked immunosorbent assay in a prevalidation sample set. Seventy-one differentially expressed salivary proteins were identified. Serotransferrin, haptoglobin, KRT9, and S100A9, which in previous studies were found to be most closely related to cancers, were selected as putative RCC biomarkers. Haptoglobin and S100A9 were significantly elevated in RCC compared with healthy control samples, although the expression of serotransferrin and KRT9 did not differ between the groups. Furthermore, receiver operating characteristic curves with a cut-off value of 75.49 ng/mL for S100A9 revealed a sensitivity of 87.10% and a specificity of 91.94% for discriminating RCC patients from healthy individuals. Salivary haptoglobin differentiated RCC patients from healthy controls with a sensitivity of 85.48% and specificity of 80.65% (cut-off value 43.02 µg/mL). These results provide experimental evidence to support S100A9 and haptoglobin as potential novel, noninvasive biomarkers for the diagnosis of RCC.

Keywords: saliva proteomics; renal cell carcinoma; diagnosis; S100A9; haptoglobin

1 Introduction

Renal cell carcinoma (RCC) is a significant public health issue worldwide. According to the National Central Cancer Registry of China 2015 annual report, the overall incidence of RCC was 3.35 per 105 population [1]. Currently, RCC detection relies on imaging technologies and traditional disease manifestations. However, as RCC often presents with few signs, symptoms, or laboratory abnormalities, the disease is frequently diagnosed at an advanced stage, when the prospect for a cure is limited. Therefore, the identification of efficient biomarkers for detecting RCC in clinical practice is the key to improving treatment and survival.

Using saliva as a diagnostic tool to monitor an individual’s health or disease is an appealing objective for healthcare research. Saliva is one of the most complex and important body fluids, containing water, minerals, nucleic acid, electrolytes, and proteins and reflecting a large range of physiological information [2]. Indeed, the research has shown that saliva can be used for the diagnosis of clinical diseases due to its origin, composition, function, and interaction with substances that compose plasma [3]. With the advantages of simple, noninvasive, and cost-effective methodologies, saliva-based diagnostics can be used for laboratory investigations, including basic and clinical studies of oral to systemic diseases [4]. Proteomics, a relatively new platform for research into tumor hallmarks, facilitates high-throughput screening processes in clinical diagnosis. Thus, saliva proteomics has been used extensively to detect altered expression of various substances, with varying degrees of sensitivity and specificity in a range of cancers.

The aim of the present study is to investigate and identify potential biomarkers in human saliva to facilitate the diagnosis of RCC at early and intermediate stages. We employed the isobaric tag for the relative and absolute quantification (iTRAQ) technique to compare salivary protein profiles between RCC patients and healthy subjects. Candidate protein biomarkers were selected from the iTRAQ results, and further clinical validation was performed by the real-time polymerase chain reaction (PCR) and the enzyme-linked immunosorbent assay (ELISA) using an independent sample cohort. The functions of putative biomarkers in various cancer types are only minimally understood, and the application of salivary analysis for RCC remains unclear.

2 Material and methods

2.1 Patients and sample collection

This trial was conducted and approved by the Committee on Human Research of the Second People’s Hospital of ShenZhen. A total of 62 patients with RCC and 62 age- and sex-matched healthy individuals were enrolled. Patients diagnosed with another malignancy, undergoing chemotherapy or radiotherapy, or with a cardiovascular disorder, immunodeficiency, autoimmune disorder, hepatitis or human immunodeficiency virus (HIV) infection were excluded. The characteristics of the RCC patients with respect to age, sex, histopathological type, and tumor size and stage were collected for analysis.

2.2 Sample collection

Unstimulated whole saliva was collected from each consenting participant, essentially as described previously [5]. Briefly, participants were asked to refrain from eating, drinking, or brushing teeth for at least 8 h before collection at night. Whole saliva was collected in the next morning and centrifuged at 18,000 rpm for 10 min at 4°C. The supernatant was removed, treated with protease inhibitor cocktail (10 µL/mL) (Solarbio, Beijing, China) to minimize protein degradation, and stored at −80°C.

2.3 iTRAQ analysis

The total protein concentration of the soluble fraction of saliva was quantified using the bicinchoninic acid (BCA) assay (Thermo Fish Scientific). Proteins in each sample (100 μg) were precipitated with ice-cold acetone, and the precipitated proteins were digested with trypsin at 37°C overnight. iTRAQ reagent (Applied Biosystems, CA, USA) labeling was performed, yielding healthy control sample iTRAQ regent 113 and RCC sample iTRAQ regent 114. The samples were incubated at room temperature for 4 h and then desalted and dried. The iTRAQ-labeled peptides were fractionated by the high-performance liquid chromatography (HPLC) with the strong cation exchange (SCX) chromatography (Agilent Technology, CA, USA). The samples were subsequently loaded onto a C18 column (Waters Corporation, MA, USA). The components produced by the SCX chromatography were subjected to the mass spectrometry (MS) analysis.

The raw protein data were examined using the Mascot algorithm and subjected to a search with the human International Protein Index database (version 3.45) using ProteinPilot software (Applied Biosystems, SCIEX, MA, USA). To reduce false-positive data, a strict cut-off value for protein identification was applied with an unused ProtScore >1.3 and at least one peptide with 95% confidence limits [6,7]. A ratio of >1.5 or <0.7 for protein expression between the two groups was considered significant.

The gene ontology (GO) analysis was performed using the online program DAVID (https://david.ncifcrf.gov/). Differentially expressed proteins were classified according to their biological process, molecular function, and cellular component.

2.4 RNA isolation and quantitative reverse transcription PCR (RT-qPCR)

Total RNA was isolated from the salivary samples using the mirVana™ PARIS™ kit (Life Technologies). After treatment with DNase I, the RNA was reverse transcribed into cDNA with the Thermo Scientific Maxima First-Strand cDNA Synthesis kit for mRNA detection. Quantitative PCR was performed using the Applied Biosystems 7500 PCR instrument. Relative standard curves were constructed for S100A9, KRT9, haptoglobin, serotransferrin, and an endogenous reference (GAPDH) using serial dilutions of cDNA, and these standards were included in each run. Samples of unknown concentration were quantified relative to these standard curves. S100A9, KRT9, haptoglobin, and serotransferrin mRNA levels were normalized to that of GAPDH to account for cDNA loading differences. Each sample was analyzed in triplicate, and average values were used for the subsequent statistical analysis. Primer sequences were obtained from the primer bank (https://pga.mgh.harvard.edu/primerbank/), as follows: S100A9 sense 5′-GGT CAT AGA ACA CAT CAT GGA GG-3′ and anti-sense 5′-GGC CTG GCT TAT GGT GGT G-3′; KRT9 sense 5′-GGG GCC GAT TCA GCT CTT C-3′ and anti-sense 5′-CTA CTG GCA CTA AAA CCA CCC-3′; haptoglobin sense 5′-CAG CAC AGT CCC CGA AAA GAA-3′ and anti-sense 5′-CAG TCG CAT ACC AGG TGT CC-3′; serotransferrin sense 5′-GGT GGC AGA GTT CTA TGG GTC-3′ and anti-sense 5′-ACA GTA AAG TAA GCC TAT GGG GA-3′; and GAPDH sense 5′-ACA ACT TTG GTA TCG TGG AAG G-3′ and anti-sense 5′-GCC ATC ACG CCA CAG TTT C-3′.

2.5 ELISA

ELISA was employed to quantify salivary S100A9 and haptoglobin concentrations. The human CircuLex S100A9 ELISA kit (MBL, Nagova, Japan; detection limit of 6.55 pg/mL and dilution factor of 1:50) and the human haptoglobin ELISA kit (Abcam, Cambridge, USA; detection limit of 0.078 µg/mL and dilution factor of 1:2,000) were used. ELISA was also applied to assess saliva protein levels in the RCC (n = 62) and healthy control (n = 62) groups. ELISA was performed according to the instructions provided in each kit. Concentrations of proteins were analyzed based on a four-parameter logistic curve. The R-squared (R2) values for our ELISA standard curves were typically in the range of 0.99 to 0.999.

2.6 Statistical analysis

Statistical analysis was performed using SPSS software version 19.0 and GraphPad Prism version 5.0. All variables under a normal distribution are presented as the mean ± standard deviation. Qualitative variables were analyzed with Student’s t-test. A P value of less than 0.05 was considered significant. Receiver operating characteristic (ROC) curves were utilized to assess the discriminatory value of S100A9 and haptoglobin for differentiating between the two groups.

3 Results

3.1 Clinical characteristics of RCC patients

From 2012 to 2015, 62 RCC patients and 62 healthy individuals were enrolled in this study. The demographic and clinical information of the subjects are shown in Table 1. The mean age of the RCC patients (52.3 years) was not notably different from that of the healthy controls (47.8 years). Among the RCC patients and healthy controls, 75.81% and 79.03%, respectively, were males. More than half of the patients had stage I + II disease (74.19%).

Table 1

Clinicopathological information of the enrolled participants

RCC patients (n = 62)Healthy individual (n = 62)
Age (years)52.3 ± 8.547.8 ± 10.2
Sex (n, %)
Male47 (75.81)49 (79.03)
Female15 (24.19)13 (20.97)
Histology
ccRCC35 (56.45)
non-ccRCC27 (43.55)
TNM stage
I + II46 (74.19)
III + IV16 (25.81)
C reactive protein
>10 mg/L29 (46.77)0 (0.00)
<10 mg/L33 (53.23)62 (100.00)

3.2 Analysis of the salivary proteome

To investigate differentially expressed proteins as potential biomarkers of RCC in saliva, we used an iTRAQ-based MS method to assess ten RCC patients and ten healthy control samples. A total of 1,467 proteins were quantified by MS. Fold changes in protein expression were calculated from the intensities of iTRAQ reporter ions between the groups. A total of 71 significantly differentially expressed proteins were identified in the saliva of RCC patients. Specifically, 36 proteins were downregulated (<0.7-fold) and 35 were upregulated (>1.5-fold) (Table 2). Moreover, we categorized the differentially expressed proteins according to biological processes, molecular functions, and cellular components using the GO database. Regarding biological processes, 27% of the proteins are involved in cell motion or migration, whereas 36% are involved in defense responses and inflammatory defense. The most common molecular functions identified included protein binding (53%), enzyme regulation (41%), and structural constituent of the cytoskeleton (6%). In addition, 57% of the proteins are extracellularly located (Figure 1a–c). A network of protein–protein interactions is presented in Figure 1d.

Table 2

Salivary protein biomarker candidates

AccessionGene symbolDescriptionRCC/controlP value
(A) Downregulated protein biomarkers
P68032ACTC1Actin, alpha cardiac muscle 10.2140.004
A0A087WSV8NUCB2Nucleobindin20.2610.009
H0YLF3B2MBeta-2-microglobulin 0.2650.004
P23280CA6Carbonic anhydrase 60.3420.032
C9JPQ9FGGFibrinogen gamma chain0.3450.029
F5GZQ4LDHAl-Lactate dehydrogenase A chain0.3810.005
Q5T0I0GSNGelsolin0.3880.005
P25815S100PProtein S100-P0.3910.002
P06737PYGLGlycogen phosphorylase0.4070.013
P19961AMY2BAlpha-amylase 2B0.4150.020
G3V1A4CFL1Cofilin 1 (Non-muscle)0.450.005
P68036UBE2L3Ubiquitin-conjugating enzyme E2 L30.4650.017
D3DSM0ITGB2Integrin beta0.4750.002
Q9GZZ8LACRTExtracellular glycoprotein lacritin0.4950.002
P43490NAMPTNicotinamide phosphoribosyltransferase0.5010.001
P30520ADSSAdenylosuccinate synthetase isozyme 20.5030.004
P35579MYH9Myosin-90.5030.000
P30740SERPINB1Leukocyte elastase inhibitor0.5220.047
Q9NP55BPIFA1BPI fold-containing family A member 10.5380.040
A0A0C4DGN4ZG16BZymogen granule protein 16 homolog B0.5440.006
O75083WDR1WD repeat-containing protein 10.5490.004
P02774GCVitamin D-binding protein0.5580.010
P52566ARHGDIBRho GDP-dissociation inhibitor 20.5610.047
P07737PFN1Profilin-10.5660.012
P31146CORO1ACoronin-1A0.5730.020
P55058PLTPPhospholipid transfer protein0.5750.032
P52790HK3Hexokinase-30.5790.049
P30044PRDX5Peroxiredoxin-5, mitochondrial0.5820.012
P20700LMNB1Lamin-B10.5920.004
O15144ARPC2Actin-related protein 2/3 complex subunit 20.6080.006
P26038MSNMoesin0.6110.001
B0YJC4VIMVimentin0.6190.002
P0CF74IGLC6Ig lambda-6 chain C region0.620.009
Q32Q12NME1-NME2Nucleoside diphosphate kinase0.6280.037
F5H265UBCPolyubiquitin-C0.6530.004
P14618PKMPyruvate kinase PKM0.6620.046
(B) Upregulated protein biomarkers
Q9HC84MUC5BMucin-5B1.5010.001
A0A0B4J2B5IGHV3OR16-9Protein IGHV3OR16-91.5410.003
Q9NQ38SPINK5Serine protease inhibitor Kazal-type 51.5870.018
P02766TTRTransthyretin1.6020.015
P28799GRNGranulins1.6090.030
A0A0A0MTQ6IGKV2D-28Protein IGKV2D-281.6250.022
O75594PGLYRP1Peptidoglycan recognition protein 11.6290.010
V9GYG9APOA2Apolipoprotein A-II1.6490.010
Q6UW32IGFL1Insulin growth factor-like family member 11.6810.031
Q01469FABP5Fatty acid-binding protein, epidermal1.7380.026
Q14624ITIH4Inter-alpha-trypsin inhibitor heavy chain H41.7490.010
P80188LCN2Neutrophil gelatinase-associated lipocalin1.7720.020
P06702S100A9Protein S100-A91.7910.001
A0A0B4J1X8IGHV3-43Protein IGHV3-431.7920.025
C9J9T0RPERibulose-5-phosphate-3-epimerase1.8730.006
A0A0G2JPR0C4AComplement C4-A1.8760.030
P35527KRT9Keratin, type I cytoskeletal 92.0040.002
A0A0C4DGV7RBP4Retinol-binding protein 42.1020.004
P04217A1BGAlpha-1B-glycoprotein2.1540.010
A0A0A0MS11IGHV3-13Protein IGHV3-132.1760.017
P02790HPXHemopexin2.220.008
O95274LYPD3Ly6/PLAUR domain-containing protein 32.260.010
E9PIT3F2Prothrombin2.260.033
Q14508WFDC2WAP four-disulfide core domain protein 22.2690.017
A0A075B6N7IGHA2Ig alpha-2 chain C region2.390.025
P00738HPHaptoglobin2.4260.001
Q07654TFF3Trefoil factor 32.4270.001
A0A075B7B8IGHV3OR16-12Protein IGHV3OR16-122.4430.035
P02760AMBPProtein AMBP2.5780.020
P02787TFSerotransferrin2.6770.005
P59666DEFA3Neutrophil defensin 32.6960.020
P02768ALBSerum albumin3.070.003
P31151S100A7Protein S100-A73.5940.001
A0A087WYE1IGHG1Ig gamma-1 chain C region4.640.050
P55000SLURP1Secreted Ly-6/uPAR-related protein 15.5880.000
Figure 1 Bioinformatics analysis of differentially expressed proteins. (a) Biological process. (b) Molecular function. (c) Cellular component. (d) Network of proteins analyzed.
Figure 1

Bioinformatics analysis of differentially expressed proteins. (a) Biological process. (b) Molecular function. (c) Cellular component. (d) Network of proteins analyzed.

3.3 Examination of S100A9 and haptoglobin as potential RCC biomarkers

Among the 71 differentially expressed salivary proteins, four well-documented proteins (S100A9, serotransferrin, haptoglobin, and KRT9) most closely associated with solid cancers in previous studies were selected as putative protein biomarkers. We first used the discovery sample set (n = 20) to confirm that the relative expression levels of these four genes were consistent with the iTRAQ results, with significant differences between cancer patients and healthy subjects based on RT-qPCR. As shown in Figure 2, S100A9 and haptoglobin were validated (≥2-fold change, P < 0.0001; n = 124) in RCC saliva samples, whereas serotransferrin and KRT9 expression did not exhibit differences between the groups. The expression patterns of the validated biomarkers were consistent with the iTRAQ results.

Figure 2 Discovery and verification of candidate salivary biomarkers. S100A9, haptoglobin, serotransferrin and KRT9 levels in the saliva of RCC patients (n = 62) and healthy controls (n = 62) were assessed by real-time PCR.
Figure 2

Discovery and verification of candidate salivary biomarkers. S100A9, haptoglobin, serotransferrin and KRT9 levels in the saliva of RCC patients (n = 62) and healthy controls (n = 62) were assessed by real-time PCR.

3.4 Prediction pattern of the validated biomarkers

To evaluate the clinical utility of S100A9 and haptoglobin in patients, we employed ELISA for further validation of individual saliva samples of RCC patients (n = 62) and healthy controls (n = 62). The saliva concentrations of S100A9 in the healthy controls and RCC patients were 50.79 ± 21.78 and 131.61 ± 56.61 ng/mL, respectively, and the concentration of haptoglobin in these two groups was 35.84 ± 9.86 and 56.25 ± 12.43 µg/mL, respectively. The saliva levels of S100A9 and haptoglobin in the RCC group were markedly increased compared with the control group. The expression trend of the validated biomarkers was consistent with the proteomics results (Figure 3a).

Figure 3 Efficacy of S100A9 and haptoglobin in discriminating RCC. (a) Box plots denoting 25 to 75th percentiles for the expression of S100A9 and haptoglobin in the saliva of RCC patients and healthy controls by ELISA. (b) The ROC curve analysis for salivary S1A9 and haptoglobin in the diagnosis of RCC.
Figure 3

Efficacy of S100A9 and haptoglobin in discriminating RCC. (a) Box plots denoting 25 to 75th percentiles for the expression of S100A9 and haptoglobin in the saliva of RCC patients and healthy controls by ELISA. (b) The ROC curve analysis for salivary S1A9 and haptoglobin in the diagnosis of RCC.

ROC curves were used to define the discriminatory power of the validated biomarkers between RCC patients and healthy individuals. As shown in Figure 3b and Table 3, with a cut-off value of 75.49 ng/mL, salivary S100A9 exhibited a sensitivity and specificity of 87.10% and 91.94%, respectively, in discriminating between RCC patients and normal individuals. If the cut-off value was set to 43.02 µg/mL, salivary haptoglobin differentiated RCC patients from healthy controls with a sensitivity of 85.48% and specificity of 80.65%.

Table 3

The discriminatory power of salivary S100A9 and haptoglobin for the detection of RCC

ProteinP valueAUC95% confidence intervalSensitivity (%)Specificity (%)Std errora
S100A900.9410.899–0.98387.191.940.026
Haptoglobin00.9090.858–0.96085.4880.650.021
  1. a

    Under the nonparametric assumption.

4 Discussion

RCC accounts for 2–3% of all adult malignancies. According to the Globocan data released in 2015, the prevalence and mortality rates of RCC worldwide were 4.4 and 1.8 per 105 population, respectively [8]. RCC cases are frequently incidentally diagnosed during the imaging examination for nonspecific symptoms or other abdominal disease, which now accounts for half of all new RCC cases [9]. Some reports have identified that molecules such as TRAF-1 [10], Hsp27 [11], MMPs [12] or NMP-22 [13], which exhibit altered levels in serum or urine in RCC patients, may provide useful diagnostic information. However, no standardized serum or urine biomarkers are currently available for the accurate diagnosis of RCC in early and intermediate stages. Therefore, a more efficient diagnosis technique or a biomarker is urgently needed.

Serum molecules that are also present in saliva were first discovered in the 1970s [14]. Subsequently, other molecules, such as hormone-binding globulin and monoclonal gammopathy-related paraproteins, have been reported as found in human saliva, suggesting a mass transport mechanism between serum and saliva in a nonspecific and active manner. Although the exact roles of salivary biomarkers in specific systemic diseases remain unclear, changes in salivary biomacromolecule profiles during the development of cancer have been demonstrated in vivo [15].

Quantitative proteomics coupled with the bioinformatics analysis can provide novel insight into changes occurring at the molecular level in cancer. Therefore, the purpose of this work is to explore saliva-based noninvasive and cost-effective methods for the detection of RCC. Prior to their clinical use, we must first address whether identified biomarkers can be validated in different sample cohorts and also assess the robustness of their discriminatory power for RCC differentiation. In this study, we verified that S100A9 and haptoglobin proteins exhibit the discriminatory power for differentiating RCC patients from healthy controls, with sensitivities and specificities greater than 80% (Table 3). These results strongly suggest that the abnormal expression of S100A9 and haptoglobin in saliva is closely related to RCC.

S100A9 is a posttranslation-modified, calcium-binding protein with multiple ligands that is involved in the pathogenesis of inflammatory events and the initial development of cancer cells [16,17,18,19]. According to the previous reports, S100A9 is associated with poor overall survival of non-small-cell lung cancer (NSCLC) patients [20,21]. TGF-β signaling has been shown to cooperate with S100A9 to influence cancer metastasis [22,23]; NF-κB binds to the S100A9 promoter and activates reactive oxygen species-dependent signaling pathways, protecting hepatocellular carcinoma cells from the apoptotic death [24]. S100A9 is also involved in the invasive phenotype at invasive margins of human colorectal carcinomas [25]. In breast cancer, S100A9 has been associated with high-grade disease and negative-ER and -PR status and high Ki67, p53, ERBB2, and EGFR expression [26,27]. Furthermore, S100A9 is abnormally expressed in many types of tumors, indicating that it has high value for cancer diagnosis. Our study also demonstrated that S100A9 levels were significantly increased in patients compared with healthy controls. Given that S100A9 is abnormally expressed in a variety of cancers, S100A9 in saliva may be a useful indicator for diagnosis of cancer, including RCC.

Haptoglobin is an acute-phase protein biosynthesized by the liver, and its expression is regulated by cytokines such as IL-1, IL-6 or TNF-α [28]. The level of haptoglobin is significantly increased in pathological conditions such as infection, acute inflammation, trauma, and tumors. Haptoglobin is involved in cell migration and extracellular matrix degradation, which may contribute to cancer angiogenesis or metastasis [29]. In addition, clinicopathological variables, TNM state and poor overall survival in non-small-cell lung carcinoma (NSCLC) patients have been associated with the levels of haptoglobin [30]. Recent research has further shown increased significance of co-detection of haptoglobin and CYFRA21-1 for the diagnosis of lung squamous carcinoma [31]. Thus, it has been suggested that haptoglobin may be used as a new tumor marker with a high clinical application value for cancer. In our study, haptoglobin was evaluated in the saliva of RCC patients compared with healthy controls, with an area under the ROC curve of 0.909, demonstrating high diagnostic value for RCC.

C-reactive protein (CRP) is a prognostic marker related to RCC diagnosis. We also analyzed the potential existence of a salivary biomarker with better discriminating power in detecting RCC than that of serum CRP. According to international criteria, the upper limit of serum CRP for a healthy individual is 10 mg/L. In the present study, 29 of 62 RCC patients showed CRP levels exceeding this limit, indicating that serum CRP had a sensitivity of 46.77% for the detection of resectable RCC (Table 1). Compared with the healthy individuals, the RCC patients with serum CRP levels >10 mg/L showed significantly increased S100A9 and haptoglobin levels.

Our study demonstrates that patient-based saliva proteomics is a promising model for detecting biomarkers for RCC. In particular, our findings support the putative diagnostic value of S100A9 and haptoglobin in distinguishing RCC patients from normal healthy controls. However, several limitations of this study should be noted. First, the patient data were obtained from a single center. Approval for the use of a set of biomarkers for a given clinical decision relies on the results of large multicenter trials to adjust for possible biases; thus, the value of salivary proteins as biomarkers of RCC or other types of cancers (the potential salivary biomarkers of RCC was identified in this study, but the study can only assure their potential as cancer biomarkers, rather than biomarkers for the specific case of RCC) should be further evaluated in larger studies. In addition, as RCC is typically detected at an advanced stage, it is crucial to detect RCC as early as possible to improve the rate of survival. However, the clinical stages of the RCC patients in our study were not available in subcategories, and some of the cases were in intermediate and advanced stages (III + IV, 25.81%). Finally, the exact mechanism responsible for S100A9 and haptoglobin overexpression in cancer patients must be explored in further studies.

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  1. Conflict of interest: The authors declare no conflict of interest.

Acknowledgments

The authors would like to express their gratitude for the support from the National Natural Science Foundation of China (No. 81273665) and Shenzhen City Science and Technology Development projects (JCYJ20130401113259980).

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Received: 2018-12-01
Revised: 2019-11-23
Accepted: 2020-02-07
Published Online: 2020-08-03

© 2020 Xiao Li Zhang et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
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  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
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  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
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  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
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https://doi.org/10.1515/chem-2020-0048
Keywords for this article
saliva proteomics; renal cell carcinoma; diagnosis; S100A9; haptoglobin
Creative Commons
BY 4.0

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
  48. Adsorption kinetic characteristics of molybdenum in yellow-brown soil in response to pH and phosphate
  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
  50. Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique
  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
  52. Cadmium (Cd) chloride affects the nutrient uptake and Cd-resistant bacterium reduces the adsorption of Cd in muskmelon plants
  53. Removal of H2S by vermicompost biofilter and analysis on bacterial community
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  55. A self-breaking supramolecular plugging system as lost circulation material in oilfield
  56. Synthesis, characterization, and pharmacological evaluation of thiourea derivatives
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  58. Synthesis and characterization of a novel chitosan-grafted-polyorthoethylaniline biocomposite and utilization for dye removal from water
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  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
  67. Design, synthesis and pharmacological profile of (−)-verbenone hydrazones
  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
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  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
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  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
  125. Special Issue on 13th JCC 2018
  126. The Role of H2C2O4 and Na2CO3 as Precipitating Agents on The Physichochemical Properties and Photocatalytic Activity of Bismuth Oxide
  127. Preparation of magnetite-silica–cetyltrimethylammonium for phenol removal based on adsolubilization
  128. Topical Issue on Agriculture
  129. Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions
  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
  132. Lycopene in tomatoes and tomato products
  133. Fluorescence in the assessment of the share of a key component in the mixing of feed
  134. Sulfur application alleviates chromium stress in maize and wheat
  135. Effectiveness of removal of sulphur compounds from the air after 3 years of biofiltration with a mixture of compost soil, peat, coconut fibre and oak bark
  136. Special Issue on the 4th Green Chemistry 2018
  137. Study and fire test of banana fibre reinforced composites with flame retardance properties
  138. Special Issue on the International conference CosCI 2018
  139. Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide
  140. Synthesis of amorphous aluminosilicate from impure Indonesian kaolin
  141. Special Issue on the International Conf on Science, Applied Science, Teaching and Education 2019
  142. Functionalization of Congo red dye as a light harvester on solar cell
  143. The effect of nitrite food preservatives added to se’i meat on the expression of wild-type p53 protein
  144. Biocompatibility and osteoconductivity of scaffold porous composite collagen–hydroxyapatite based coral for bone regeneration
  145. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  146. Effect of natural boron mineral use on the essential oil ratio and components of Musk Sage (Salvia sclarea L.)
  147. A theoretical and experimental study of the adsorptive removal of hexavalent chromium ions using graphene oxide as an adsorbent
  148. A study on the bacterial adhesion of Streptococcus mutans in various dental ceramics: In vitro study
  149. Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study
  150. Special Issue on Chemistry Today for Tomorrow 2019
  151. Diabetes mellitus type 2: Exploratory data analysis based on clinical reading
  152. Multivariate analysis for the classification of copper–lead and copper–zinc glasses
  153. Special Issue on Advances in Chemistry and Polymers
  154. The spatial and temporal distribution of cationic and anionic radicals in early embryo implantation
  155. Special Issue on 3rd IC3PE 2020
  156. Magnetic iron oxide/clay nanocomposites for adsorption and catalytic oxidation in water treatment applications
  157. Special Issue on IC3PE 2018/2019 Conference
  158. Exergy analysis of conventional and hydrothermal liquefaction–esterification processes of microalgae for biodiesel production
  159. Advancing biodiesel production from microalgae Spirulina sp. by a simultaneous extraction–transesterification process using palm oil as a co-solvent of methanol
  160. Topical Issue on Applications of Mathematics in Chemistry
  161. Omega and the related counting polynomials of some chemical structures
  162. M-polynomial and topological indices of zigzag edge coronoid fused by starphene
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