A Quantitative Proteomic Approach for Identification of Potential Biomarkers in Hepatocellular Carcinoma

Chaerkady, Raghothama; Harsha, H. C.; Nalli, Anuradha; Guček, Marjan; Vivekanandan, Perumal; Akhtar, Javed; Cole, Robert N.; Simmers, Jessica L.; Schulick, Richard D.; Singh, Sujay; Torbenson, Michael; Pandey, Akhilesh; Thuluvath, Paul J.

doi:10.1021/pr800197z

Cited by 125 publications

(101 citation statements)

References 45 publications

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“…Ornithine, citrulline, and arginine were detected significantly decreased in the serum of HCC patients as compared with healthy controls (34). Furthermore, ornithine decreased gradually from stage I to IV.…”

Section: Discussionmentioning

confidence: 81%

“…Coincidentally, these three amino acids participate in the urea cycle (UC) (35), which allows for the disposal of excess nitrogen and takes place only in mammals' hepatocyte. A recent report on proteomic analysis of UC revealed the down-regulation of urea cycle enzymes (34), and the UC activity in HepG2 cells (a cell line of HCC) was also found decreased (36). As a result, aspartic acid, a nitrogen supplier in UC, was hence accumulated as the increased level of aspartic acid was detected in serum of HCC patients.…”

Section: Discussionmentioning

confidence: 99%

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Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Chen

Xie

Wang

et al. 2011

Molecular & Cellular Proteomics

261

118

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Hepatocellular carcinoma (HCC) is a common malignancy in the world with high morbidity and mortality rate. Identification of novel biomarkers in HCC remains impeded primarily because of the heterogeneity of the disease in clinical presentations as well as the pathophysiological variations derived from underlying conditions such as cirrhosis and steatohepatitis. The aim of this study is to search for potential metabolite biomarkers of human HCC using serum and urine metabolomics approach. Sera and urine samples were collected from patients with HCC (n ‫؍‬ 82), benign liver tumor patients (n ‫؍‬ 24), and healthy controls (n ‫؍‬ 71). Metabolite profiling was performed by gas chromatography time-of-flight mass spectrometry and ultra performance liquid chromatography-quadrupole time of flight mass spectrometry in conjunction with univariate and multivariate statistical analyses. Forty three serum metabolites and 31 urinary metabolites were identified in HCC patients involving several key metabolic pathways such as bile acids, free fatty acids, glycolysis, urea cycle, and methionine metabolism. Differentially expressed metabolites in HCC subjects, such as bile acids, histidine, and inosine are of great statistical significance and high fold changes, which warrant further validation as potential biomarkers for HCC. However, alterations of several bile acids seem to be affected by the condition of liver cirrhosis and hepatitis. Quantitative measurement and comparison of seven bile acids among benign liver tumor patients with liver cirrhosis and hepatitis, HCC patients with liver cirrhosis and hepatitis, HCC patients without liver cirrhosis and hepatitis, and healthy controls revealed that the abnormal levels of glycochenodeoxycholic acid, glycocholic acid, taurocholic acid, and chenodeoxycholic acid are associated with liver cirrhosis and hepatitis. HCC patients with alpha fetoprotein values lower than 20 ng/ml was successfully differentiated from healthy controls with an accuracy of 100% using a panel of metabolite markers. Our work shows that metabolomic profiling approach is a promising screening tool for the diagnosis and stratification of HCC patients.Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.004945, 1-13, 2011. Hepatocelluar carcinoma (HCC)1 is the fifth most common cancer (1) and the third leading cause of cancer-related death (2) with a five-year survival rate of less than 7% (3). The morbidity of HCC in Southeast Asia and sub-Saharan Africa is greater than 20 cases per 100,000 population, whereas in North America and Western Europe is much lower, less than 5 per 100,000 population (4). However, a dramatically increasing incidence of HCC in the world, especially in the United States has been reported in recent years, primarily because of chronic alcohol use and chronic hepatitis C infection (5). Diabetic and metabolic diseases of the liver have been known to contribute to an increased incidence of HCC in recent years (6, 7). Despite significant progress in cancer diagnosis and treatment, the morbidity...

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Chen

Xie

Wang

et al. 2011

Molecular & Cellular Proteomics

261

118

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“…This is a key glycolytic enzyme, that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Literature data shows that ALDOA is over-expressed in many types of cancers, including hepatocellular carcinoma [22], squamous cell lung cancer [23,24], osteosarcoma [25], colorectal cancer [26]. The recognized non-glycolytic functions of ALDOA include: participation to signal transduction [27], vesicle trafficking [28], cell motility [29] and epithelial-to-mesenchymal transition [30].…”

Section: Fructose-bisphosphate Aldolase a Aldoa (Aldoa)mentioning

confidence: 99%

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

Pucci‐Minafra¹,

Cara²,

Musso³

et al. 2017

Preprint

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Abstract:The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The fragments were selected from patients with invasive ductal carcinoma of the breast, the most common and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers, useful for diagnostic and prognostic categorization of patients, in assessing postsurgical therapeutic regimes. The proteomic screening, by 2D-IPG and mass spectrometry, allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients, and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is generally supported by two concurrent pathways: the inhibition of apoptosis and the stimulation of cellular proliferation. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. To our knowledge this report on large-scales proteomics of breast cancer is currently a unique approach in the literature that offers the opportunity to evaluate the presence and recurrence of proteins to be used as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.

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“…Mass spectrometry techniques have become the dominant means of protein identification (20). The use of isobaric tags for relative and absolute quantitation (iTRAQ) combined with multidimensional liquid chromatography (LC) and tandem MS analysis (21) is emerging as a powerful methodology in the search for diseasespecific targets and biomarkers using cell lines (22)(23)(24)(25)(26)(27)(28)(29)(30), tissues (31)(32)(33)(34)(35)(36)(37), and body fluids (38,39). The iTRAQ method places tags on primary amines (NH 2 -terminal or -amino group of the lysine side chain), allowing detection of most tryptic peptides.…”

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confidence: 99%

Differential Protein Expression Profiling by iTRAQ-Two-dimensional LC-MS/MS of Human Bladder Cancer EJ138 Cells Transfected with the Metastasis Suppressor KiSS-1 Gene

Ruppen

Grau

Orenes‐Piñero

et al. 2010

Molecular & Cellular Proteomics

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KiSS-1 is a metastasis suppressor gene reported to be involved in the progression of several solid neoplasias. The loss of KiSS-1 gene expression has been shown to be inversely correlated with increasing tumor stage, distant metastases, and poor overall survival in bladder tumors. To identify the molecular pathways associated with the metastasis suppressor role of KiSS-1 in bladder cancer, we carried out a proteomics analysis of bladder cancer cells (EJ138) transiently transfected with a vector encompassing the full-length KiSS-1 gene using an iTRAQ (isobaric tags for relative and absolute quantitation) approach. Protein extracts collected after 24-and 48-h transfection were fractionated and cleaved with trypsin, and the resulting peptides were labeled with iTRAQ reagents. The Bladder cancer represents the fourth most common malignancy among men and the eighth cause of male cancer deaths (1). Bladder cancer can be classified based on the depth of invasion. Clinically, ϳ75% of transitional cell carcinomas (TCCs) 1 are non-muscle-invasive (pTis, pTa, and pT1), 20% are muscle infiltrating (pT2-pT4), and 5% are metastatic at the time of diagnosis (1). Low grade tumors are always papillary and usually non-invasive, whereas high grade tumors can be either papillary or non-papillary and are often invasive. Patients diagnosed with localized TCC have a 5-year relative survival rate over 90%. However, patients presenting with regional and distant metastatic disease spread have 5-year relative survival rates of lower than 50 and 10%, respectively (1). Bladder cancer progression and the development of secondary metastases follow complex sequential steps. The changes at the genetic and/or epigenetic level to the many genes involved in critical cell functions are not completely understood (2).KiSS-1 has been shown to suppress metastases without affecting tumorigenicity in melanoma and breast cancer cells (3-7). It maps to chromosome 1q32 (8) and is regulated by genes mapping to chromosome 6 (3-7). KiSS-1 encodes a 145-amino acid protein, which is processed into kisspeptins of several sizes (9 -11). Kisspeptins have been shown to control the onset of puberty and inhibit cancer metastasis of different tumor types (9 -11). Experimental and clinical studies indicate KiSS-1 to be a functionally active metastasis suppressor gene in several solid tumors (12-19). Molecular profiling analysis revealed that KiSS-1 was lost in advanced cell 1 The abbreviations used are: TCC, transitional cell carcinoma; EF, error factor; FDR, false discovery rate; iTRAQ, isobaric tags for relative and absolute quantitation; RB, retinoblastoma; TP53, tumor protein 53; CI, confidence interval; EV, empty vector; Ct, cycle threshold. Research

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A Quantitative Proteomic Approach for Identification of Potential Biomarkers in Hepatocellular Carcinoma

Cited by 125 publications

References 45 publications

Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

Differential Protein Expression Profiling by iTRAQ-Two-dimensional LC-MS/MS of Human Bladder Cancer EJ138 Cells Transfected with the Metastasis Suppressor KiSS-1 Gene

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