The Prognostic Significance of Tryptophanyl-tRNA Synthetase in Colorectal Cancer

Department of Surgery, University of Uppsala, Uppsala, Sweden.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 11/2009; 18(11):2949-56. DOI: 10.1158/1055-9965.EPI-09-0456
Source: PubMed


Tryptophanyl-tRNA synthetase (TrpRS) is an aminoacyl-tRNA synthetase involved in protein synthesis and regulation of RNA transcription and translation and is an inhibitor of angiogenesis. TrpRS has been shown to be differentially expressed in colorectal cancer (CRC) and has thus been identified as a potential prognostic marker. The aim of this study was to analyze the correlation of TrpRS to the prognosis of patients diagnosed and treated for CRC within a defined population.
With a polyclonal, monospecific IgG antibody, TrpRS expression was assessed by immunohistochemistry on tissue microarrays with tumors from a population-based CRC cohort (n = 320). Staining intensity and fraction of positive tumor cells were recorded. A Cox multivariate model including TrpRS expression, carcinoembryonic antigen, age, stage, tumor differentiation, and lymphatic and vascular vessel invasion was used to calculate the hazard ratio and 95% confidence interval (95% CI) for time to recurrence, disease-free survival, and overall survival.
Low expression of TrpRS correlated to increased risk for lymph node metastasis (P = 0.025) and a more advanced tumor stage (P = 0.001). Patients with tumors and increased levels of TrpRS expression had better survival than patients with low expression levels. Multivariate analyses revealed significantly better disease-free survival (relative risk, 0.59; 95% CI, 0.38-0.95) for patients with high expression than for patients with low expression of TrpRS. For colon cancer patients, a reduced risk for recurrence was seen in patients with increased TrpRS expression (relative risk, 0.23; 95% CI, 0.07-0.80).
Low expression of TrpRS in tumor tissue correlates with increased risk for recurrence and worse survival in patients with CRC. This can be related to its antiangiogenic properties and could aid in the future selection of new drugs in the treatment of CRC.

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    • "The molecular mechanism for the angiostatic effect of mini-WARS is linked to its formation of a complex with VE-cadherin which causes interference with VEGFR2 signaling20. A low level of mini-WARS is also correlated with poor prognoses in patients with colorectal cancer, suggesting that it may serve an anti-cancer role21. By yet another mechanism, glutamyl-prolyl-tRNA synthetase is phosphorylated in response to IFN-γ causing its release from the multisynthetase complex. "
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    Scientific Reports 02/2013; 3:1317. DOI:10.1038/srep01317 · 5.58 Impact Factor
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    • "The first step in ARS activity is amino acid activation with formation of aminoacyladenylate and release of inorganic pyrophosphate (ATP-PP i exchange), and the second step is formation of aminoacyl-tRNA. In colorectal cancer (CRC), changes in TrpRS expression correlate with survival: a low protein expression in human tissues correlated with a worse cancer prognosis (increased risk for recurrence and worse survival) than a higher human TrpRS (hTrpRS) expression [1]. In human pancreatic cancer (PC) cells, high messenger RNA (mRNA) and protein TrpRS expression correlates with higher growth rate and metastatic ability, whereas hypoxic state associates with reduced hTrpRS expression. "
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    ABSTRACT: Tryptophanyl-tRNA synthetase (TrpRS) expression alters in colorectal (CRC), pancreatic (PC), and cervical (CC) cancers. Here, phosphorylation of unfolded TrpRS and its fragments is stimulated by human cancer sera (CS; n = 13) and serum of rabbit tumor induced by Rous sarcoma virus, unaffected by donor sera (NS; 11/15) and abolished by alkaline phosphatase. At 20 years of follow-up, serum-inducible TrpRS phosphorylation found years before healthy donors (3/15) diagnosed with PC, CRC, or leukemia. I have examined a specificity of serum-inducible TrpRS phosphorylation and found, surprisingly, that serine phosphorylation of unfolded TrpRS is stimulated by anti-TrpRS rabbit antisera but is unaffected by rabbit nonimmune sera and antisera to other antigens. Anti-TrpRS immunoglobulin G (IgG) inhibits phosphorylation of full-length TrpRS and stimulates phosphorylation of its 20-kDa fragment. Phosphorylation of this fragment is stimulated also by CS but not NS. 2-Mercaptoethanol and cyclic AMP exerted synergistic inhibitory effect on TrpRS phosphorylation. Anti-TrpRS sera and casein act as chaperones increasing TrpRS phosphorylation through refolding. Histone-specific protein kinase activity in CS (n = 44) and anti-TrpRS sera was lower than that in NS (n = 11), rabbit nonimmune sera and antisera to other antigens. TrpRS inhibitors, tryptamine, and tryptophanol stimulate in vivo accumulation of enzymatically inactive, nonphosphorylated, aggregated and anti-TrpRS IgG refoldable TrpRS. Phosphorylation of postsurgical tissues (n = 18) reveals TrpRS in ovarian cancer (OVC) and CC but not in normal placenta and liver. In OVC, TrpRS phosphorylation increase correlates with elevated tryptophan-dependent ATP-inorganic pyrophosphate exchange. Although not inducing cancer, TrpRS triggers signaling concomitant with cancer.
    Translational oncology 12/2011; 4(6):377-89. DOI:10.1593/tlo.11220 · 2.88 Impact Factor
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