Potential Biomarker Of Poor Prognosis Research Articles

Transient receptor potential melastatin‐related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer with a tendency to invade surrounding healthy tissues, leading to a largely incurable disease. Despite many advances in modern medicine, there is still a lack of early biomarkers as well as efficient therapeutical strategies. The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel that is involved in maintaining Ca(2+) and Mg(2+) homeostasis. It has been recently reported to regulate cell differentiation, proliferation and migration. However, the role of TRPM7 in PDAC progression is far to be understood. In our study, we show that TRPM7 is 13-fold overexpressed in cancer tissues compared to the healthy ones. Furthermore, TRPM7 staining is stronger in tumors with high grade, suggesting a correlation between TRPM7 expression and PDAC progression. Importantly, TRPM7 expression is inversely related to patient survival. In BxPC-3 cell line, dialyzing the cytoplasm during the patch-clamp whole-cell recording with a 0-Mg(2+) solution activated a nonselective current with a strong outward rectification. This cation current is inhibited by intracellular Mg(2+) and by TRPM7 silencing. The downregulation of TRPM7 by small interference RNA dramatically inhibited intracellular Mg(2+) fluorescence and cell migration without affecting cell proliferation, suggesting that TRPM7 contributes to Mg(2+) entry and cell migration. Moreover, external Mg(2+) following TRPM7 silencing fully restored the cell migration. In summary, our results indicate that TRPM7 is involved in the BxPC-3 cell migration via a Mg(2+)-dependent mechanism and may be a potential biomarker of poor prognosis of PDAC.

Identification of phosphorylation sites on the E3 ubiquitin ligase UBR5/EDD

UBR5 (ubiquitin protein ligase E3 component n-recognin 5)/EDD (E3 ligase identified by differential display) is an E3 ubiquitin ligase that is a potential biomarker for poor prognosis for recurrent, platinum-resistant ovarian cancer. UBR5 has a role in the DNA damage response and many such proteins are regulated by phosphorylation. UBR5 is a 309 kDa nuclear phosphoprotein that we previously identified as a substrate of the MAP kinase ERK2. With its 477 potential phosphorylation sites, little is known about UBR5 phosphorylation and how it may regulate protein function. Currently, thirty-four sites of phosphorylation on UBR5 have been reported in the literature, mostly identified by large scale proteomics studies of tissues or of cells after various treatments; however, no studies have specifically targeted the identification of UBR5 phosphorylation sites. In this study, we used Liquid Chromatography-Mass Spectrometry (LC-MS/MS) to obtain a total sequence coverage of 64.3% from combining tryptic and GluC digests on UBR5 isolated from transfected COS-1 cells. We identified 24 sites of phosphorylation, 18 of which are novel sites. This data enhances our knowledge of UBR5 phosphorylation and provides a framework for the study of how phosphorylation affects UBR5 function.

P52 Neutrophil dysfunction: a potential biomarker of poor prognosis in acute liver failure?

IntroductionIn acute liver failure (ALF) an exaggerated systemic inflammatory response can result in neutrophil activation with subsequent tissue damage from release of proteolytic enzymes and reactive oxygen species, contributing to...

Serum YKL-40 in risk assessment for colorectal cancer. A population based, prospective study of 4,987 subjects at risk of colorectal cancer

4136 Background: Early detection of colorectal cancer (CRC) translates into improved survival. YKL-40 is produced by CRC cells and tumor associated macrophages. YKL-40 may play a role in cancer cell proliferation and differention, metastasis potential and angiogenesis. High serum YKL-40 is a potential biomarker of poor prognosis in patients with cancer, including CRC, and is independent of CEA and LDH. Highest serum YKL-40 is found in patients with metastatic cancer. We tested the hypothesis that serum YKL-40 would improve detection of CRC. Methods: Serum YKL-40 was determined by ELISA (Quidel) in a prospective, population based study of 4,987 subjects (age 18–97 years, 2,284 males and 2,704 females) referred to endoscopy (sigmoideoscopy n=1,720, colonoscopy n=3,206, rectoscopy n=53, unknown n=9) due to symptoms or risk factors for CRC. The subjects had a blood sample collected at the time of endoscopy (Jan 2004 - Dec 2005). Baseline variables including life style variables, current medication and co-morbidity including malignant disease (registered using ICD-10 codes) within the last 5 years. The measurements of serum YKL-40 were performed blinded in a randomized order at the completion of the study. Results: 189 colon cancers (3.8%), 114 rectal cancers (2.3%), 921 adenomas (18.5%), 10 other cancers (0.2%), and 1,217 other findings (24.4%) were found. Co-morbidity was observed in 2,624 subjects. Univariate analysis showed that high serum YKL-40 predicted CRC (OR=1.6, 95% CI: 1.4–1.7, p<0.0001, AUC=0.69 (AUC is the area under the ROC curve)). Restricting the analysis to subjects without other findings or co-morbidity demonstrated increased discrimination of serum YKL-40 (OR=2.5, 95% CI: 2.2–2.9, p<0.0001, AUC=0.79) Multivariate logistic regression analysis including serum YKL-40, age, sex, BMI, smoking, alcohol intake and co-morbidity demonstrated that serum YKL-40 independently predicted CRC (OR=1.56, 95% CI: 1.34–1.81, p<0.0001, AUC=0.75). Restricting the analysis to subjects with no co-morbidity showed that serum YKL-40 was significant (OR=1.95, 95% CI:1.53–2.48, p<0.0001, AUC=0.80). Conclusion: These results suggest that serum YKL-40 could be useful in the assessment of risk for colorectal cancer. No significant financial relationships to disclose.

Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma

The nel-like1 (NELL1) gene maps to chromosome 11p15, which frequently undergoes loss of heterozygosity in esophageal adenocarcinoma (EAC). NELL1 promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction in 259 human esophageal tissues. Hypermethylation of this promoter showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and EAC from normal esophagus (NE) (P<0.001). NELL1 normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's (D) and EAC than in NE (P<0.0000001). NELL1 hypermethylation frequency was zero in NE but increased early during neoplastic progression, to 41.7% in BE from patients with Barrett's alone, 52.5% in D and 47.8% in EAC. There was a significant correlation between NELL1 hypermethylation and BE segment length. Three (11.5%) of 26 ESCCs exhibited NELL1 hypermethylation. Survival correlated inversely with NELL1 hypermethylation in patients with stages I-II (P=0.0264) but not in stages III-IV (P=0.68) EAC. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced NELL1 methylation and increased NELL1 mRNA expression. NELL1 mRNA levels in EACs with an unmethylated NELL1 promoter were significantly higher than those in EACs with a methylated promoter (P=0.02). Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC.