Transketolase-Like Protein 1 and Glucose Transporter 1 in Gastric Cancer.

BACKGROUND: The glucose metabolism of cancer cells differs from that of noncancerous cells. Transketolase-like protein 1 (TKTL1) and glucose transporter 1 (GLUT1) both play a role in this process. These biochemical tumor markers are overexpressed in several types of human cancer. OBJECTIVE: We sought to determine if TKTL1 and/or GLUT1 expression predicts prognosis in gastric cancer. METHODS: In this retrospective study, we selected 284 patients who underwent surgery for gastric cancer at the Helsinki University Hospital. We used immunohistochemistry to assess the expression of TKTL1 and GLUT1, combined with clinicopathological data. RESULTS: Positive expression of TKTL1 was associated with positive expression of GLUT1, age over 65 years, male gender, advanced stage (II-IV), and advanced tumors (T2-T4). Patients with a positive expression of TKTL1 had a poorer prognosis than those with no expression (p = 0.042, Breslow test). GLUT1 positivity was associated with higher age and with the intestinal type of gastric cancer but did not carry any prognostic value. CONCLUSION: In conclusion, our study showed that positive expression of TKTL1 correlates with a poor prognosis in gastric cancer.

Tumor-associated trypsin inhibitor (TATI) and tumor-associated trypsin-2 (TAT-2) predict outcomes in gastric cancer.

Introduction: Tumor-associated trypsin inhibitor (TATI) limits serine proteases, promotes carcinogenesis in several cancers and functions as an acute-phase reactant. Tumor-associated trypsin-2 (TAT-2), a proteolytic target enzyme for TATI, can enhance invasion by promoting extracellular matrix degradation. Here, we aimed to study serum TATI and TAT-2 levels, including the TAT-2/TATI ratio, as prognostic and diagnostic biomarkers in gastric cancer. We compared the results with the plasma level of C-reactive protein (CRP).Material and Methods: We selected 240 individuals operated on for gastric adenocarcinoma at the Helsinki University Hospital, Finland, between 2000 and 2009. We determined the preoperative serum TAT-2, TATI and plasma CRP levels using time-resolved immunofluorometric assays using monoclonal antibodies.Results: The medium serum TAT-2 level was higher among gastric cancer patients [8.68 ng/ml; interquartile range (IQR) 5.93-13.2] than among benign controls (median 5.41 ng/ml; IQR 4.12-11.8; p = .005). Five-year survival among patients with a high serum TAT-2 was 22.9% [95% confidence interval (CI) 11.7-34.1], compared to 52.2% (95% CI 44.6-59.8; p < .001) among those with a low level. The five-year survival among patients with a high serum TATI was 30.6% (95% CI 20.4-40.8), compared to 52.9% (95% CI 44.7-61.1; p < .001) among those with a low level. The serum TATI level remained significant in the multivariable survival analysis (hazard ratio 2.01; 95% CI 1.32-3.07). An elevated plasma CRP level associated with a high serum TATI level (p = .037).Conclusions: This study shows for the first time that a high serum TAT-2 may function as a prognostic biomarker in gastric cancer and that TAT-2 levels may be elevated compared to controls. Additionally, we show that the prognosis is worse among gastric cancer patients with a high serum TATI. These biomarkers serve as prognostic factors particularly among patients with a metastatic or a locally advanced disease.

High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1.

Matrix metalloproteinase 14 (MMP14), a membrane-associated matrix metalloproteinase, has been shown to influence the invasion and metastasis of several solid tumors. Prospero homeobox protein 1 (PROX1), involved in the development and cell fate determination, is also expressed in malignant diseases functioning either as a tumor-suppressing or oncogenic factor. In certain cancers PROX1 appears to transcriptionally suppress MMP14 expression. This study, therefore, aimed to explore the association between MMP14 and PROX1 and understand their potential as prognostic biomarkers in gastric cancer. The cohort consisted of 313 individuals operated for gastric adenocarcinoma between 2000 and 2009 in the Department of Surgery, Helsinki University Hospital. MMP14 and PROX1 expressions were studied using immunohistochemistry in the patient sample and using immunoblotting and immunofluorescence in gastric cancer cell lines. We generated survival curves using the Kaplan-Meier method, determining significance via the log-rank test. A high MMP14 expression associated with being ≥67 years (P = .041), while a positive nuclear PROX1 expression associated with tumors of a diffuse histological type (P = .041) and a high cytoplasmic PROX1 expression (P < .001). Five-year disease-specific survival among patients with a high MMP14 expression was 35.9% (95% confidence interval [CI] 24.9-46.9), compared to 45.3% (95% CI 38.0-52.6) for patients with a low MMP14 (P = .030). Survival was worse specifically among those with a high MMP14 and absent nuclear PROX1 expression (hazard ratio [HR] 1.65; 95% CI 1.09-2.51; P = .019). Thus, this study confirms that a high MMP14 expression predicts a worse survival in gastric cancer, revealing for the first time that survival is particularly worse when PROX1 is low.

Evaluation of toll-like receptors as prognostic biomarkers in gastric cancer: high tissue TLR5 predicts a better outcome.

Toll-like receptors (TLRs), key proteins in innate immunity, appear to contribute to the inflammatory environment in carcinogenesis. Thus, we aimed to evaluate the tissue expressions of TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 as potential prognostic biomarkers in gastric cancer. We applied immunohistochemistry to study tissue samples from 313 patients operated on for gastric adenocarcinoma between 2000 and 2009 at the Department of Surgery, Helsinki University Hospital, Finland. A high expression of each TLR studied associated with the high expression of each other and with the intestinal-type histology (p < 0.001 for all). Five-year disease-specific survival among patients with a high TLR5 was 53.4% (95% confidence interval [CI] 43.4-63.4), whereas among patients with a low TLR5 it was 37.6% (95% CI 30.0-45.2; p = 0.014). A high TLR5 expression functioned as a marker of a better prognosis, particularly among those with a stage II disease (hazard ratio [HR] 0.33; 0.13-0.83; p = 0.019) or an intestinal-type cancer (HR 0.58; 95% CI 0.34-0.98; p = 0.043). In this study we show, for the first time, that a high TLR5 tissue expression may identify gastric cancer patients with a better prognosis, particularly among those with a stage II disease or an intestinal-type cancer.

High serum MMP-14 predicts worse survival in gastric cancer.

Matrix metalloproteinases (MMPs), endopeptidases with diverse biochemical functions, can promote cancer cell invasion and metastasis by degrading the extracellular matrix. A high matrix metalloproteinase-14 (MMP-14) expression in gastric cancer tissue has been associated with metastasis and poor prognosis. To further understand this association, we investigated serum MMP-14 as a biomarker in gastric cancer patients. The patient cohort consisted of 240 gastric adenocarcinoma patients who underwent surgery at Helsinki University Hospital, Finland, between 2000 and 2009. We determined the soluble MMP-14 serum levels using an enzyme-linked immunosorbent assay. We then calculated the associations between serum levels and clinicopathologic variables using the Mann-Whitney U-test or the Kruskal-Wallis test. We constructed survival curves using the Kaplan-Meier method and calculating the hazard ratios using the Cox proportional hazard model. We revealed a positive association between a high serum MMP-14 level and stages III-IV (p = 0.029), and between a high serum MMP-14 and distant metastasis (p = 0.022). Patients with a low serum MMP-14 had a 5-year disease-specific survival of 49.2% (95% confidence interval [CI] 45.5-52.9), whereas patients with a high serum MMP-14 had a 5-year survival of 22.1% (95% CI 15.2-29.0; p = 0.001). High serum MMP-14 was a statistically significant prognostic factor among patients with an intestinal type of cancer (hazard ratio [HR] 3.54; 95% CI 1.51-8.33; p = 0.004), but not among patients with a diffuse type. The serum MMP-14 level remained an independent prognostic factor in our multivariate survival analysis (HR 1.55; 95% CI 1.02-2.35; p = 0.040). This study indicates for the first time that high serum soluble MMP-14 levels in gastric cancer serves as a marker for a poor prognosis, possibly indicating the presence of distant metastases.

Serum MMP-8 and TIMP-1 as prognostic biomarkers in gastric cancer.

Despite gastric cancer being rare nowadays in Western countries, it remains one of the leading causes of cancer death worldwide. The course of the disease varies, so the individual gastric cancer patient's prognosis is difficult to determine. The need for new biomarkers is crucial. The aim of this study was to evaluate the prognostic value of serum matrix metalloproteinase-8, serum tissue inhibitor of metalloproteinase-1, and tissue matrix metalloproteinase-8 in patients with gastric cancer. Preoperative serum samples from 233 patients with gastric cancer were retrospectively analyzed. Serum levels of matrix metalloproteinase-8 were analyzed with immunofluorometric assay, and tissue inhibitor of metalloproteinase-1 levels were determined by enzyme-linked immunosorbent assay. We also determined the tissue expression of matrix metalloproteinase-8 in 276 gastric cancer samples by immunohistochemistry. Survival data and death causes came from patient records, the Population Register Center of Finland, and Statistics Finland. Patients with a low (<31 ng/mL) or high (>131 ng/mL) serum matrix metalloproteinase-8 level had a considerably unfavorable prognosis (p = 0.002). Those patients with a high (≥170 ng/mL) serum tissue inhibitor of metalloproteinase-1 level also had a poor prognosis (p < 0.001), and the latter remained significant in multivariable analysis (hazard ratio = 1.85; 95% confidence interval: 1.26-2.72; p = 0.002). The molar ratio of serum matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 levels with low (<0.07) or high (>0.30) molar ratios predicted a worse prognosis (p = 0.020). Tissue matrix metalloproteinase-8 did not influence prognosis. These results suggest that serum matrix metalloproteinase-8, tissue inhibitor of metalloproteinase-1, and the ratio of matrix metalloproteinase-8/ tissue inhibitor of metalloproteinase-1 may prove useful biomarkers for prediction of prognosis in patients with gastric cancer.

Positive cytoplasmic UCHL5 tumor expression in gastric cancer is linked to improved prognosis.

Gastric cancer is the second most common cause of cancer-related mortality worldwide. Accurate prediction of disease progression is difficult, and new biomarkers for clinical use are essential. Recently, we reported that the proteasome-associated deubiquitinating enzyme UCHL5/Uch37 is a new prognostic marker in both rectal cancer and pancreatic ductal adenocarcinoma. Here, we have assessed by immunohistochemistry UCHL5 tumor expression in gastric cancer. The study cohort comprised 650 patients, who underwent surgery in Helsinki University Hospital, Finland, between 1983 and 2009. We investigated the association of cytoplasmic UCHL5 tumor expression to assess clinicopathological parameters and patient survival. Positive cytoplasmic UCHL5 tumor immunoexpression is linked to increased survival of patients with small (<5 cm) tumors (p = 0.001), disease stages I-II (p = 0.025), and age 66 years or older (p = 0.037). UCHL5 is thus a potential marker in gastric cancer with new prognostic relevance.

High PROX1 expression in gastric cancer predicts better survival.

BACKGROUND: PROX1 is a transcription factor involved in the development of various organs. It has also an important function in colorectal cancer progression. The aim of this study was to investigate the prognostic role of PROX1 expression in gastric cancer. METHODS: We evaluated PROX1 expression in gastric cancer by immunohistochemistry of tumor-tissue microarrays including tumor specimens from 283 patients who underwent surgery at Helsinki University Hospital. We investigated the association of PROX1 expression with clinicopathologic variables and patient survival. RESULTS: Cytoplasmic PROX1 reactivity was high in 56 (20.5%) and low in 217 (79.5%) cases. Low PROX1 immunostaining associated with diffuse cancer type (p = 0.002). In subgroup analysis, PROX1 was a significant marker of better prognosis in patients aged under 66 (p = 0.007), in those with intestinal cancer (p = 0.025), among men (p = 0.019), and in tumors of less than 5 cm diameter (p = 0.030). Patients with high PROX1 expression had a cancer-specific 5-year survival of 65.6% (95% CI 52.7-78.5), compared to 37.1% (95% CI 30.2-44.0) for those with low expression (p = 0.004, log-rank test). This result remained significant in multivariable analysis (HR = 0.56; 95% CI 0.35-0.90; p = 0.017). CONCLUSION: In gastric cancer, high cytoplasmic PROX1 expression is an independent marker of better prognosis.

Podocalyxin as a Prognostic Marker in Gastric Cancer.

BACKGROUND: Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein associated with aggressive tumor phenotype and poor prognosis in several forms of cancer. The aim of this study was to investigate PODXL expression in gastric cancer by use of two different antibodies. METHODS: By tumor-tissue microarrays and immunohistochemistry we evaluated PODXL expression in tumor specimens from 337 patients who underwent surgery for gastric adenocarcinoma at Helsinki University Hospital. We used two different antibodies: HPA2110, which is a polyclonal antibody and an in-house monoclonal antibody called HES9, to investigate the association of PODXL expression with clinicopathologic variables and patient survival. RESULTS: PODXL staining was positive by the polyclonal antibody in 153 (57.5%) cases and by the monoclonal antibody in 212 (76%). Polyclonal antibody expression was associated with intestinal cancer type (p<0.001). Monoclonal antibody staining was associated with age over 66 (p = 0.001), with intestinal cancer (p<0.001), and with small tumor size (≤ 5 cm; p = 0.024). Both antibodies were associated with high S-phase fraction (p = 0.022; p = 0.010), and high tumor proliferation index (Ki-67; p = 0.003; p = 0.001). PODXL positivity by the polyclonal antibody indicated reduced gastric-cancer-specific 5-year survival of 24.0% (95% CI 16.9-31.1), compared to 43.3% (95% CI 33.7-52.9) for patients with PODXL negativity (p = 0.001). The result remained significant in multivariable analysis (HR = 3.17; 95% CI 1.37-7.34, p = 0.007). CONCLUSION: In gastric cancer, PODXL expression by the polyclonal antibody HPA2110 is an independent marker of poor prognosis.

Frequencies of single-nucleotide polymorphisms of SLCO1A2, SLCO1B3 and SLCO2B1 genes in a Finnish population.

Organic anion transporting polypeptides 1A2, 1B3 and 2B1 (OATP1A2, OATP1B3 and OATP2B1) are expressed in tissues important for pharmacokinetics, and mediate the cellular influx of various endogenous and exogenous compounds, including drugs. The aim of the study was to investigate the frequencies of single-nucleotide polymorphisms (SNP) of SLCO1A2, SLCO1B3 and SLCO2B1 in a Finnish population. The distribution of nine non-synonymous SLCO1A2, SLCO1B3 and SLCO2B1 SNPs was determined in 552 healthy Finnish Caucasian participants by using allelic discrimination with TaqMan 5'nuclease assays. The SLCO1A2 c.38T>C (p.Ile13Thr) and c.516C>T (p.Glu172Asp) SNPs were found with variant allele frequencies of 12.9% (95% confidence interval: 11.0-15.0) and 7.2% (5.8-8.8). The variant allele frequencies of SLCO1B3 c.334T>G (p.Ser112Ala), c.699G>A (p.Met233Ile) and c.767G>C (p.Gly256Ala) were 77.0% (74.4-79.4), 76.9% (74.3-79.3) and 12.8% (10.9-14.9), respectively. None of the participants carried the SLCO1B3 c.1309G>A (p.Gly437Ser) SNP. The SLCO2B1 c.601G>A (p.Val201Met), c.935G>A (p.Arg312Gln) and c.1457C>T (p.Ser486Phe) variant allele frequencies were 2.1% (1.4-3.1), 13.6% (11.7-15.7) and 2.8% (2.0-4.0), respectively. The SLCO1B3 c.334T>G and c.699G>A SNPs were in a nearly complete linkage disequilibrium (r² = 0.99, D' = 1.00), all other SNP pairs showed only a weak correlation. In conclusion, non-synonymous sequence variations of SLCO1A2, SLCO1B3 and SLCO2B1 occur at high frequencies in the Finnish population.