Yuan-Yu Wang

SPARC Is Associated with Gastric Cancer Progression and Poor Survival of Patients

Purpose: The present study investigated the clinical significance of secreted protein, acidic and rich in cysteine (SPARC), in the development and progression of gastric cancer. Experimental Design: Immunohistochemistry was used to analyze SPARC, integrin β1, and matrix metalloproteinase (MMP)-2 expression in 436 clinicopathologically characterized gastric cancer cases. Results: SPARC, integrin β1, and MMP-2 protein levels were upregulated in gastric cancer lesions compared with adjacent noncancerous tissues. SPARC protein was detected in 334 of 436 human gastric cancer cases and was highly expressed in 239 tumors. We also found a positive correlation between expression of SPARC and MMP2, and SPARC and integrin β1. In stages I, II, and III, the 5-year survival rate of patients with a high expression of SPARC was significantly lower than those in patients with low expression. In stage IV, SPARC expression did not correlate with the 5-year survival rate. Further multivariate analysis suggested that the depth of invasion; lymph node and distant metastasis; tumor-node-metastasis stage; and upregulation of SPARC, MMP-2, and integrin β1, were independent prognostic indicators for the disease. Conclusions: Our study provided a basis for the development of a novel biomarker for diagnosis and prognosis of gastric cancer. Expression of SPARC in gastric cancer is significantly associated with lymph node and distant metastasis, high MMP2 expression, high intergrin β1 expression, and poor prognosis. SPARC, intergrin β1, and MMP-2 protein could be useful markers to predict tumor progression. Clin Cancer Res; 16(1); 260–8

High-Level Expression of S100A4 Correlates with Lymph Node Metastasis and Poor Prognosis in Patients with Gastric Cancer

BackgroundThe present study investigated the clinical significance of S100 calcium binding protein A4 in the development, progression, and metastasis of gastric cancer.MethodsTumor tissue, adjacent normal tissue, and lymph node and peritoneal metastases were obtained from patients with gastric cancer, and their gene expression profiles were analyzed by Affymetrix GeneChip® HG-U133A2.0 array. The expression of S100A4 was detected by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) in gastric tumor tissue and lymph node and peritoneum metastasis. Immunohistochemistry was employed to analyze S100A4 expression in 436 clinicopathologically characterized gastric cancer cases and in corresponding distant metastases from 61 patients.ResultsA total of 434 genes and 169 expressed sequence tags were upregulated by at least twofold in the tumor tissue. The expression of S100A4 in lymph node and peritoneal metastases was significantly higher than that in gastric tumor tissue. The expression of S100A4 messenger RNA (mRNA) or protein differed significantly among gastric tumor tissue, matched normal gastric mucosa, and lymph node and peritoneal metastases. Further multivariate analysis suggested that depth of invasion, lymph node and distant metastases, tumor–node–metastasis (TNM) stage, and upregulation of S100A4 were independent prognostic indicators for the disease.ConclusionGene expression profiles are a useful way to perform simultaneously large-scale analysis of the expression level of thousands of genes. Expression of S100A4 in gastric cancer is associated significantly with lymph node and distant metastases, and poor prognosis. S100A4 may be a useful marker to predict development, progression, and metastasis of gastric cancer.

ADAM 10 is associated with gastric cancer progression and prognosis of patients

The metalloproteinase domain‐containing protein 10 (ADAM 10) has been implicated in the development and progression of gastric cancer.

Clinicopathologic significance of miR-10b expression in gastric carcinoma

We have investigated microRNA (miRNA) expression profiles of gastric cancer and the clinicopathologic significance of miR-10b expression in gastric carcinoma. miRCURY LNA Arrays (v.16.0; Exiqon, Vedbaek, Denmark) were used to screen miRNAs in 17 gastric cancers. Reverse transcriptase polymerase chain reaction was performed to determine the expression of miR-10b in 56 gastric tumors. Expression of miR-10b in 436 paraffin-embedded cancer tissues was also investigated. In gastric cancer, 49 miRNAs were overexpressed by 2.0-fold or greater, and 39 miRNAs were down-regulated by 1.5-fold or greater, whereas miR-10b was up-regulated by 2.98-fold. miR-10b was highly expressed in gastric cancer and correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage, and prognosis. In stages I, II, and III, the 5-year survival rate of patients with high levels of miR-10b expression was significantly lower than that in patients with low levels of expression. In stage IV, the expression level of miR-10b did not correlate with the 5-year survival rate. miR-10b may play an important role in progression and prognosis of gastric cancer.

Overexpression of matrix metalloproteinase 11 in human gastric carcinoma and its clinicopathologic significance.

Matrix metalloproteinase 11 (stromelysin-3) has recently been reported to play a key role in human tumor progression and poor clinical outcome. The aim of this study was to investigate the significance of matrix metalloproteinase 11 expression in gastric cancer. Using real-time quantitative reverse-transcription polymerase chain reaction analysis and immunohistochemistry, we studied matrix metalloproteinase 11 expression levels in non-malignant gastric tissues and in gastric cancer tissues. The association between matrix metalloproteinase 11 expression levels and tumor stage and grade, as well as metastatic potential, was analyzed. Our results show that matrix metalloproteinase 11 expression was significantly higher in gastric cancer specimens compared with nonmalignant tissues at both transcriptional and protein levels, indicating its positive role in the development of gastric cancer. In addition, increased matrix metalloproteinase 11 expression levels were associated with advanced-stage and high-grade tumors, suggesting its involvement in the progression of gastric cancer. More importantly, increased matrix metalloproteinase 11 expression in gastric cancer specimens was correlated with increased expression of IGF-1, a molecule known to stimulate the proliferation, enhanced survival, and migration of cancer cells. Our results demonstrate that matrix metalloproteinase 11 is a novel factor in the development and progression of gastric cancer and suggest that matrix metalloproteinase 11 is a marker for advanced gastric cancer.

L1 and epithelial cell adhesion molecules associated with gastric cancer progression and prognosis in examination of specimens from 601 patients.

BackgroundL1 cell adhesion molecule (L1CAM) and epithelial cell adhesion molecule (EPCAM) have been implicated in the development and progression of gastric cancer. The present study investigated the clinical significance of L1CAM and EPCAM in the development, progression and prognosis of gastric cancer.MethodsExpression of L1CAM and EPCAM were examined immunochemically in 601 clinicopathologically characterized gastric cancer cases.ResultsL1CAM protein was detected in 23.9% of human non-tumor mucosa samples. All samples expressed L1CAM protein at low levels. High expression of L1CAM protein was detected in 163 (27.1%) tumors. Expression of L1CAM correlated with age, tumor location, size of tumors, Lauren’s classification, depth of invasion, lymph node and distant metastases, regional lymph node stage, Tumor-Node-Metastasis (TNM) stage and prognosis. EPCAM protein was detected in 45.7% of human non-tumor mucosa samples. All samples expressed EPCAM protein at low levels. High expression of EPCAM protein was detected in 247 (41.1%) tumors. Expression of EPCAM correlated with age, tumor location, size of tumors, Lauren’s classification, depth of invasion, lymph node and distant metastases, regional lymph node stage, TNM stage and prognosis. Cumulative 5-year survival rates of patients with high expression of both L1CAM and EPCAM were significantly lower than in patients with low expression of both.ConclusionsExpression of L1CAM and EPCAM in gastric cancer was significantly associated with lymph node and distant metastasis, and poor prognosis. L1CAM and EPCAM proteins could be useful markers to predict tumor progression and prognosis.

Expression and prognostic significance of CEACAM6, ITGB1, and CYR61 in peripheral blood of patients with gastric cancer.

We examined CEACAM6, ITGB1, and cyr61 concentrations from patients with gastric cancers (GCs) to assess their clinical application for diagnosing and monitoring diseases.

Abnormal expression of miR-301a in gastric cancer associated with progression and poor prognosis.

miR‐301a is significantly overexpressed in many cancers. However, its expression and biological role in gastric cancer remain poorly understood. We investigated microRNA‐301a (miR‐301a) expression in gastric cancer and determined its effects on cancer cell behavior and its clinical significance in the development and progression of gastric cancer.

Clinical utility of measuring expression levels of KAP1, TIMP1 and STC2 in peripheral blood of patients with gastric cancer

BackgroundWe examined preoperative kinesin II-associated protein (KAP1), TIMP metallopeptidase inhibitor 1 (TIMP1) and stanniocalcin 2 (STC2) expression levels in patients with gastric cancers to assess their clinical application for diagnosing and monitoring diseases.MethodsReal-time reverse transcription-polymerase chain reaction was used to detect the expression levels of KAP1, TIMP1, STC2, talin 2 (TLN2), sushi-repeat-containing protein, X-linked 2 (SRPX2) and secreted protein, acidic, cysteine-rich (SPARC) in the patients’ peripheral blood karyocytes. The data were analyzed with receiver operating characteristics (ROC) curves.ResultsA total of 112 patients with gastric cancer, 42 patients with recurrence and 107 healthy volunteers were recruited. There were significant correlations between KAP1, TIMP1 and STC2 levels, and TNM tumor stages and distant metastases. The area under the ROC curves (AUC) of KAP1 was 0.803 ± 0.040 (P = 0.0001), the AUC of TIMP1 was 0.767 ± 0.043 (P = 0.0001) and the AUC of STC2 was 0.769 ± 0.045 (P = 0.0001), thus differentiating preoperative gastric cancer patients from healthy volunteers by ROC curve analysis. The AUC of STC2 was 0.739 ± 0.070 (P = 0.004) and the AUC of KAP1 was 0.418 ± 0.088 (P = 0.319), thus differentiating recurrence of gastric cancer from healthy volunteers by ROC curve analysis. High TIMP1 and STC2 expression levels were suspected to be poor prognostic factors of disease recurrence in patients with gastric cancer.ConclusionsKAP1, TIMP1 and STC2 expression levels may be potential biomarkers for the screening, diagnosis, prognosis and surveillance of gastric cancer.

Systems biology approach to identification of biomarkers for metastatic progression in gastric cancer

PurposeGastric cancer is usually diagnosed at later stages (stages III and IV) in China, and the overall 5-year survival rate is low at 40%. Metastases are responsible for the majority of cancer fatalities. The molecular mechanisms governing metastasis are poorly understood.MethodsWe have analyzed gene expression data based on gene interaction networks and molecular pathways rather than separate genes utilizing hierarchical cluster analysis, Gene ontology analysis and pathway analysis.ResultsWe have analyzed gene expression data from advanced gastric cancer tissues, corresponding adjacent noncancerous gastric tissues and its peritonium metastasis. Our studies indicated that metastatic tumor was related to changes in apoptosis pathway and proteasome degradation pathway, TRAF2 and IRF3 are up-regulated in apoptosis pathway, NEDD4 and UBE1 are up-regulated in proteasome degradation pathway.ConclusionThe advent of high-throughput investigation of gene using Microarray technology, a systems approach relying on groups of interacting genes is essential for understanding the processes of cancer. We have identified apoptosis pathway and proteasome degradation pathway associated with metastasis.