Zihua Chen

Overexpression of EphA2, MMP-9, and MVD-CD34 in hepatocellular carcinoma: Implications for tumor progression and prognosis

Aim:  To investigate the expression of erythropoietin‐producing hepatocellular (Eph)A2 receptor, matrix metalloproteinase (MMP)‐9, and angiogenesis in hepatocellular carcinoma (HCC), in order to reveal their expression correlations with tumor invasion, metastasis, and prognosis.

Upregulation of autophagy-related gene-5 (ATG-5) is associated with chemoresistance in human gastric cancer.

Autophagy-related gene-5 (ATG-5) is one of the key regulators of autophagic cell death. It has been widely regarded as a protective molecular mechanism for tumor cells during the course of chemotherapy. In the present study, we investigated the expression pattern of ATG-5 and multidrug resistance-associated protein-1 (MRP-1) in 135 gastric cancers (GC) patients who were treated with epirubicin, cisplatin and 5-FU adjuvant chemotherapy (ECF) following surgical resection and explored their potential clinical significance. We found that both ATG-5 (77.78%) and MRP-1 (79.26%) were highly expressed in GC patients. ATG-5 expression was significantly associated with depth of wall invasion, TNM stages and distant metastasis of GC (P<0.05), whereas MRP-1 expression was significantly linked with tumor size, depth of wall invasion, lymph node metastasis, TNM stages and differentiation status (P<0.05). ATG-5 expression was positively correlated with MRP-1 (rp = 0.616, P<0.01). Increased expression of ATG-5 and MPR-1 was significantly correlated with poor overall survival (OS; P<0.01) and disease free survival (DFS; P<0.01) of our GC cohort. Furthermore, we demonstrated that ATG-5 was involved in drug resistant of GC cells, which was mainly through regulating autophagy. Our data suggest that upregulated expression of ATG-5, an important molecular feature of protective autophagy, is associated with chemoresistance in GC. Expression of ATG-5 and MRP-1 may be independent prognostic markers for GC treatment.

Expression of EphA2 and E-cadherin in Gastric Cancer: Correlated with Tumor Progression and Lymphogenous Metastasis

In this study, gastric cancer progression was correlated with the over-expression of erythropoietin-producing hepatocellular (Eph)A2 receptor and down-expression of epithelial cadherin (E-cadherin). Immunohistochemistry of EphA2 and E-cadherin were performed on these tumor samples from 165 primary lesions of gastric cancer. The results showed that expression of EphA2 was obviously increased in gastric cancer tissues (P < 0.01), which was positively correlated with the depth of cancer invasion, tumor-node-metastasis (TNM) stage and lymph node metastasis (P < 0.05). Meanwhile, the expression of E-cadherin was significantly reduced (P < 0.01), which was negatively correlated with the depth of cancer invasion, grade of tumor differentiation, TNM stage and lymph node metastasis (P < 0.05). The correlation between EphA2 and E-cadherin expression was negative (r = −0.198, P = 0.011). In conclusion, either the over-expression of EphA2 or the down-expression of E-cadherin is correlated with cancer progression and lymphogenous metastasis in gastric cancer, suggesting that both of them may play an important role in tumor progression and metastasis.

Over-Expression of EphA2 and EphrinA-1 in Human Gastric Adenocarcinoma and Its Prognostic Value for Postoperative Patients

This study aims to investigate the expression and significance of EphA2 and EphrinA-1 in human gastric adenocarcinoma progression and prognosis. The expression of EphA2 and EphrinA-1 was detected in the cell lines and tissues of gastric adenocarcinoma. Different expression levels of EphA2 and EphrinA-1 were found in two cell lines. The expression of EphA2 and EphrinA-1 was significantly higher in gastric adenocarcinoma tissues than in normal tissues. Statistical analysis showed a significant correlation of EphA2 expression with the depth of tumor invasion, tumor-node-metastasis (TNM) stages, and lymph node metastasis. EphrinA-1 over-expression was significantly correlated with TNM stages and lymph node metastasis, while EphA2 expression was found to be an independent prognostic factor of postoperative gastric adenocarcinoma. In conclusion, the increased expression of EphA2 and EphrinA-1 plays an important role in the progression of human gastric adenocarcinoma, in which elevated EphA2 expression is an independent factor that indicates poor prognosis in postoperative gastric adenocarcinoma.

Overexpression of EphA2 correlates with epithelial–mesenchymal transition-related proteins in gastric cancer and their prognostic importance for postoperative patients

The expression of EphA2 and three epithelial–mesenchymal transition-related proteins (E-cadherin, β-catenin and vimentin) was detected by immunohistochemistry in human gastric cancer and normal gastric mucosa. The expression of EphA2 and vimentin was significantly higher in gastric cancer tissues than in normal gastric mucosa tissues, and similar results were found for negative E-cadherin expression and ectopic β-catenin expression. Further analysis showed that the expression of EphA2 was closely correlated with the depth of tumor invasion, tumor–node–metastasis (TNM) stages and lymph node metastasis. Down-regulated expression of the epithelial protein E-cadherin, overexpression of the mesenchymal protein vimentin and ectopic expression of β-catenin were associated with the depth of tumor invasion, tumor differentiation, TNM stages and lymph node metastasis. The Spearman rank test indicated that the positive expression of EphA2 was negatively associated with E-cadherin expression and was positively correlated with β-catenin ectopic expression and vimentin expression. In addition, the Kaplan–Meier survival analysis showed that the overexpression of EphA2 and vimentin, ectopic expression of β-catenin and down-regulation of E-cadherin indicate a poor outcome. Moreover, multivariate Cox analysis showed that TNM stages, lymph node metastasis, EphA2 expression, E-cadherin expression and β-catenin ectopic expression were independent prognostic factors for postoperative gastric cancer. These findings indicate that the overexpression of EphA2 correlates with the loss of epithelial proteins and the appearance of mesenchymal proteins. Therefore, EphA2 may play a role in epithelial–mesenchymal transition in gastric cancer.

Expression levels of insulin-like growth factor-1 and multidrug resistance-associated protein-1 indicate poor prognosis in patients with gastric cancer.

Background/Objectives: Insulin-like growth factor-1 receptor (IGF-1R) displays a key role in tumor transformation and metastasis. It also makes tumor cells more resistant to chemotherapy. The aim of this study was to investigate the correlation between IGF-1R and multidrug resistance-associated protein-1 (MRP-1), and the clinical significance of their expression in gastric carcinoma (GC). Methods: IGF-1R and MRP-1 expressed in 113 specimens were detected by immunohistochemistry. The correlation between IGF-1R and MRP-1 expression was determined. In addition, the association of their expression with clinicopathological features and survival data of GC was also analyzed. Results: IGF-1R (75.2%) and MRP-1 (69.0%) were frequently expressed in GC. IGF-1R was associated with tumor size, quantity of stroma, depth of wall invasion, lymph node metastasis, TNM stages and differentiation status of GC (p < 0.05). MRP-1 was associated with tumor size, quantity of stroma, lymph node metastasis, distant metastasis and TNM stages (p < 0.05). IGF-1R over-expression positively correlated with MRP-1 over-expression (rp = 0.39, p < 0.01). IGF-1R and MPR-1 over-expression were correlated with poor prognosis of GC (p < 0.01). 102 patients receiving adjuvant FOLFOX-4 chemotherapy who co-expressed IGF-1R/MRP-1 had poor prognosis (p < 0.05). Conclusions: The levels of co-expression of IGF-1R/MRP-1 in GC may predict the therapeutic effect of chemotherapy and prognosis of GC.

A clinicopathological study on the expression of cadherin-17 and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma.

AIMS To analyse the clinicopathological characteristics of the expression of cadherin-17 (CDH17) and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma, and to evaluate the clinical significance of these two markers in the histological classification and prognosis of gastric carcinoma. MATERIALS AND METHODS CDH17, CDX2 protein expression in paraffin-embedded specimens gathered from 166 patients with gastric carcinoma were detected by immunohistochemistry. The association of CDH17, CDX2 protein expression with the clinicopathological characteristics, and with the prognosis of gastric carcinoma were subsequently assessed. RESULTS CDH17, nucleus and cytoplasm CDX2 expression were positively expressed in 101/166 (60.8%), 59/166 (35.5%) and 57/166 (34.3%) gastric carcinoma patients, respectively. The expression of both CDH17 and CDX2 is associated with the intestinal-type gastric carcinoma (P<0.01). Positive expression of CDH17 was significantly associated with the depth of gastric wall invasion (P=0.04), lymph node metastasis (P<0.01) and stages of gastric carcinoma (P=0.01). Positive expression of CDX2 in the nucleus was mainly found in male patients (P=0.02), in early stage (P=0.01) and medullary-type gastric carcinoma (P=0.02). There was a negative association between nuclear CDX2 expression and lymph node metastasis of gastric carcinoma (P<0.01). The combined expression of CDH17 and CDX2 was significantly lower in diffuse-type carcinoma than intestinal- or mixed-type carcinoma (P<0.01 and P=0.01, respectively). The patients with CDH17 expression associated with poor prognosis of gastric carcinoma (P<0.01), as opposed to patients with CDX2 expression (P<0.01). The survival rate of patients with CDH17+/CDX2- expression was the lowest (P<0.01), and conjoined expressions of CDH17+/CDX2- and CDH17+/CDX2+ were independent prognostic indicators of gastric carcinoma (both P<0.01). CONCLUSION The results suggest that the expression of CDH17 or CDX2 may be an important feature of gastric carcinoma. A combined detection of CDH17/CDX2 co-expression may benefit us in predicting the prognosis of gastric carcinoma.

Gastric cancer pharmacogenetics: progress or old tripe?

Gastric cancer remains the second most frequent cause of cancer-related mortality. While surgery is traditionally the initial treatment for early-stage disease, the addition of chemotherapy has been shown to significantly increase overall survival and progression-free survival in advanced and metastatic stages of disease. However, despite the incorporation of newer chemotherapies and regimens into gastric cancer clinical trials, the response rate and median overall survival for treated patients has not significantly improved throughout the years; therefore, newer therapeutic approaches to improve upon the medication selection process are warranted. Treatment and dose selection based on patient factors, such as genetic variation, may provide a more rational and potentially more powerful means of personalizing chemotherapy. This review provides an update on the current status of pharmacogenetic studies regarding germline DNA mutations that may alter response to chemotherapeutic agents used to treat gastric cancer, including perspectives on clinical translation and future work.

Niemann-Pick disease resulting in spontaneous splenic rupture in an adult: Report of a case

Niemann-Pick disease (NPD) is an inherited metabolic disorder, which has been classified into types A, B, C, and D. Niemann-Pick disease rarely causes spontaneous splenic rupture: to our knowledge, only four such cases have ever been reported. We report the case of a 53-year-old man with NPD manifesting as spontaneous splenic rupture. Ultrasound showed a ruptured large spleen with hemoperitoneum, and he underwent emergency splenectomy. Histopathological examination confirmed that there were numerous accumulated “Pick cells,” defined as foamy histiocytes, in the spleen.

miR-302b inhibits tumorigenesis by targeting EphA2 via Wnt/ β-catenin/EMT signaling cascade in gastric cancer

BackgroundEphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, this study aims to identify microRNAs that target it and serve as key regulators of gastric carcinogenesis.MethodsWe identified several potential microRNAs targeting EphA2 by bioinformatics websites and then analyzed the role of miR-302b in modulating EphA2 in vitro and in vivo of GC, and it’s mechanism.ResultsOur analysis identified miR-302b, a novel regulator of EphA2, as one of the most significantly downregulated microRNA (miRNA) in GC tissues. Overexpression of miR-302b impaired GC cell migratory and invasive properties robustly and suppressed cell proliferation by arresting cells at G0–G1 phase in vitro. miR-302b exhibited anti-tumor activity by reversing EphA2 regulation, which relayed a signaling transduction cascade that attenuated the functions of N-cadherin, β-catenin, and Snail (markers of Wnt/β-catenin and epithelial-mesenchymal transition, EMT). This modulation of EphA2 also had distinct effects on cell proliferation and migration in GC in vivo.ConclusionsmiR-302b serves as a critical suppressor of GC cell tumorigenesis and metastasis by targeting the EphA2/Wnt/β-catenin/EMT pathway.