Ziwen Long

Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer

Circular RNAs (circRNAs) comprise a novel class of widespread non-coding RNAs that may regulate gene expression in eukaryotes. However, the characterization and function of circRNAs in human cancer remain elusive. Here we identified at least 5500 distinct circRNA candidates and a series of circRNAs that are differentially expressed in gastric cancer (GC) tissues compared with matched normal tissues. We further characterized one circRNA derived from the PVT1 gene and termed it as circPVT1. The expression of circPVT1 is often upregulated in GC tissues due to the amplification of its genomic locus. circPVT1 may promote cell proliferation by acting as a sponge for members of the miR-125 family. The level of circPVT1 was observed as an independent prognostic marker for overall survival and disease-free survival of patients with GC. Our findings suggest that circPVT1 is a novel proliferative factor and prognostic marker in GC.

Clinicopathologic features and prognostic factors in alpha-fetoprotein- producing gastric cancers: Analysis of 104 cases

There were no comprehensive studies on the clinicopathologic features and prognosis of alpha‐protein‐producing gastric cancer. The aim of this study was to elucidate the clinicopathologic characteristics and prognostic factors of alpha‐fetoprotein (AFP)‐producing gastric cancer.

Analysis of Clinicopathologic Features and Prognostic Factors in Hepatoid Adenocarcinoma of the Stomach

ObjectiveTo investigate the different nature between hepatoid adenocarcinoma of the stomach (HAS) and common stomach cancer without the hepatoid differentiation areas (non-HAS). MethodsFrom January 1996 to December 2007, 45 patients were diagnosed as HAS on the basis of the characteristic histologic features resembling hepatocellular carcinoma in Fudan University Shanghai Cancer Center. The clinicopathologic features and the relevant prognosis of these patients were evaluated. In addition, 225 stage-matched common stomach cancer patients were selected as controls. ResultsHistologically, the polygonal tumor cells were arranged in trabecular fashion or solid nests separated by narrow fibrous stroma composed of sinusoid-like capillaries. Immunohistochemically, the tumor cells were positive for α-fetoprotein. Under transmission electron microscope, numerous circular granules of dense electron were found in the cytoplasm. HAS showed a higher rate of vascular invasion, lymph node metastasis, and liver metastasis than non-HAS. The 5-years survival rates of HAS and non-HAS were 9% and 44%, respectively. The prognosis of HAS was poorer than that of non-HAS (P<0.05). ConclusionHAS had different clinicopathologic features and prognosis from non-HAS.

The Prognostic Significance of Apoptosis-Related Biological Markers in Chinese Gastric Cancer Patients

Background and Objective The prognosis varied among the patients with the same stage, therefore there was a need for new prognostic and predictive factors. The aim of this study was to evaluate the relationship of apoptosis-related biological markers such as p53, bcl-2, bax, and c-myc, and clinicopathological features and their prognostic value. Methods From 1996 to 2007, 4426 patients had undergone curative D2 gastrectomy for gastric cancer at Fudan University Shanghai Cancer Center. Among 501 patients, the expression levels of p53, bcl-2, bax, and c-myc were examined by immunohistochemistry. The prognostic value of biological markers and the correlation between biological markers and other clinicopathological factors were investigated. Results There were 339 males and 162 females with a mean age of 57. The percentages of positive expression of p53, bcl-2, bax, and c-myc were 65%, 22%, 43%, and 58%, respectively. There was a strong correlation between p53, bax, and c-myc expression (P = 0.00). There was significant association between bcl-2, and bax expression (P<0.05). p53 expression correlated with histological grade (P = 0.01); bcl-2 expression with pathological stage (P = 0.00); bax expression with male (P = 0.02), histological grade (P = 0.01), Borrmann type (P = 0.01), tumor location (P = 0.00), lymph node metastasis (P = 0.03), and pathological stage (P = 0.03); c-myc expression with Borrmann type (P = 0.00). bcl-2 expression was related with good survival in univariate analysis (P = 0.01). Multivariate analysis showed that bcl-2 expression and pathological stage were defined as independent prognostic factors. There were significant differences of overall 5-year survival rates according to bcl-2 expression or not in stage IIB (P = 0.03). Conclusion The expression of bcl-2 was an independent prognostic factor for patients with gastric cancer; it might be a candidate for the gastric cancer staging system.

Clinicopathological Characteristics and Survival Outcomes of Primary Signet Ring Cell Carcinoma in the Stomach: Retrospective Analysis of Single Center Database.

Purpose To investigate the clinicopathological features and prognosis of signet ring cell carcinoma of the stomach (SRC). Methods A total of 1464 gastric cancer patients who underwent curative gastrectomy from 2000 to 2008 at a single center were evaluated. Signet ring cell carcinoma (SRC) was defined as the presence of at least 50% signet ring cells in the pathologic specimen. The clinicopathological parameters and prognosis of SRC were analyzed by comparing with non-signet ring cell carcinoma (NSRC). Results Of 1464 patients, 138 patients (9.4%) were classified as SRC. There were significant differences in gender, age, tumor location, TNM stage, p21 expression, and p53 expression between SRC and NSRC. The 5-year survival rates of SRC and NSRC were 36.2% and 49.5%, respectively. The prognosis of SRC was poorer than that of NSRC (P <0.001). Multivariate analysis showed that SRC histology was an independent factor for poor prognosis (P <0.001). Conclusion Patients with SRC tend to present with a more advanced stage and poorer prognosis than patients with other types of gastric carcinoma.

High expression of WISP1 in colon cancer is associated with apoptosis, invasion and poor prognosis

Colon cancer (CC) likes many epithelial-derived cancers, resulting from a complex tumorigenic process. However, the exactly mechanisms of development and progression of CC are still unknown. In this study, integrated analysis in the GSE33113 and Fudan University Shanghai Cancer Center Hospital datasets revealed that WISP1 expression was significantly increased in CC cases, positivity correlated with the advanced pathologic stage and a poor prognosis was more likely in CC patients with higher levels of WISP1. Downregulation of WISP1 inhibited cell proliferation and invasion through increasing apoptosis and blocking cell cycle at G1 phase in CC LOVO and RKO cells. Besides, Gene set enrichment analysis (GSEA) revealed that relative genes involved in the Cell adhesion molecules and Cytokine-cytokine receptor interaction pathways were enriched in WISP1-higher expression patients. Western blot analysis showed that Cell adhesion molecules pathway associated genes (ICAM- 1, VCAM-1, SDC2 and CDH2) and Cytokine-cytokine receptor interaction pathway associated genes (VEGFC, CCL18, CXCR4 and TGFBR1) were also modulated by WISP1 downregulation. Then, we found that the protein β-catenin was identified as a binding partner of WISP1 and mediated the functions of WISP1 through promoting cell proliferation and invasion in LOVO and RKO cells. Further in vivo tumor formation study in nude mice indicated that inhibition of WISP1 delayed the progress of tumor formation and inhibited PCNA expression. These results indicate that WISP1 could act as an oncogene and may serve as a promising therapeutic strategy for colon cancer.

Analysis of Lymph Node Metastasis Correlation with Prognosis in Patients with T2 Gastric Cancer

Purpose To investigate the correlated factors for lymph node metastasis and prognosis for patients with T2 gastric cancer. Methods A total of 442 patients with T2 gastric cancer who underwent gastrectomy from January 1996 to December 2009 were evaluated. The clinicopathological parameters were analyzed for lymph node metastasis and prognosis, including gender, age, tumor size, tumor location, histological type, depth of invasion, vascular tumor emboli, nervous invasion, resection type, and pathological stage. Results The rate of lymph node metastasis was 45.9%. Univariate analysis showed that depth of invasion, tumor size, and vascular tumor emboli were associated with lymph node metastasis. Logistic regression demonstrated that depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. The 5-year survival rate was 64.0%. Multivariate analysis showed that tumor size, tumor location, resection type, and pathological stage were independent prognostic factors. Based on tumor size, there were significant differences of 5-year survival between small size tumor (<6 cm) and large size tumor (≥6 cm) according to stage IIA (P = 0.006). Based on tumor location, there were significant differences of 5-year survival among different tumor location according to stage IB. Based on resection type, there were significant differences of overall 5-year survival between curative surgery and palliative surgery according to stage IIB (P = 0.015) and IIIA (P = 0.001). Conclusion Depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. Tumor size, tumor location, resection type, and pathological stage were independent prognostic factors.

Involvement of Bmi-1 gene in the development of gastrointestinal stromal tumor by regulating p16Ink4A/p14ARF gene expressions: An in vivo and in vitro study

OBJECTIVE This study was conducted in order to explore the role that Bmi-1 plays during the development of a gastrointestinal stromal tumor (GIST) by regulation of the p16Ink4A and p14ARF expressions. METHODS Eighty-six patients diagnosed with GIST were selected to take part in this experiment. The Bmi-1 protein expressions in GIST and adjacent normal tissues were detected using immunohistochemistry and further analyzed by using photodensitometry. To monitor and track the progression of the GIST, a 3-year follow-up was conducted for all affected patients. After cell transfection, the GIST cells were assigned into the control group (without transfection), the negative control (NC) group (transfected with Bmi-1-Scramble plasmid), and the Bmi-1 shRNA group (transfected with the pcDNA3.1-Bmi-1 shRNA plasmid). Protein and mRNA expressions collected from Bmi-1, p16lnk4A, P14ARF, cyclin D1, and CDK4 were measured using both the RT-qPCR and western blotting methods Cell senescence was assessed and obtained by using the β-Galactosidase (β-Gal) activity assay. The use of a Soft agar colony formation assay and CCK-8 assay were performed in order to detect the cell growth and subsequent proliferation. Cell invasion and migration were analyzed using the Transwell assay and scratch test. RESULTS Bmi-1 in the GIST tissues was found to be significantly higher and the p16lnk4A and P14ARF expressions were lower than those in the adjacent normal tissues. Bmi-1 was negatively correlated with p16lnk4A and P14ARF expressions according to the correlation analysis. Bmi-1 expression was associated with the TNM stage, postoperative recurrence, metastasis, tumor size, and the 5-year survival rate. Area under ROC curve was calculated at 0.884, and sensitivity, specificity, and accuracy of Bmi-1 predicting the GIST were 67.44%, 97.67%, and 65.12%, respectively. Patients exhibiting a high Bmi-1 expression in the GIST tissues had lower survival rates than those with low Bmi-1 expression. In comparison with the control group, P14ARF, and p16lnk4A were up-regulated, while cyclinD 1 and CDK4 were down-regulated, cell senescence was promoted, and cell proliferation, invasion, and migration also showed some regression in the Bmi-1 shRNA group. CONCLUSIONS These collection of data indicated that the down-regulated Bmi-1 might inhibit the proliferation, invasion, and migration of GIST cells and can be subsequently linked to the incidence and developing a prognosis of GIST.

Phase II trial of preoperative chemoradiation plus perioperative SOX chemotherapy in patients with locally advanced gastric cancer

The ideal treatment strategy of patients with locally advanced gastric adenocarcinoma is unclear. The aim of this study is to evaluate the efficacy and feasibility of preoperative chemoradiation in these patients.

MDM2 binding protein as a predictor of metastasis and a novel prognostic biomarker in patients with gastric cancer

MDM2 binding protein (MTBP) has been revealed to be involved in cancer progression and metastasis. However, the role and clinical implication of MTBP expression in gastric cancer (GC) remains poorly understood. The present study aimed to investigate the clinicopathological significance of MTBP and the prognostic determinant in GC. The expression level of MTBP was examined in cancerous and matched adjacent noncancerous gastric mucosa tissues by reverse transcription-quantitative polymerase chain reaction and western blotting. MTBP expression levels were evaluated by immunohistochemical analysis of tissue microarrays for 352 patients, and association between the expression levels and prognosis in patients with GC were investigated. Kaplan-Meier analysis and Coxs regression models were used to investigate the associations between MTBP expression and prognosis of GC patients. The results of the present study revealed decreased MTBP mRNA (P=0.005) and protein (P=0.001) expression levels in tumor tissue compared with in matched adjacent normal tissue mucosa. MTBP expression level in GC was associated with gender (P=0.026), lymph node metastasis (P<0.001), distant metastasis (P=0.026) and pathological tumor-node-metastasis stage (P<0.001). Kaplan-Meier survival analysis demonstrated that patients with high MTBP expression levels exhibited longer survival times compared with patients with low MTBP expression levels. The multivariate logistic regression analysis revealed that MTBP was independently associated with the presence of lymph node [OR, 0.282; 95% confidence interval (CI), 0.161–0.494; P<0.001] and distant metastasis (OR, 0.365; 95% CI, 0.138–0.965; P=0.042). Furthermore, the multivariate Cox analysis revealed that low MTBP expression level was significantly associated with longer overall survival time and was recognized as an independent prognostic factor of patients survival. MTBP expression level was significantly associated with progression and metastasis in GC, suggesting that MTBP may be used as a predictive marker for patient prognosis of GC.