Xianzi Wen

Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) has been studied to be involved in the development and progression of several human malignancies. However, little is unveiled regarding the complex mechanisms of TNFRSF11B in human gastric cancer (GC). The clinical significance of TNFRSF11B was assessed in 70 and 160 GC tissues using immunohistochemistry method and gene microarray analysis, respectively. The biological function of TNFRSF11B was studied in vitro and in vivo assays. Immunofluorescence assay was used to evaluate the expression of β-catenin in the nucleus. The expression of β-catenin and related protein was determined by Western blot. The interaction between TNFRSF11B and GSK3β was detected by co-immunoprecipitation. We demonstrated that TNFRSF11B was highly expressed in the cytoplasm of GC and associated with the patient poor outcome. Our studies showed that TNFRSF11B in GC cells significantly promoted cell proliferation, migration, invasion in vitro and tumorigenic ability in vitro and in vivo. Meanwhile, TNFRSF11B inhibited GC cell apoptosis. The proportion of nuclear active β-catenin showed positively correlation with TNFRSF11B expression. TNFRSF11B directly combined with GSK-3β upregulating its phosphorylation, and increased expression of β-catenin and its downstream effectors. Collectively, these findings demonstrate that TNFRSF11B promote the aggressive phenotypes of GC cells and activated Wnt/β-catenin signaling. Accordingly, TNFRSF11B had potential as a biomarker and inhibition of TNFRSF11B expression might offer a new therapeutic target for GC patients.

Purpose: Emerging evidence has shown that long noncoding RNAs (lncRNAs) participate in oncogenesis and tumor progression. We previously found a novel lncRNA p4516 which was closely associated with prognosis by preliminary study of lncRNA expression profile from paired tumors and nontumor tissues in 198 gastric cancer (GC) patients. However, the exact biological functions and the underlying molecular mechanisms of p4516 in gastric tumorigenesis still remain unclear. Materials and methods: The RNA fluorescence in situ hybridization (RNA-FISH) analysis, cytoplasmic and nuclear RNA isolation and qRT-PCR were applied to determine the subcellular localization of p4516. Expression levels of p4516 were assessed using qRT-PCR in both GC cell lines and in 142 primary GC tissues. Correlations between p4516 expression and GC patients’ clinicopathological parameters were analyzed. Gain- and loss-of-function experiments were employed to investigate the role of p4516 in proliferation, migration and invasion both in vitro and in vivo. In addition, Western blotting and immunohistochemical staining were used to examine the protein expression levels. Results: LncRNA p4516 was mainly localized in the nucleus of GC cells and p4516 tended to have higher expression levels in GC cells compared to the normal gastric mucosa-derived cells GES-1. Furthermore, higher expression levels of p4516 correlated with worse clinical outcomes in GC patients and acted as an independent prognostic biomarker. Functional analysis revealed that p4516 participated in the regulation of GC cell proliferation, invasion and migration both in vivo and in vitro. Moreover, p4516 was involved in epithelial–mesenchymal transition (EMT) in GC cells. Conclusion: Our study demonstrated the oncogenic role of novel lncRNA p4516 in the gastric carcinogenesis for the first time. High expression of p4516 may act as prognostic marker in patient with gastric cancer.

Background: Glucose-6-phosphate isomerase (GPI) is a glycolytic-related enzyme that interconverts glucose-6-phosphate and fructose-6-phosphate in the cytoplasm. This protein is also secreted into the extracellular matrix by cancer cells and is, therefore, also called autocrine motility factor (AMF). Methods: To clarify the roles of AMF/GPI in gastric cancer (GC), we collected 335 GC tissues and the corresponding adjacent noncancerous tissues, performed immunohistochemical studies, and analyzed the relationship between AMF/GPI expression and the patients’ clinicopathologic features. Results: AMF/GPI expression was found to be significantly higher in the GC group than in the corresponding noncancerous tissue group (P Conclusion: These findings suggest that AMF/GPI overexpression is involved in carcinogenesis and promotes the aggressive phenotypes of GC cells.

Background We recently reported that miR-1 was one of the most significantly downregulated microRNAs in gastric cancer (GC) patients from The Cancer Genome Atlas microRNA sequencing data. Here we aim to elucidate the role of miR-1 in gastric carcinogenesis. Methods We measured miR-1 expression in human GC cell lines and 90 paired primary GC samples, and analyzed the association of its status with clinicopathological features. The effect of miR-1 on GC cells was evaluated by proliferation and migration assay. To identify the target genes of miR-1, bioinformatic analysis and protein array analysis were performed. Moreover, the regulation mechanism of miR-1 with regard to these predicted targets was investigated by quantitative PCR (qPCR), Western blot, ELISA, and endothelial cell tube formation. The putative binding site of miR-1 on target genes was assessed by a reporter assay. Results Expression of miR-1 was obviously decreased in GC cell lines and primary tissues. Patients with low miR-1 expression had significantly shorter overall survival compared with those with high miR-1 expression (P = 0.0027). Overexpression of miR-1 in GC cells inhibited proliferation, migration, and tube formation of endothelial cells by suppressing expression of vascular endothelial growth factor A (VEGF-A) and endothelin 1 (EDN1). Conversely, inhibition of miR-1 with use of antago-miR-1 caused an increase in expression of VEGF-A and EDN1 in nonmalignant GC cells or low-malignancy GC cells. Conclusions MiR-1 acts as a tumor suppressor by inhibiting angiogenesis-related growth factors in human gastric cancer. Downregulated miR-1 not only promotes cellular proliferation and migration of GC cells, but may activates proangiogenesis signaling and stimulates the proliferation and migration of endothelial cells, indicating the possibility of new strategies for GC therapy.

Lysosome-associated transmembrane-4 beta (LAPTM4B) is an oncogene that participates tumorgenesis in a variety of human solid tumors, and it has two alleles named as LAPTM4B*1 and *2. The present study aimed to identify the association of LAPTM4B genotype with clinicopathological features and prognosis in colorectal and esophageal cancer patients. Genotypes of LAPTM4B were determined by PCR in 167 colon cancer cases (72 patients in a discovery cohort and 95 patients in a testing cohort), 160 rectal cancer cases and 164 esophageal cancer cases. Association between the LAPTM4B gene polymorphism and clinicopathological variables was calculated by Chi-square test or Fisher’s exact test. Patient survival differences were calculated by the Kaplan-Meier method. Prognostic factors were determined with Log-rank test and Cox regression model. LAPTM4B *1/1 was more frequently detected in colon cancer patients with lymph node metastasis and TNM III+IV stages in total colon cancer (discovery + testing cohorts). LAPTM4B *2/2 decreased in recurrent patients in total colon cancer patients (P = 0.045). Kaplan-Meier survival curves and Log-rank test showed that LAPTM4B*1 was correlated with shorter overall survival (OS) in discovery and testing cohorts of colon cancer (P = 0.0254 and 0.0292, respectively), but not in rectal and esophageal cancer cases (P = 0.7669 and 0.9356, respectively). Multivariate analysis showed that LAPTM4B genotype was an independent prognostic factor for OS in total colon cancer [P = 0.004, hazard ratio (HR) = 0.432; 95% confidence interval (CI) = 0.243–0.768], but not in rectal and esophageal cancers (P = 0.791, HR = 1.073, 95% CI = 0.638–1.804 and 0.998, HR = 1.000, 95% CI = 0.663–1.530, respectively). These findings suggested that LAPTM4B allele *1 was a risk factor associated with poor prognosis in patients with colon cancer, but not in patients with rectal or esophageal cancers. LAPTM4B genotype status might be a useful prognostic indicator for patients that need surgical operation in colon cancer.

Background: Various human epithelial origin cancers produce cytoplasmic immunoglobulin (Ig) G. Recent studies have elucidated that it was related with the tumorigenesis. This study was aimed to identify relationship between the cancer cell-derived IgG expression level and clinical parameters in gastric cancer (GC). Methods: Cancer cell-derived IgG expression was assessed using immunohistochemistry analysis in 231 primary GC tissues. The role of cancer cell-derived IgG on cell proliferation, migration and invasion were assessed. Results: Our results indicated that IgG was overexpressed in GC tissues (42.2%, 46/109) than in adjacent tissues (11.0%, 12/109, Pvs. 37.2%, respectively). Upon univariate analysis, IgG positive group had significantly lower 5-year overall survival than the negative group (P=0.0361). Multivariate analysis showed IgG expression was an independent prognostic indicator for 5-year overall survival of patients with GC (P=0.018). Furthermore, knockdown of IgG by short interfering RNA (siRNA) resulted in reducing proliferation, migration and invasion of GC cell. Conclusions: Our results showed that cancer cell-derived IgG overexpression might be correlated with GC progression, and would be a novel biomarker to predict the prognosis of patients with GC.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal apoptosis inducer and believed to have promise in cancer therapy, yet part of cancer cells exhibit resistance to TRAIL-mediated apoptosis. This necessitates the exploration of agents that resensitizes cancer cells to TRAIL. In our study, we found that Trichostatin A (TSA), an histone deacetylase (HDAC) inhibitor, augmented TRAIL-induced apoptosis in gastric cancer cells in a caspase-dependent manner. Besides, upregulation of DR5 and downregulation of anti-apoptotic proteins including XIAP, Mcl-1, Bcl-2 and Survivin also contributed to this synergism. Noticeably, TSA treatment inhibited Forkhead boxM1 (FOXM1), which expression level showed negative correlation with TRAIL sensitivity. Similarly, silencing of FOXM1 by small interfering RNA (siRNA) resensitized cancer cells to TRAIL and strengthened the TRAIL-augmenting effect of TSA. In addition, we demonstrated the depletion of FOXM1 was a consequence of the inactivation of ERK mediated by TSA. Collectively, it was first shown that TSA potentiated TRAIL sensitivity via ERK/FOXM1 pathway in gastric cancer cells. FOXM1 might serve as a biomarker for predicting sensitivity to TRAIL.

Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer