Prognostic significance of artemin in gastric cancer and its role in tumorigenesis.

BACKGROUND: Abundant evidence suggests that a neurotrophic factor, artemin (ARTN), is involved in the tumorigenesis and progression in several malignancies. However, the biological functions of ARTN in gastric cancer (GC) remain poorly elucidated. METHODS: ARTN expression was evaluated by immunohistochemistry in GC tissue, and its clinical and prognosis significance was analyzed. Cell counting kit-8 (CCK-8), transwell chamber assay, and western blot were used to detect the effects of ARTN knockdown on GC cell behavior in vitro. RESULTS: ARTN was highly expressed in GC tissue, and its positive expression predicted poor prognosis of GC. In vitro studies showed that ARTN knockdown inhibited the STAT3 phosphorylation, thus impeding cell proliferation and DNA synthesis in GC. Furthermore, the promotion of ARTN on the migration and invasion of GC cells was achieved by regulating the expression of MMP9 and E-cadherin. CONCLUSIONS: ARTN might be a promising prognostic marker and a potential therapeutic target for GC.

Neurofibromatosis type-1 is a prognostic indicator in human gastric carcinoma.

We investigated whether the Neurofibromatosis type-1(NF1) gene was of prognostic relevance to gastric cancer (GC) patients. Immunohistochemical staining of 160 matched GC tumor and adjacent normal tissue samples showed that 58.1% (93/160) of GC samples were NF1-positive as compared to 94.4% (151/160) of normal tissue samples (χ2=58.05, P <0.001). qRT-PCR analysis revealed that NF1 mRNA expression is lower in GC tissues than normal tissues (χ2=34.23, P <0.001). Moreover, NF1 protein and mRNA levels were associated with T stage (P <0.05) and TNM (P <0.001). No association was observed with other clinicopathological parameters, including gender, age, tumor size, lymph-node metastasis, cancer differentiation and distant metastasis (all P >0.05). Kaplan-Meier analysis revealed that negative or low NF1 were associated with poor overall survival (OS) in gastric cancer patients (P<0.001). Further univariate and multivariate cox regression analysis also showed that NF1 expression was an independent risk factor of survival of GC patients. These data show that NF1 has prognostic relevance to clinical outcomes in gastric cancer patients.

Association between the expression levels of tumor necrosis factor-α-induced protein 8 and the prognosis of patients with gastric adenocarcinoma.

The present study aimed to investigate the expression levels of tumor necrosis factor-α-induced protein 8 (TNFAIP8) in gastric adenocarcinoma. TNFAIP8 expression levels in gastric adenocarcinoma tissue samples (with and without lymph node metastasis), adjacent normal tissue samples and metastatic lymph node tissue samples were detected by immunohistochemistry. The correlation between TNFAIP8 expression levels and clinicopathological data and gastric adenocarcinoma prognosis was analyzed. The results demonstrated that TNFAIP8 expression in gastric adenocarcinoma tissue samples and metastatic lymph node tissue samples markedly increased at a rate of 47.2% (50/106) and 81.7% (49/60), respectively, as compared with the adjacent normal tissue samples in which no TNGFAIP8 expression was detected (0%). This increase in TNFAIP8 expression was statistically significant. TNFAIP8 expression rates in the primary tumors (60%, 36/60) of patients with lymph node metastasis were significantly higher compared with the primary tumors of patients without lymph node metastasis (30.4%, 14/46). TNFAIP8 expression was associated with an increase in the severity of TNM stage, tumor grade, vascular invasion, lymph node metastasis and serum CA72-4 levels. The overall survival rate of patients with gastric adenocarcinoma and high TNFAIP8 expression was poorer compared with patients with low TNFAIP8 expression, and TNFAIP8 expression was negatively correlated with patient prognosis. The results also demonstrated that TNFAIP8 was an independent prognostic marker in gastric adenocarcinoma (relative risk, 1.736; P=0.029). In conclusion, the results of the present study demonstrated that TNFAIP8 expression was associated with the occurrence, development and metastasis of gastric adenocarcinoma, and negatively correlated with the prognosis of patients with gastric adenocarcinoma. TNFAIP8 may therefore serve as a prognostic factor for gastric adenocarcinoma.

Effect and prognostic significance of the KAI1 gene in human gastric carcinoma.

The present study aimed to explore the effect and mechanism of the Kangai 1 (KAI1) gene in regulating the migration and invasion of gastric carcinoma cells, and the prognostic significance of this gene in gastric cancer patients. Immunohistochemistry and in situ hybridization were used to investigate the role of KAI1 in the progression and prognosis of gastric cancer. The pEGFP-N1-KAI1 plasmid was transfected into human gastric carcinoma SGC7901 cells using liposomes. The effect of transfection with the KAI1 gene was measured using a reverse transcription-semi-quantitative polymerase chain reaction (RT-sqPCR) assay. The Transwell chamber assay was used to study the metastatic and invasive ability of SGC7901 cells. Gastric cancer metastasis-associated genes, including hypoxia-inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2, MMP-9, basic fibroblast growth factor (bFGF), and urease plasminogen activator (uPA) were measured by RT-sqPCR prior to and following transfection with the KAI1 gene. The expression of KAI1 protein and mRNA was associated with the differentiation degree of gastric cancer, presence of lymph node metastasis, tumor-node-metastasis stage, depth of invasion and the survival time of patients. The migratory and invasive abilities of SGC7901 cells were significantly decreased subsequent to transfection with the KAI1 gene, and the expression of bFGF and uPA was downregulated. It was concluded that the tumor suppressor gene KAI1 inhibits the migration and invasion of gastric carcinoma cells, possibly by suppressing the expression of uPA. Patients that expressed KAI1 may demonstrate an improved prognosis.

Outcomes for jejunal interposition reconstruction compared with Roux-en-Y anastomosis: A meta-analysis.

AIM: To compare the clinical outcomes between jejunal interposition reconstruction and Roux-en-Y anastomosis after total gastrostomy in patients with gastric cancer. METHODS: A systematic literature search was conducted by two independent researchers on PubMed, EMBASE, the Cochrane Library, Google Scholar, and other English literature databases, as well as the Chinese Academic Journal, Chinese Biomedical Literature Database, and other Chinese literature databases using "Gastrostomy", "Roux-en-Y", and "Interposition" as keywords. Data extraction and verification were performed on the literature included in this study. RevMan 5.2 software was used for data processing. A fixed-effects model was applied in the absence of heterogeneity between studies. A random effects model was applied in the presence of heterogeneity between studies. RESULTS: Ten studies with a total of 762 gastric cancer patients who underwent total gastrostomy were included in this study. Among them, 357 received jejunal interposition reconstruction after total gastrostomy, and 405 received Roux-en-Y anastomosis. Compared with Roux-en-Y anastomosis, jejunal interposition reconstruction significantly decreased the incidence of dumping syndrome (OR = 0.18, 95%CI: 0.10-0.31; P < 0.001), increased the prognostic nutritional index [weighted mean difference (WMD) = 6.02, 95%CI: 1.82-10.22; P < 0.001], and improved the degree of postoperative weight loss [WMD = 2.47, 95%CI: -3.19-(-1.75); P < 0.001]. However, there is no statistically significant difference in operative time, hospital stay, or incidence of reflux esophagitis. CONCLUSION: Compared with Roux-en-Y anastomosis, patients who underwent jejunal interposition reconstruction after total gastrostomy had a lower risk of postoperative long-term complications and improved life quality.

CD40 expression and its prognostic significance in human gastric carcinoma.

This study aimed to detect the relationship between CD40 (protein and mRNA) expression and human gastric cancer and to determine the prognostic significance of CD40 in gastric cancer patients. We collected 128 cases of gastric cancer specimens, and the expression of CD40 (protein and mRNA) was measured by immunohistochemistry and in situ hybridization. Our study indicated that CD40 is constitutively expressed in human gastric carcinoma tissues. Positive expression of CD40 (protein and mRNA) in gastric cancer tissues was closely related to the tumor TNM stage and the presence of distant metastasis, with CD40 mRNA also being correlated with the presence of lymphatic metastasis. Furthermore, the expression of CD40 (protein and mRNA) is closely related to the prognosis of gastric cancer patients. The expression of CD40 protein and mRNA is positively correlated with the presence of distant (for both protein and mRNA) and lymphatic (for mRNA only) metastasis, and an increased tumor TNM stage in gastric carcinoma. Patients who express low levels of CD40 may have a better prognosis than those who have higher levels of CD40.

CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma.

Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in tumor progression. Epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. This study aimed to investigate the roles and underlying mechanisms of SDF-1/CXCR4 axis in EMT process of glioblastoma. In the present study, CXCR4 activation and inhibition in U87 were induced with exogenous SDF-1 and with CXCR4 small interfering RNA (siRNA), respectively. CXCR4 downstream signal molecules AKT, ERK, and EMT biomarkers (vementin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. Our results showed that SDF-1 can induce AKT and ERK phosphorylation in a dose-dependent manner, and endogenous CXCR4 can be blocked thoroughly by CXCR4 siRNA in U87. Notably SDF-1 alone treatment can induce the upregulation of vementin, snail, and N-cadherin of U87; besides, the downregulation of E-cadherin also occurred. On the contrary, CXCR4 siRNA significantly prohibited SDF-1-induced AKT and ERK phosphorylation, at the same time, EMT biomarker changes were not observed. Function analysis revealed that CXCR4 siRNA obviously interfered with U87 cell migration and proliferation, according to wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the SDF-1/CXCR4 axis in glioblastoma, and then involved in the tumor cell invasion and proliferation via activation of PI3K/AKT and ERK pathway. Our study lays a new foundation for the treatment of glioblastoma through antagonizing CXCR4.

The correlation of bone morphogenetic protein 2 with poor prognosis in glioma patients.

Glioma is the most common type of human intracranial cancers and has poor prognosis. Bone morphogenetic protein 2 (BMP2) plays important roles in cancer cell signalings (Vecht et al. Oncologist 19:751-9, 2014). Here, we aimed to investigate the correlation of BMP2 with patient prognosis as well as pathological indicators. Immunohistochemistry was used to test BMP2 proteins in 45 gliomas of distinct malignancy grade, and Kaplan-Meier survival analysis was performed to assess prognostic significance. BMP2 protein was also detected in cell lines by Western blot. We observed that BMP2 protein was stained in 44.4% (20 out of 45) of all glioma tissues, including 32.1% of low-grade (I + II) gliomas and 52.9% of high-grade (III + IV) gliomas. Grade IV gliomas potently expressed BMP2 proteins. Western blot showed BMP2 protein expressed in cell lines NHA, A172, T98G, U87, and U251. In addition, BMP2 expression was significantly associated with WHO grade (p = 0.024). According to log-rank test and Cox regression model, BMP2 can be suggested as an independent prognostic factor, apart from WHO grade. Taken together, BMP2 is differently highly expressed in different grades of gliomas and correlated to WHO grade. BMP2 also independently indicates poor prognosis in old glioma patients, which is indicative of an effectively therapeutic target.

Cell surface nucleolin is crucial in the activation of the CXCL12/CXCR4 signaling pathway.

Recently, CXCL12-CXCR4 has been focused on therapeutic strategies for papillary thyroid carcinoma (PTC) and other cancers. At the same time, cell surface nucleolin is also over-expressed in PTC and others. Interestingly, a few reports suggest that either CXCR4 or cell surface nucleolin is a co-receptor for HIV-1 entry into CD4+ T cells, which indicates that there is a relationship between CXCR4 and nucleolin. In this study, antibody and siRNA were used to identify effects of cell surface nucleolin and CXCR4 on cell signaling; soft-agar colony formation assay and Transwell assay were used to determine roles of nucleolin and CXCR4 in cell proliferation and migration. Importantly, co-immunoprecipitation was used to demonstrate the relationship between CXCR4 and nucleolin. Results showed CXCR4 and nucleolin were co-expressed in PTC cell line K1, B-CPAP, and TPC-1. Either cell surface nucleolin or CXCR4 was necessary to prompt extracellular signal-regulated kinase phosphorylation. When blocked, CXCR4 or nucleolin can significantly affect TPC-1 proliferation and migration (p < 0.01). Co-immunoprecipitation analysis identified that nucleolin can bind and interact with CXCR4 to activate CXCR4 signaling. This study suggests that nucleolin is crucial in the activation of CXCR4 signaling, which affects cell growth, migration, and invasiveness. Further, nucleolin may interact with other receptors. Our study also offers new ideas for cancer therapy.

miRNA-21 inhibition enhances RANTES and IP-10 release in MCF-7 via PIAS3 and STAT3 signalling and causes increased lymphocyte migration.

MicroRNAs (miRNAs) are a class of small endogenous gene regulators that have been implicated in various developmental and pathological processes. However, the precise identities and functions of miRNAs involved in antitumor immunity are not yet well understood. miRNA-21 is an oncogenic miRNA that can be detected in various tumours. In this study, we report that a miRNA-21 inhibitor enhances the release of chemoattractants RANTES and IP-10 in the MCF-7 breast cancer cell line and results in increased lymphocyte migration. Thus, miRNA-21 is a potential therapeutic target for cancer immunotherapy. We further demonstrated that PIAS3, a protein inhibitor of activated STAT3, is a target of miRNA-21 in MCF-7. Thus, miRNA-21 is a novel miRNA regulating immune cell recruitment, which acts at least in part via its inhibition of PIAS3 expression and oncogenic STAT3 signalling in tumour cells.

Circulating microRNA-21 as noninvasive predictive biomarker for response in cancer immunotherapy.

A pre-existing T cell-inflamed tumor microenvironment is predictive of clinical outcome to immunotherapy, but the mechanisms of immune effector cells infiltration of tumors are not clear. MicroRNAs are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level. Additionally, circulating miRNAs might be useful as noninvasive biomarkers of disease and therapy response. Previous studies indicate that STAT3 activity in tumor cells affects immune cells recruitment, which is prerequisite for effective T cell therapy. MiRNA-21 is one of the cell-free miRNAs that has recently been identified as a potential regulator of STAT3. Meanwhile, miRNA-21 is an oncogenic miRNA that could be detected in various tumors. Therefore, we get the hypotheses that circulating miRNA-21 is a potential predictive biomarker for response in cancer immunotherapy and so a novel therapeutic target.

[Topotecan in combination with cisplatin in the treatment of recurrent small cell lung cancer].

BACKGROUND: There is no effective regimen for recurrent small cell lung cancer patients now. The aim of this study is to assess the activity and toxicity of topotecan combined with cisplatin in the treatment of recurrent small cell lung cancer patients. METHODS: Twenty-eight patients with progressive disease after one first-line regimen enrolled in the study from May 2002 to October 2004. Topotecan was given at the dose of 1.2mg/m² from 1st to 4th days and cisplatin was administered at the dose of 25mg/m² from 5th to 7th days in a cycle of 3 weeks. The patients could be evaluated at least after 2 cycles. RESULTS: One patient got complete response and ten patients got partial response in this group. The overall response rate was 39.3% , and the response rate of refractory group and sensitive group was 37.5% (3/8) and 40.0% (8/20) respectively. The median time to progression was 4.2 months. The main toxicity was hematological toxicity. Grade III+IV neutropenia occurred in 42.9% (12/28) of the patients. CONCLUSIONS: The regimen of topotecan and cisplatin shows better activity in retreated small cell lung cancer patients. The main toxicity is hematological toxicity and can be tolerated.