Association between IL-1B gene polymorphisms and Helicobacter pylori infection: A meta-analysis.

BACKGROUND: To clarify the impact of IL-1B gene polymorphisms (IL-1B-511C/T, IL-1B-31C/T, IL-1B+3954C/T) in Helicobacter pylori (H. pylori) infection by mean of a meta-analysis. METHODS: The relevant studies were retrieved from PubMed, Web of Science, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases until September 9, 2018. Odds ratio (OR) and its 95% confidence intervals (CIs) were used to assess the associations. Statistical analyses of this meta-analysis were conducted by using STATA 12 software. RESULTS: Totally, 45 articles including 9606 cases and 5654 controls were enrolled in this meta-analysis. Our results indicated that IL-1B-511C/T polymorphism was significantly related to an increased the risk of H. pylori infection under recessive model (OR = 1.13, 95% CI: 1.00-1.27, P = 0.048). However, no significant associations were obtained between H. pylori infection and IL-1B-31C/T as well as IL-1B+3954C/T polymorphisms under all models. In addition, subgroup analyses were also performed by country, study design, and detection methods of H. pylori. CONCLUSIONS: This meta-analysis suggested that IL-1B-511C/T polymorphism was related to the risk of H. pylori infection. Further larger studies with high quality are needed to conform these findings.

Expression and clinical significance of retinoid X receptor α in esophageal carcinoma.

PURPOSE: Esophageal carcinoma (EC) is one of the most aggressive type cancers and dysregulation of retinoid X receptor α (RXRα) involves various tumors. However, the relationship of RXRα with the clinicopathological factors of EC, particularly prognostic characteristics, remains unclear. This present study was to evaluate the effect of RXRα expression in the development of EC. METHODS: The mRNA and protein expression level of RXRα in EC and normal esophageal tissues using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, respectively. The subcellular localization was detected by immunohistochemistry (IHC) analysis. The clinicopathological parameters were included age, sex, tumor size, differentiation, TNM stages and lymph node metastasis. Kaplan-Meier method and Cox's regression analyses were performed to evaluate the prognosis of 60 patients with EC. RESULTS: RXRα was elevated in EC tissues comparing with normal esophageal tissues at both mRNA and protein levels. The overexpression level of RXRα was closely associated to the tumor differentiation, TNM stage and lymph node metastasis of patients with EC. In addition, EC patients with RXRα high expression had significantly lower disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed RXRα expression as an independent predictor for the DFS and OS rate of patients with EC. CONCLUSIONS: Our results showed that overexpression of RXRα was correlated with unfavorable prognosis, suggesting that RXRα may serve as a potential targeted therapeutic marker in the treatment of EC.

Efficient isolation and proteomic analysis of cell plasma membrane proteins in gastric cancer reveal a novel differentiation and progression related cell surface marker, R-cadherin.

Cell plasma membrane proteins, playing a crucial role in cell malignant transformation and development, were the main targets of tumor detection and therapy. In this study, CyDye/biotin double-labeling proteomic approach was adopted to profile the membrane proteome of gastric cancer cell line BGC-823 and paired immortalized gastric epithelial cell GES-1. Real-time PCR, Western blotting, and immunohistochemical staining were used to validate the differential expression of a novel identified cell surface marker R-cadherin in gastric cancer cells and tissues. Clinicopathological study and survival analysis were performed to estimate its roles in tumor progression and outcome prediction. Real-time PCR and Western blotting showed that the expression level of R-cadherin in gastric cancer were significantly lower than non-cancerous epithelial cell and tissues. Clinicopathological study indicated that R-cadherin was dominantly expressed on cell surface of normal gastric epithelium, and its expression deletion in gastric cancer tissues was associated with tumor site, differentiation, lymph node metastasis, and pTNM (chi-square test, P < 0.05). Those patients with R-cadherin positive expression displayed better overall survivals than negative expression group (log-rank test, P = 0.000). Cox multivariate survival analysis revealed lacking the expression of R-cadherin was a main independent predictor for poor clinical outcome in gastric cancer (RR = 5.680, 95 % CI 2.250-14.341, P < 0.01). We have established a fundamental membrane proteome database for gastric cancer and identified R-cadherin as a tumor differentiation and progression-related cell surface marker of gastric cancer. Lacking the expression of R-cadherin indicates poor prognosis in patients with gastric cancer.

Retinoid X receptor α enhances human cholangiocarcinoma growth through simultaneous activation of Wnt/ß-catenin and nuclear factor-κB pathways.

Retinoid X receptor α (RXRα) plays important roles in the malignancy of several cancers such as human prostate tumor, breast cancer, and thyroid tumor. However, its exact functions and molecular mechanisms in cholangiocarcinoma (CCA), a chemoresistant carcinoma with poor prognosis, remain unclear. In this study we found that RXRα was frequently overexpressed in human CCA tissues and CCA cell lines. Downregulation of RXRα led to decreased expression of mitosis-promoting factors including cyclin D1and cyclin E, and the proliferating cell nuclear antigen, as well as increased expression of cell cycle inhibitor p21, resulting in inhibition of CCA cell proliferation. Furthermore, RXRα knockdown attenuated the expression of cyclin D1 through suppression of Wnt/ß-catenin signaling. Retinoid X receptor α upregulated proliferating cell nuclear antigen expression through nuclear factor-κB (NF-κB) pathways, paralleled with downregulation of p21. Thus, the Wnt/ß-catenin and NF-κB pathways account for the inhibition of CCA cell growth induced by RXRα downregulation. Retinoid X receptor α plays an important role in proliferation of CCA through simultaneous activation of Wnt/ß-catenin and NF-κB pathways, indicating that RXRα might serve as a potential molecular target for CCA treatment.

Correlation Between Tumor Vasculogenic Mimicry and Poor Prognosis of Human Digestive Cancer Patients: A Systematic Review and Meta-Analysis.

Vasculogenic mimicry (VM) is a new pattern of blood supplement independent of endothelial vessels, which is related with tumor invasion, metastasis and prognosis. However, the role of VM in the prognosis of cancer patients is controversial. This study aimed to perform a meta-analysis of the published data to attempt to clarify the prognostic value of VM in the digestive cancer. Relevant studies were retrieved from the PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure and VIP databases published before March 29, 2018. Studies were included if they detected VM in the digestive cancer and analyzed the overall survival (OS) or disease-free survival (DFS) according to VM status. Two independent reviewers screened the studies, extracted data, and evaluated the quality of included studies with the Newcastle-Ottawa scale. Meta-analysis was performed using STATA 12.0 software. A total of 22 studies with 2411 patients were included in this meta-analysis. Meta-analysis showed that VM was related with the poor OS (HR = 2.30, 95% CI: 2.06-2.56, P < 0.001) and DFS (HR = 2.60, 95% CI: 2.07-3.27, P < 0.001) of patients with digestive cancer. Subgroup analysis showed VM was related with tumor differentiation, lymph node metastasis and TNM stage. Moreover, the present meta-analysis was reliable, and there was no obvious publication bias. This meta-analysis suggested that VM was a poor prognosis of digestive cancer patients. Further large and well-designed studies are required.

Oncogenic activity of insulin in the development of non-small cell lung carcinoma.

Insulin is associated with the progression of numerous different types of cancer. However, the association between insulin and non-small cell lung carcinoma (NSCLC) remains unknown. The aim of the present study was to evaluate the role of insulin in the proliferation, migration and drug resistance of NSCLC cells, and to determine whether the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway was involved. NSCLC cells were treated with insulin in the absence or presence of LY294002, an inhibitor of the PI3K/Akt pathway. Following co-incubation with insulin, cell proliferation and drug resistance were measured by MTT; cell migration was examined by wound healing and Transwell assays; and the expression of cyclin A, proliferating cell nuclear antigen (PCNA), p27, matrix metalloproteinase 3 (MMP3), P-gp and proteins involved in the PI3K/Akt pathway were assessed via western blotting. The results of the current study demonstrated that insulin enhanced the proliferation, migration and drug resistance of NSCLC cells. Correspondingly, insulin upregulated the expression of cyclin A, PCNA, MMP3, P-gp and downregulated p27 expression in NSCLC cells. Following treatment with insulin, it was demonstrated that phospho-Akt expression increased in a dose-dependent manner. However, the effects of insulin on NSCLC cells was inhibited by the PI3K/Akt pathway inhibitor LY294002. Therefore, the results of the current study indicate that insulin is associated with the development of NSCLC by activating the PI3K/Akt pathway. This may improve understanding of the mechanism of action of insulin in NSCLC in the future.

Magnolol suppresses the proliferation and invasion of cholangiocarcinoma cells via inhibiting the NF-κB signaling pathway.

BACKGROUND: Magnolol has shown the potential anticancer properties against a variety of cancers. However, the role of magnolol in cholangiocarcinoma (CCA) cells is unknown. In this study, we assessed the effect of magnolol on the CCA cells. METHODS: CCA cells were treated with magnolol in the absence or presence of TNFα, the activator for NF-κB. After co-incubation with magnolol, cell proliferation and growth were examined by MTT, colony formation and xenograft tumors; cell cycle was analyzed by flow cytometry; cell migration and invasion were detected by wound healing and transwell assays; the expression of PCNA, Ki67, CyclinD1, MMP-2, MMP-7 and MMP-9 and NF-κB pathway were evaluated by using Western blot. RESULTS: Magnolol inhibited the abilities of CCA cell growth, migration and invasion accompanying with a decreased expression of PCNA, Ki67, MMP-2, MMP-7 and MMP-9 (all P<0.05). TREATMENT: with magnolol induced cell cycle arrest in G1 phase with a downregulation of cell cycle protein CyclinD1 (all P<0.05). In addition, magnolol suppressed the expression of p-IκBα and p-P65 and the effect of magnolol on CCA cells could be inhibited by TNFα. CONCLUSIONS: Magnolol could inhibit the growth, migration and invasion of CCA cells through regulation of NF-κB pathway, and these data indicate that magnolol is a potential candidate for treating of CCA.

Oncogenic retinoic acid receptor α promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3ß/ß-catenin signaling.

Retinoic acid receptor α (RARα) plays important roles in the progression of several cancers such as leukemia, breast cancer, and lung cancer. In this study, we demonstrated that RARα protein was frequently overexpressed in human CRC specimens and CRC cell lines. RARα knockdown decreased cell survival, proliferation, and colony formation in vitro and tumorigenic potential in nude mice. Specifically, RARα knockdown inhibited cell cycle progression at G1 phase through upregulation of cell cycle inhibitor p21, and downregulation of cyclinD1. Furthermore, RARα was directly recruited to the p21 promoter to inhibit the expression of p21. Simultaneously, RARα contributed to the progression of CRC cells in part due to upregulation of cyclinD1 via activation of GSK3ß/ß-catenin pathway. Molecular mechanism studies revealed RARα interacted with GSK3ß and led to decreased expression of GSK3ß at ser9, followed by increased ß-catenin expression. Taken together, our results signified the importance of RARα in CRC and demonstrated that RARα promotes CRC progression through suppressing p21 transcription and enhancing GSK3ß/ß-catenin signaling. RARα might become a potential molecular target for the treatment of CRC.

Positive feedback loop of IL-1ß/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RARα overexpression was related with pathological differentiation. Functionally, RARα knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RARα knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RARα in GC were closely associated with Akt signaling activation. Moreover, overexpression of RARα was induced by IL-1ß/Akt signaling activation, which suggested a positive feedback loop of IL-1ß/Akt/RARα/Akt signaling in GC. Taken together, we demonstrated that RARα was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.

Upregulation of retinoic acid receptor-ß reverses drug resistance in cholangiocarcinoma cells by enhancing susceptibility to apoptosis.

Retinoic acid receptor ß (RARß), a known tumor suppressor gene, is frequently silenced in numerous malignant types of tumor. Recent reports have demonstrated that loss of RARß expression may be responsible, in part, for the drug resistance observed in clinical trials. However, little is known about the role of RARß in regulating drug sensitivity in patients with cholangiocarcinoma (CCA) with a high risk of mortality and poor outcomes. In the present study, low RARß expression was observed in the majority of CCA tissues investigated (28/33, 84.8%). In addition, the CCA cell line QBC939, which exhibits low RARß expression, was found to be significantly resistant to chemotherapeutic agents compared with SK­ChA­1, MZ­ChA­1 and Hccc9810 CCA cell lines, which exhibit high RARß expression. Furthermore, upregulation of RARß significantly enhanced the sensitivity of QBC939 cells to common chemotherapeutic agents both in vitro and in vivo. Upregulation of RARß was shown to increase the expression of proapoptotic genes bax, bak and bim, in addition to caspase­3 activity, and decrease the expression of antiapoptotic genes bcl­2, bcl­xL and mcl­1. As a result, CCA cells were more susceptible to caspase­dependent apoptosis. Taken together, these data suggest that RARß upregulation rendered CCA cells more sensitive to chemotherapeutic agents by increasing the susceptibility of cells to caspase-dependent apoptosis. These results support the hypothesis that RARß may be an ideal chemosensitization target for the treatment of patients with drug-resistant CCA.

IL-1ß induced RXRα overexpression through activation of NF-κB signaling in gastric carcinoma.

BACKGROUND: Abnormal expression of Retinoid X Receptor α (RXRα) seems to be a frequent incident in a variety of cancers. However, the expression pattern and the mechanisms in gastric carcinoma (GC) remain unclear. METHODS: In GC tissues and cell lines, the expression levels of RXRα mRNA and protein were detected by Q-PCR and Western blot, respectively; the localization of RXRα was evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC). The effect of IL-1ß on RXRα expression and localization was detected by Western blot and ICC. Nuclear factor-κB (NF-κB) pathway was assessed via Western blot. RESULTS: RXRα expression was markedly elevated at both mRNA and protein levels in GC tissues and cell lines (all P<0.05). The abnormal overexpression of RXRα was predominantly visualized in cytoplasm. IL-1ß significantly induced cytoplasmic expression of RXRα in a time-dependent manner. Co-incubation with IL-1ß enhanced phospho-IKKα (p-IKKα) expression and this effect could be inhibited by the specific inhibitor for NF-κB (all P<0.01). CONCLUSIONS: IL-1ß upregulated RXRα through activation of NF-κB signaling and these suggested a possible clinic significance of retinoid receptor expression in the diagnosis and treatment of GC.

Use of CEA and CA15-3 to Predict Axillary Lymph Node Metastasis in Patients with Breast Cancer.

PURPOSE: The clinical significance of preoperative serum levels of carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) in breast cancer is controversial. The purpose of this study was to assess the clinical value of preoperative serum levels of CEA and CA 15-3 on the risk of axillary lymph node metastasis (ALNM) in patients with breast cancer. METHODS: This retrospective study analyzed 1148 breast cancer patients whose preoperative CEA and CA 15-3 levels were measured. The association of these tumor markers and clinicopathologic parameters with ALNM was determined by univariate and multivariate analysis. RESULTS: A median of 15 lymph nodes were removed. Seven hundred seventy-eight (67.8%) patients had node-negative disease and 370 (32.2%) had ALNM. Univariate analysis showed that tumor location (P = 0.024), stage (P = 0.001), grade (P < 0.001), lymphovascular invasion (LVI) (P < 0.001), CEA level (P < 0.001), CA15-3 level (P < 0.001), and breast cancer subtype (BCS) (P < 0.001) were significantly associated with ALNM. ALNM was present in 4.5% of patients with normal CEA and 11.6% of patients with elevated CEA. ALNM was present in 8.0% of patients with normal CA15-3 and 17.0% of patients with high CA15-3. Multivariate logistic regression analysis showed that tumor location, stage, grade, LVI, CEA, CA15-3, and BCS were significantly and independently associated with ALNM (P < 0.05 for all). CONCLUSION: The probability of ALNM was greater in patients with elevated preoperative serum levels of CEA and CA15-3. CEA and CA15-3 appear to be independent predictors of ALNM in breast cancer.

ß-escin reverses multidrug resistance through inhibition of the GSK3ß/ß-catenin pathway in cholangiocarcinoma.

AIM: To develop a safe and effective agent for cholangiocarcinoma (CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of ß-escin in combination with chemotherapy on CCA cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of ß-escin and common chemotherapeutics on the proliferation of human CCA cells (QBC939, Sk-ChA-1, and MZ-ChA-1). Immunocytochemistry was used to detect the expression of P-glycoprotein (P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/ß-catenin pathway. The protein levels of P-gp, pS9-GSK3ß, pT216-GSK3ß, GSK3ß, ß-catenin, and p-ß-catenin were further confirmed by western blotting. RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil (5-FU) cells to 5-FU, vincristine sulfate (VCR), or mitomycin C was significantly enhanced by ß-escin compared with either agent alone (P<0.05). In addition, the combination of ß-escin (20 µmol/L) with 5-FU and VCR was synergic with a combination index<1. Further investigation found that the mRNA and protein expression of P-gp was down-regulated by ß-escin. Moreover, ß-escin induced GSK3ß phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of ß-catenin. Interestingly, activation of the GSK3ß/ß-catenin pathway induced by Wnt3a resulted in up-regulation of P-gp, which was effectively abolished by ß-escin, indicating that ß-escin down-regulated P-gp expression in a GSK3ß-dependent manner. CONCLUSION: ß-escin was a potent reverser of P-gp-dependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3ß/ß-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.