Hongbo Wang

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro

Ceramide is a bioactive lipid which functions as a tumor suppressor, mediating processes such as apoptosis, growth arrest, senescence and differentiation. The effects of ceramide in ovarian cancers have not been well established. The objective of the present study was to investigate the effects of C2‑ceramide treatment in A2780 ovarian cancer cells and its possible molecular mechanism. C2‑ceramide-induced proliferation inhibition was analyzed using an MTT assay and Trypan blue test. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling were used to identify the induction of apoptosis. Transmission electron microscopy was used to confirm the formation of autophagosomes. Quantitative polymerase chain reaction was performed to analyze the messenger RNA expression of the autophagy and cell death associated genes and western blotting was used to analyze the protein expression of beclin 1, LC3, Akt, forkhead box O3 (FOXO3) and adenosine monophosphate-activated protein kinase in ovarian cancer cells. It was found that C2‑ceramide inhibited A2780 cell proliferation in a time‑ and dose‑dependent manner and C2‑ceremide induced A2780 cell apoptosis and autophagy. However, C2‑ceramide‑induced autophagy did not result in cell death, but instead protected ovarian cancer cells from apoptosis. Akt inhibition and FOXO3 activation were implicated in C2‑ceramide‑treated ovarian cancer cells. Furthermore, FOXO3 target genes, which were associated with autophagy (MAP1LC3, GABARAP and GABARAPL1) and cell death (BNIP3, BNIP3L, BIM and PUMA), were upregulated. The present study has shown that C2‑ceramide induced apoptosis and autophagy in ovarian cancer cells. FOXO3 transcription was upregulated, which may contribute to C2‑ceramide‑induced apoptosis and autophagy.

CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis

CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an indicator of tumor prognosis. This current meta-analysis systematically reevaluated the predictive potential of CD147/EMMPRIN in various cancers. We searched PubMed and Embase databases to screen the literature. Fixed-effect and random-effect meta-analytical techniques were used to correlate CD147 expression with outcome measures. A total of 53 studies that included 68 datasets were eligible for inclusion in the final analysis. We found a significant association between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. In addition, CD147/EMMPRIN overexpression predicted a high risk for chemotherapy drugs resistance. CD147/EMMPRIN is a central player in tumor progression and predicts a poor prognosis, including in patients who have received chemo-radiotherapy. Our results provide the evidence that CD147/EMMPRIN could be a potential therapeutic target for cancers.

Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis

Background/Objective Vascular endothelial growth factor (VEGF) is the most important promotor of angiogenesis. Some studies indicate that anti-angiogenic agents that interfere with VEGF and its receptor (VEGFR), i.e., anti-VEGF/VEGFR agents, may be applied to treat endometriosis. This meta-analysis investigated the efficacy of anti-VEGF/VEGFR agents in animal models of endometriosis. Methods A systematic literature search was performed for animal studies published in English or Chinese from January 1995 to June 2016, which evaluated the effect of anti-VEGF/VEGFR agents on endometriosis. The databases were: PubMed, Web of Science, BIOSIS, Embase, and CNKI. The quality of included studies was assessed using the SYRCLE tool. The random-effect models were used to combine the results of selected studies. Heterogeneity was assessed using H2statistic and I2 statistic. Subgroup analyses were performed to determine the source of heterogeneity in endometriosis scores and follicle numbers. Results We identified 13 studies that used anti-VEGF/VEGFR agents in various animal models. The meta-analysis showed that anti-VEGF/VEGFR agents were associated with smaller size (standardized mean difference (SMD) –0.96, 95% CI –1.31 to –0.62; P < 0.0001) and weight (SMD –1.70, 95% CI –2.75 to –0.65; P = 0.002) of endometriosis lesions, relative to the untreated controls, as well as a lower incidence rate of endometriosis (risk ratio 0.26, 95% CI 0.07 to 0.93; P = 0.038) and endometriosis score (SMD –1.17, 95% CI –1.65 to –0.69; P < 0.0001); the number of follicles were similar (SMD –0.78, 95% CI –1.65 to 0.09; P = 0.08). Conclusions Anti-VEGF/VEGFR agents appeared to inhibit the growth of endometriosis, with no effect on ovarian function. Anti-angiogenic therapy may be a novel strategy in treating endometriosis.

Stromal cells of endometrial carcinoma promotes proliferation of epithelial cells through the HGF/c-Met/Akt signaling pathway

Tumor microenvironment participates in the endometrial carcinoma pathogenesis. This study focuses on the interaction between endometrial cancer stromal cells and epithelial cells from normal endometrium tissue using in vitro transwell coculture system and in vivo xenograft model. We demonstrate that cancer interstitial (CI) cells stimulate normal epithelial (NE) cell proliferation. Tumor xenograft model confirmed the pro-proliferative effect of CI cells on epithelial cell growth. Tumor suppressor PTEN was reduced, and oncogene K-ras was increased in epithelial cells cocultured with CI cells. Moreover, we observed increased expression of hepatocyte growth factor (HGF) in CI cells and tumor xenografts derived from the coculturing system. Higher HGF secretion activated Akt signaling pathway, which was reversed by HGF receptor inhibitor (crizotinib). These results demonstrate that endometrial carcinoma stromal cells stimulate epithelial cell proliferation via the HGF/c-Met/Akt signaling pathway.

Prognostic and diagnostic significance of lncRNAs expression in cervical cancer: a systematic review and meta-analysis

Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in cervical cancer (CC) and presumably serve as diagnostic or prognostic markers. We thus performed a systematic review and meta-analysis to evaluate the clinical values of dysregulated lncRNAs in CC. A literature search was performed using the electronic databases PubMed, Embase, and Web of Science. A total of 22 relevant studies were eligible, including 21 on clinicopathological features, 18 on prognosis, and 4 on diagnosis. For clinicopathological features, HOTAIR expression was positively associated with tumor size (odds ratio [OR]=2.19, 95% confidence interval [CI] 1.42-3.38, P=0.000) and lymph node metastasis (OR=6.04, 95% CI 3.51-10.42, P=0.000). For the prognostic values, up-regulated HOTAIR had an unfavorable impact on overall survival ([OS]; hazard ratio [HR]=1.94, 95%CI 1.17-3.22, P=0.011) and disease-free survival (HR=2.61, 95%CI 1.35-5.05, P=0.004), and high PVT1 expression was correlated with shorter OS (HR=1.66, 95%CI 1.21-2.29, P=0.002). For the diagnostic values, the pooled result showed an area under the curve (AUC) of 0.85, with 85% sensitivity and 81% specificity in discriminating patients with CC from healthy controls. Overall, we conclude that lncRNAs might serve as promising indicators for prognostic and diagnostic evaluation of patients with CC.Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in cervical cancer (CC) and presumably serve as diagnostic or prognostic markers. We thus performed a systematic review and meta-analysis to evaluate the clinical values of dysregulated lncRNAs in CC. A literature search was performed using the electronic databases PubMed, Embase, and Web of Science. A total of 22 relevant studies were eligible, including 21 on clinicopathological features, 18 on prognosis, and 4 on diagnosis. For clinicopathological features, HOTAIR expression was positively associated with tumor size (odds ratio [OR]=2.19, 95% confidence interval [CI] 1.42-3.38, P=0.000) and lymph node metastasis (OR=6.04, 95% CI 3.51-10.42, P=0.000). For the prognostic values, up-regulated HOTAIR had an unfavorable impact on overall survival ([OS]; hazard ratio [HR]=1.94, 95%CI 1.17-3.22, P=0.011) and disease-free survival (HR=2.61, 95%CI 1.35-5.05, P=0.004), and high PVT1 expression was correlated with shorter OS (HR=1.66, 95%CI 1.21-2.29, P=0.002). For the diagnostic values, the pooled result showed an area under the curve (AUC) of 0.85, with 85% sensitivity and 81% specificity in discriminating patients with CC from healthy controls. Overall, we conclude that lncRNAs might serve as promising indicators for prognostic and diagnostic evaluation of patients with CC.

Tumor Necrosis Factor Alpha rs1800629 Polymorphism and Risk of Cervical Lesions: A Meta-Analysis

Background Tumor necrosis factor- alpha (TNF-α) is an inflammatory cytokine which may play important role on the immune response may control the progression of cervical lesions. There is a possible association between TNF-α rs1800629 G/A polymorphism and cervical lesions, but previous studies report conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk. Methods Literature searches of Pubmed, Embase, Web of Science, and Wanfang databases were performed for all publications on the association between TNF-α rs1800629 polymorphism and cervical lesions through December 15, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the strength of the association. Results Twenty individual case-control studies from 19 publications with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models (For A versus G: OR 1.22, 95%CI 1.04–1.44, Pu200a=u200a0.017; for AA versus GG: OR 1.32, 95%CI 1.02–1.71, Pu200a=u200a0.034). Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Caucasians but not in Asians. Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer (For A versus G: OR 1.24, 95%CI 1.05–1.47, Pu200a=u200a0.011; for AA versus GG: OR 1.31, 95%CI 1.01–1.70, Pu200a=u200a0.043; for AA/GA versus GG: OR 1.25, 95%CI 1.01–1.54, Pu200a=u200a0.039). Conclusion The meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians.

Prognostic significance of L1 cell adhesion molecule in cancer patients: A systematic review and meta-analysis

The L1 cell adhesion molecule (L1CAM) extensively participates in nervous system development and the malignant progression of human tumours. The prognostic value of L1CAM for the survival of patients with solid tumours remains controversial. The present meta-analysis was thus performed to highlight the relationship between L1CAM expression and prognosis in cancer patients. Relevant publications were identified after searching several widely used databases, including PubMed, EMBASE and the ISI Web of Science. A fixed-effect or random-effect meta-analytical model was employed to correlate L1CAM expression with different outcome measures in both entire tumours and stratified subgroups. 37 studies in total with 8552 patients were eligible for the final analysis. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) suggested that high L1CAM expression had an unfavourable impact on overall survival (HR=2.06, 95%CI 1.65-2.57, P<0.001), disease-specific survival (HR=2.45, 95%CI 1.48-4.05, P<0.001), disease-free survival (HR=2.42, 95%CI 1.4-4.19, P=0.002) and progression-free survival/recurrence-free survival (HR=2.07, 95%CI 1.41-3.05, P<0.001). Subgroup analysis revealed a similar correlation in most tumour types. Overall, L1CAM might be an effective poor prognostic factor for patients with various tumour types.

S100A4 promotes endometrial cancer progress through epithelial-mesenchymal transition regulation

Epithelial-mesenchymal transition (EMT) is a major cause of endometrial cancer (EC) to initiate invasion and metastasis. S100A4, a calcium-binding protein, is implicated in multistage of tumorigenesis and tumor progression. The correlation between S100A4 and EMT in EC is still unclear. This study was aimed to clarify the role of S100A4 in EC and the relationship between S100A4 expression and EMT markers. S100A4, E-cadherin, and vimentin were detected in tissues of EC patients (n=50) by immunohistochemistry. The impact of S100A4 on EC cell proliferation, migration and invasion was investigated via RNA interference, and the correlation between S100A4 and EMT markers were also explored. The results showed that S100A4 was significantly increased in epithelial cells of EC compared with the normal endometrium (P<0.05), also S100A4 level was positively related to age (P=0.021), histological grade (P<0.001), and lymph node metastasis (P<0.001). Additionally, silencing of S100A4 remarkably attenuated EC cell migration and invasion. Significant morphological change accompanied with the downregulation of EMT markers, E-cadherin and vimentin were also observed. Aberrant S100A4 expression may predict EC progression and play an important role in regulating EC cell invasion through EMT regulation. Hence, S100A4 is a promising therapeutic target.

Quantitative assessment of the association between CYP1A1 A4889G polymorphism and endometrial cancer risk.

Cytochrome P450 1A1 (CYP1A1) A4889G polymorphism was supposed to be associated with endometrial cancer risk, but previous studies reported conflicting results. We therefore performed a meta-analysis of all relevant studies to get a comprehensive assessment of the association between CYP1A1 A4889G polymorphism and endometrial cancer risk. The pooled odds ratios (OR) with the corresponding 95xa0% confidence interval (95xa0% CI) was calculated to assess the association. Finally, ten studies with a total of 1,682 endometrial cancer cases and 2,510 controls were finally included into the meta-analysis. Meta-analysis of the total ten studies showed that CYP1A1 A4889G polymorphism was not associated with endometrial cancer risk (ORG versus Au2009=u20091.14, 95xa0% CI 0.83–1.57, PORu2009=u20090.417; ORGG versus AAu2009=u20091.23, 95xa0% CI 0.70–2.18, PORu2009=u20090.470; ORGG versus AA/AGu2009=u20091.03, 95xa0% CI 0.59–1.81, PORu2009=u20090.919; ORGG/AG versus AAu2009=u20091.22, 95xa0% CI 0.82–1.81, PORu2009=u20090.336). Subgroup analyses by ethnicity further showed that there was also no obvious association between CYP1A1 A4889G polymorphism and endometrial cancer risk in both Caucasians and Asians. Sensitivity analysis by excluding single study in turns showed that the pooled estimations were not stable. Therefore, evidence for currently available data suggests that CYP1A1 A4889G polymorphism is not associated with endometrial cancer risk. However, more studies with large number of participants are needed to further assess the association precisely.

The suppressive role of calcium sensing receptor in endometrial cancer

Studies have shown that calcium sensing receptor (CaSR) is involved in the progressions of several human cancers. However, the role of CaSR in endometrial cancer remains unknown. This study provides a preliminary analysis of the CaSR effect on endometrial cancer development. Ectopic CaSR expression by lentiviral transfection (CaSR-OV) in Ishikawa cells significantly increased intracellular calcium ([Ca2+]i) levels and cell apoptosis. E-cadherin and β-catenin expression and complex formation at the membrane were increased in CaSR-OV Ishikawa cells relative to control Ishikawa cells (vector). Furthermore, CaSR-OV Ishikawa cells showed a reduced invasive potential, which was attributed to E-cadherin/β-catenin complex formation. Moreover, a reduction in CaSR expression in endometrial cancer relative to normal specimens was evident by immunohistochemistry and was positively associated with E-cadherin, but not β-catenin, expression. Furthermore, VEGFR3 was significantly down-regulated in CaSR-OV Ishikawa cells. Additionally, an immunohistochemical analysis showed that VEGFR3 was significantly increased in endometrial cancer compared with the normal endometrium and was inversely correlated with CaSR expression. However, the CaSR knockdown produced the opposite effects. These findings suggest an inhibitory role for CaSR in endometrial cancer. Therefore, reduced CaSR expression may be a suitable explanation and valuable predictor for endometrial cancer progression.