Liye Fu

Association Between MDM2 SNP309 T>G and Risk of Gastric Cancer: A Meta-analysis

BACKGROUNDnAs a negative regulator of P53, MDM2 plays an important role in carcinogenesis; a polymorphism in its promoter region. SNP309 T>G, is known to increase the expression of MDM2, thus being considered related to higher susceptibility to neoplasia. However, no agreement has been achieved regarding its effects on gastric cancer.nnnMETHODSnThe present systematic meta-analysis was performed based on comprehensive literature search from Pubmed, Web of science and CBM databases.nnnRESULTSnIt was suggested from 6 independent studies that the GG genotype is associated with a significantly increased risk of gastric cancer (Recessive: OR = 1.43, 95% CI = 1.08-1.91, P = 0.013), and subgroup analysis also confirmed the relationship (English publications-recessive model: OR = 1.45, 95% CI = 1.10-1.91, P = 0.009; Studies in China-recessive model: OR = 1.58, 95% CI = 1.08-2.30, P = 0.017). No publication bias was detected.nnnCONCLUSIONnThe meta-analysis indicated a significant inverse association between GG genotype carriage and elevated risk of gastric cancer. However, more studies and detailed information are needed to fully address the topic.

Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway

Bufalin, a digoxin-like active component of the traditional Chinese medicine Chan Su, exhibits potent antitumor activities in many human cancers. Bufalin induces mitochondria-dependent apoptosis in cancer cells, but the detailed molecular mechanisms are largely unknown. hTERT, the catalytic subunit of telomerase, protects against mitochondrial damage by binding to mitochondrial DNA and reducing mitochondrial ROS production. In the present study, we investigated the effects of bufalin on the cell viability, ROS production, DNA damage, and apoptosis of CAPAN-2 human pancreatic and CAL-27 human oral cancer cells. Bufalin reduced CAPAN-2 and CAL-27 cell viability with IC50 values of 159.2u2009nM and 122.6u2009nM, respectively. The reduced cell viability was accompanied by increased ROS production, DNA damage, and apoptosis and decreased expression of hTERT. hTERT silencing in CAPAN-2 and CAL-27 cells by siRNA resulted in increased caspase-9/-3 cleavage and DNA damage and decreased cell viability. Collectively, these data suggest that bufalin downregulates hTERT to induce mitochondria-dependent apoptosis in CAPAN-2 and CAL-27 cells. Moreover, bufalin increased the phosphorylation of JNK and p38-MAPK in CAPAN-2 and CAL-27 cells, and blocking the JNK/p38-MAPK pathway using the JNK inhibitor SP600125 or the p38-MAPK inhibitor SB203580 reversed bufalin-induced hTERT downregulation. Thus, the JNK/p38 pathway is involved in bufalin-induced hTERT downregulation and subsequent induction of apoptosis by the mitochondrial pathway.

RETRACTED ARTICLE: Comprehensive assessment of the association between tumor necrosis factor alpha G238A polymorphism and liver cancer risk

Tumor necrosis factor alpha (TNF-α) has been suggested to play an important role in the development and liver cancer. TNF-α 238 G/A polymorphism was hypothesized to increase the risk of liver cancer, but findings from previous studies were controversial. To explore a more precise estimation of the relationship between TNF-α 238 G/A polymorphism and liver cancer, we performed a meta-analysis. PubMed, Embase, and China Biology Medicine databases were searched for all publications on this association through March 12, 2013. Odds ratios (ORs) with its 95xa0% confidence intervals (CIs) were used to assess the strength of this association. Eleven studies with 1,406 liver cancer cases and 2,386 noncancer controls were included into this meta-analysis. Overall, there was a significant association between TNF-α 238 G/A polymorphism and increased risk of liver cancer under all three genetic models (A vs. G, OR 1.51, 95xa0% CI 1.20–1.89, Pu2009<u20090.001, I2u2009=u200937.7xa0%; AG vs. GG, OR 1.49, 95xa0% CI 1.01–2.21, Pu2009=u20090.045, I2u2009=u200953.2xa0%; AA/AG vs. GG, OR 1.76, 95xa0% CI 1.35–2.30, Pu2009<u20090.001, I2u2009=u200936.5xa0%). The sensitivity analysis further strengthened the validity of the positive association. Subgroup analysis of nine studies from Asian countries showed that there was a significant association between TNF-α 238 G/A polymorphism and increased risk of liver cancer in Asians (A vs. G, OR 1.35, 95xa0% CI 1.03–1.76, Pu2009=u20090.027, I2u2009=u200940.2xa0%; AA/AG vs. GG, OR 1.56, 95xa0% CI 1.14–2.15, Pu2009=u20090.006, I2u2009=u200941.9xa0%). In conclusion, TNF-α 238 G/A polymorphism is significantly associated with increased risk of liver cancer, especially in Asians.

Suppression of tumor necrosis factor receptor-associated protein 1 expression induces inhibition of cell proliferation and tumor growth in human esophageal cancer cells

Tumor necrosis factor receptor‐associated protein 1 (TRAP1) is a molecular chaperone involved in multidrug resistance and antiapoptosis in some human tumors, but its regulatory mechanisms have not been revealed in esophageal squamous cell carcinoma (ESCC). In this study, 138 specimens of ESCC were analyzed. TRAP1 was overexpressed in ESCC, particularly in poorly differentiated tumors. To further explore the molecular regulatory mechanism, we constructed specific small interfering RNA‐expressing vectors targeting Trap1, and knocked down Trap1 expression in the esophageal cancer cell lines ECA109 and EC9706. Knockdown of Trap1 induced increases in reactive oxygen species and mitochondrial depolarization, which have been proposed as critical regulators of apoptosis. The cell cycle was arrested in G2/M phase, and in vitro inhibition of cell proliferation was confirmed with 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐tetrazolium bromide and bromodeoxyuridine assays. Furthermore, re‐expression of TRAP1 in Trap1 small interfering RNA‐transfected ESCC cells restored cell proliferation and cell apoptosis. Bioluminescence of subcutaneously xenografted ESCC tumor cells demonstrated significant inhibition of in vivo tumor growth by Trap1 knockdown. This study shows that TRAP1 was overexpressed in most patients with ESCC, and caused an increase in antiapoptosis potency. TRAP1 may be regarded as a target in ESCC biotherapy.

Stable knockdown of protein kinase CK2-alpha (CK2α) inhibits migration and invasion and induces inactivation of hedgehog signaling pathway in hepatocellular carcinoma Hep G2 cells.

Protein kinase CK2-alpha (CK2α), one isoform of the catalytic subunits of serine/threonine kinase CK2, has been indicated to participate in tumorigenesis of various malignancies, including hepatocellular carcinoma (HCC). In the present study, in order to explore the potential role of CK2α in human HCC, we employed short hairpin RNA (shRNA)-mediated RNA interference (RNAi) technology to inhibit the endogenous CK2α expression in HCC cells and established a Hep G2 cell line with stable knockdown of CK2α. Results from wound healing and transwell invasion assays indicated that stable knockdown of CK2α markedly inhibited Hep G2 cell migration and invasion as compared with those transfected with a negative control plasmid. This alteration was accompanied with expression down-regulation of matrix metalloproteinase (MMP)-2, MMP-9, Snail, Slug, Vimentin, and up-regulation of epithelial cadherin (E-cadherin). Moreover, CK2α silencing also induced inactivation of Hedgehog signaling pathway by inhibiting Gli1 and Patched homolog 1 (PTCH1) expressions in HCC cells. Collectively, these results demonstrate that knockdown of CK2α can suppress cell migration and invasion, reduces expression of MMPs, inhibits epithelial-mesenchymal transition (EMT) process and induces inactivation of Hedgehog pathway in HCC cells in vitro. Our study provides in vitro evidence to demonstrate that the pathogenesis of human HCC may be correlated with the high expression of CK2α.

Association between the XRCC3 C241T polymorphism and lung cancer risk in the Asian population

X-ray repair cross-complementing group 3 (XRCC3) plays a vital role in maintaining the stability of genome by homologous recombination repair for DNA double-strand breaks. The genetic polymorphism of XRCC3 C241T has been implicated in lung cancer risk, but the findings across published studies in Asians are inconsistent and inconclusive. To estimate the precise association of XRCC3 C241T polymorphism with lung cancer risk, a meta-analysis of all currently available studies in Asians was performed. A comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases was conducted for eligible studies based on the inclusion criteria. The pooled odds ratios (ORs) with corresponding 95xa0% confidence intervals (CIs) were calculated to assess the association. Besides, subgroup analysis and sensitivity analysis were also performed for further estimation. Seven available studies with a total of 7,398 subjects were finally included into this meta-analysis. The overall ORs indicated that the XRCC3 C241T polymorphism was not associated with a lung cancer risk among Asians in all genetic contrast modes (ORT allele vs. C alleleu2009=u20091.08, 95xa0% CI 0.95–1.24, PORu2009=u20090.252; ORTT vs. CCu2009=u20091.30, 95xa0% CI 0.69–2.45, PORu2009=u20090.426; ORCT vs. CCu2009=u20091.07, 95xa0% CI 0.93–1.24, PORu2009=u20090.363; ORTT + CT vs. CCu2009=u20091.08, 95xa0% CI 0.94–1.24, PORu2009=u20090.300; ORTT vs. CC + CTu2009=u20091.29, 95xa0% CI 0.68–2.43, PORu2009=u20090.439). We failed to identify significant association between the XRCC3 C241T polymorphism and risk of lung cancer in Chinese and population-based studies. Interestingly, the pooled ORs in hospital-based studies indicated that the XRCC3 C241T variant carriers were more susceptible to lung cancer (ORT allele vs. C alleleu2009=u20091.27, 95xa0% CI 1.04–1.56, PORu2009=u20090.019; ORCT vs. CCu2009=u20091.26, 95xa0% CI 1.01–1.57, PORu2009=u20090.045; ORTT + CT vs. CCu2009=u20091.28, 95xa0% CI 1.03–1.59, PORu2009=u20090.027). Sensitivity analysis confirmed the stability and liability of all results. This meta-analysis suggests that the XRCC3 C241T polymorphism may not exert a risk effect on the lung cancer risk in Asians, although a statistically significant association was observed among the hospital-based studies. Thus, the precise relationship between the XRCC3 C241T variant and lung cancer risk needs further confirmation in future studies with large available data.

β-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma

β-Catenin (CTNNB1 gene coding protein) is a component of the Wnt signaling pathway that has been shown to play an important role in the formation of certain cancers. Abnormal accumulation of CTNNB1 contributes to most cancers. This research studied the involvement of β-catenin in renal cell carcinoma (RCC) cell proliferation, apoptosis, migration, and invasion. Proliferation, cell cycle, and apoptosis were analyzed by using Cell Counting Kit-8 and by flow cytometry. Migration and invasion assays were measured by transwell analysis. Real-time polymerase chain reaction and Western blot analysis were used to detect the expression of CTNNB1, ICAM-1, VCAM-1, CXCR4, and CCL18 in RCC cell lines. It was found that CTNNB1 knockdown inhibited cell proliferation, migration, and invasion and induced apoptosis of A-498 cells. CTNNB1 overexpression promoted cell proliferation, migration, and invasion and inhibited apoptosis of 786-O cells. Moreover, knockdown of CTNNB1 decreased the levels of ICAM-1, VCAM-1, CXCR4, and CCL18 expression, but CTNNB1 overexpression increased the expression of ICAM-1, VCAM-1, CXCR4, and CCL18. Further in vivo tumor formation study in nude mice indicated that inhibition of CTNNB1 delayed the progress of tumor formation through inhibiting PCNA and Ki67 expression. These results indicate that CTNNB1 could act as an oncogene and may serve as a promising therapeutic strategy for RCC.

Relationship of PTTG expression with tumor invasiveness and microvessel density of pituitary adenomas: a meta-analysis.

AIMSnMany existing studies have demonstrated that pituitary tumor transforming gene (PTTG) expression may contribute to the development of pituitary adenomas (PAs), but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the relationships of PTTG expression with tumor invasiveness and microvessel density of pituitary adenomas.nnnMETHODSnWe searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through September 1st, 2013. Meta-analysis was performed using the STATA 12.0 software. The crude odds ratio (OR) with 95% confidence interval (CI) was calculated.nnnRESULTSnFifteen clinical cohort studies were included with a total of 752 pituitary adenoma patients. The meta-analysis results revealed that patients with invasive pituitary adenomas had higher positive expression of PTTG than those of noninvasive patients (OR=6.68, 95% CI=3.72-11.99, p<0.001). We also found a significant difference in the microvessel density between invasive and noninvasive patients (OR=1.81, 95% CI=0.39-3.23, p<0.001). No publication bias was detected in this meta-analysis (all p>0.05).nnnCONCLUSIONnThe present meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas. Thus, detection of PTTG expression may be useful for the prediction of malignancy degree in pituitary adenomas.

Identification of TGF-β-activated kinase 1 as a possible novel target for renal cell carcinoma intervention.

Renal cell carcinoma (RCC) is common renal malignancy within poor prognosis. TGF-β-activated kinase 1 (TAK1) plays vital roles in cell survival, apoptosis-resistance and carcinogenesis through regulating nuclear factor-κB (NF-κB) and other cancer-related pathways. Here we found that TAK1 inhibitors (LYTAK1, 5Z-7-oxozeanol (5Z) and NG-25) suppressed NF-κB activation and RCC cell (786-O and A489 lines) survival. TAK1 inhibitors induced apoptotic cytotoxicity against RCC cells, which was largely inhibited by the broad or specific caspase inhibitors. Further, shRNA-mediated partial depletion of TAK1 reduced 786-O cell viability whiling activating apoptosis. Significantly, TAK1 was over-expressed in human RCC tissues, and its level was correlated with phosphorylated NF-κB. Finally, kinase inhibition or genetic depletion of TAK1 enhanced the activity of vinblastine sulfate (VLB) in RCC cells. Together, these results suggest that TAK1 may be an important oncogene or an effective target for RCC intervention.

Ror2, a Developmentally Regulated Kinase, Is Associated With Tumor Growth, Apoptosis, Migration, and Invasion in Renal Cell Carcinoma

Renal cell carcinoma (RCC) represents one of the most resistant tumors to radiation and chemotherapy. Current therapies for RCC patients are inefficient due to the lack of diagnostic and therapeutic markers. The expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. In the present study, we investigated the receptor tyrosine kinase-like orphan receptor 2 (Ror2), a new tumor-associated kinase, in RCC primary tumors and cell lines. Knockdown of Ror2 expression in RCC cells with specific shRNA significantly reduced cell proliferation and induced apoptosis. Using in vitro migration and Matrigel invasion assays, we found that cell migration and invasive ability were also significantly inhibited. In RCC, Ror2 expression correlated with expression of genes involved at the cell cycle and migration, including PCNA, CDK1, TWIST, and MMP-2. Furthermore, in vivo xenograft studies in nude mice revealed that administration of a Ror2 shRNA plasmid significantly inhibited tumor growth. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.