Rina Sa

αV Integrin Induces Multicellular Radioresistance in Human Nasopharyngeal Carcinoma via Activating SAPK/JNK Pathway

Background Tumor cells acquire the capacity of resistance to chemotherapy or radiotherapy via cell–matrix and cell–cell crosstalk. Integrins are the most important cell adhesion molecules, in which αV integrin mainly mediating the tight contact between tumor cells. Methodology/Principal Findings To investigate the role of αV integrin in multi-cellular radioresistance (MCR) of human nasopharyngeal carcinoma (NPC), we performed immunohistochemistry and Western blotting to find that the expression of αV integrin in the tumor tissue of radioresistant patients is much higher than that in radiosensitive patients. In vitro, we cultured human NPC cell line CNE-2 cells as multi-cellular spheroids (MCSs) or as monolayer cells (MCs), and found that the expression of αV integrin in MCSs is significantly higher than that in MCs. MTT, flow cytometry and clonogenic suvival assays showed that MCSs are less sensitive to X-ray irradiation than MCs while blocking of αV integrin in MCSs dramatically reversed their radioresistance. Furthermore, as detected by Western blotting, MCSs displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway in presence of irradiation. Blocking of αV integrin in MCSs decreased the expression of phosphorylated JNK. Additionally, blocking of SAPK/JNK signaling pathway synergistically induced apoptosis of MCSs exposed to irradiation by increasing the expression of cleaved caspase-3. In vivo, we found that irradiation combined with αV integrin blocking treatment significantly enhanced the radiosensitivity of NPC xenografts. Conclusions Our results indicate a novel role of αV integrin in multi-cellular radioresistance of NPCs.

The E-cadherin (CDH1) -C160A polymorphism and colorectal cancer susceptibility: a meta-analysis.

E-cadherin, encoded by the CDH1 gene, involves in invasion and metastasis of cancer cells. CDH1 -C160A polymorphism was shown to contribute to genetic susceptibility to colorectal cancer (CRC). However, the results from different studies remain controversial. This study was conducted to further explore the association between CDH1 -C160A genetic polymorphism and CRC susceptibility by means of a meta-analysis. A comprehensive literature search was conducted to identify all case-control studies of CDH1 -C160A polymorphism and risk for CRC. A total of nine eligible studies, including 7954 CRC cases and 7369 controls, were identified to the meta-analysis. On the whole, the meta-analysis indicated that CDH1 -C160A genetic polymorphism could reduce the risk of CRC under AA versus CC contrast (odds ratio [OR]=0.86, 95% confidence interval [CI]=0.75-0.98, p(heterogeneity)=0.11), recessive model (OR=0.88, 95% CI=0.77-0.99, p(heterogeneity)=0.23), dominant model (OR=0.92, 95% CI=0.87-0.99, p(heterogeneity)=0.11), and allele A versus allele C contrast (OR=0.93, 95% CI=0.88-0.98, p(heterogeneity)=0.26). A conclusion could be drawn from the research that CDH1 -C160A polymorphism provides a possible protection against CRC, which is especially evident in Caucasian and hospital populations.

Genetic association between PER3 genetic polymorphisms and cancer susceptibility: a meta-analysis.

AbstractThe genes along the circadian pathways control and modulate circadian rhythms essential for the maintenance of physiological homeostasis through self-sustained transcription-translation feedback loops. PER3 (period 3) is a circadian pathway gene and its variants (rs1012477, 4/5-repeat) have frequently been associated with human cancer. The mixed findings, however, make the role of the 2 variants in cancer susceptibility elusive. We aimed in this article to clarify the association of PER3 variants with cancer.We collected genetic data from 8 studies, providing 6149 individuals for rs1012477 and 5241 individuals for 4/5-repeat. Based on the genotype and allele frequency, we chose the fixed-effects model to estimate risk of cancer.Overall analysis did not suggest a global role of rs1012477 in cancer susceptibility. For PER3 4/5-repeat variant, we found a moderate increase in risk of cancer among individuals with the 5-allele compared to individuals with the 4-allele, although this association was not statistically significant (homozygous model: odds ratio [OR] 1.17, 95% confidence interval [CI] 0.81–1.67; recessive model: OR 1.17, 95% CI 0.82–1.67). No substantial heterogeneity was revealed in this analysis.Our meta-analysis provides no evidence supporting a global association of PER3 genetic variants with the incidence of cancer.

Genetic association between TRAIL-R1 Thr209Arg and cancer susceptibility.

We aimed to determine the indecisive association between tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) Thr209Arg polymorphism and inherited susceptibility to cancer. A meta-analysis combining data on 9,517 individuals was performed to assess the association between TRAIL-R1 Thr209Arg and cancer incidence. The summary ORs with 95% CI calculated with the fixed effects model suggested that Thr209Arg was not significantly associated with cancer susceptibility (homozygous model: OR 0.98, 95% CI 0.88–1.09; heterozygous model: OR 0.95, 95% CI 0.87–1.04; allele frequency model: OR 0.99, 95% CI 0.94–1.05; dominant model: OR 0.98, 95% CI 0.91–1.05; recessive model: OR 1.01, 95% CI 0.92–1.10). Stratified analysis by ethnicity and cancer type yielded similar null associations. These statistical data suggest that Thr209Arg in exon 4 of the TRAIL-R1 gene may not represent a modifier of susceptibility to cancer.

Genetic Association Between NFKBIA -881A>G Polymorphism and Cancer Susceptibility.

Abstract Several epidemiological studies have focused on the role of nuclear factor-kappa-B inhibitor-alpha (NFKBIA) -881 A>G polymorphism in cancer susceptibility. However, the published data have led to contentious results. This study was designed to examine the association between -881 A>G polymorphism and cancer risk. Comprehensive search of PubMed, Web of science and Embase, identified a total of 5 case-control studies. To assess the association, comparison among all subjects plus subgroup analysis by ethnicity was performed and odds ratio (OR) along with 95% confidence interval (CI) was calculated with the fixed-effect model or the random-effects model dependent on the heterogeneity. The pooling data consisting of 1965 cancer cases and 2717 cancer-free controls demonstrated no significant association with overall cancer risk. However, the subgroup of Asian populations showed statistical evidence for an increase in risk of cancer (GG vs. AA, OR, 2.14; 95% CI, 1.03–4.46; GG + GA vs. AA, OR, 1.22; 95% CI, 1.01–1.47; GG vs. GA + AA, OR, 2.09; 95% CI, 1.01–4.34). This investigation on the association of -881 A>G polymorphism and cancer susceptibility reveals that -881 A>G polymorphism may act as a candidate for cancer development in Asian populations.

Association of Fas -1377 G/A Polymorphism with Susceptibility to Cancer

Background The relationship between Fas -1377 G/A polymorphism and cancer susceptibility has been implicated in accumulating data. However, the data presented inconsistent results. This study was devised to investigate the association of Fas -1377 G/A polymorphism and cancer susceptibility in a large number of participants. Methods The databases of PubMed, Embase, and Web of Science were searched and a total of 27 case-control studies including 13,355 cases and 16,078 controls were included in this meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed-effects model. Statistical analyses were performed by using Stata software. Results The results suggested that Fas -1377 G/A polymorphism was overall associated with cancer susceptibility (additive model: OR, 1.16, 95%CI = 1.06–1.27, P heterogeneity  = 0.381; recessive model: OR, 1.19, 95%CI = 1.10–1.29, P heterogeneity  = 0.137). In the subgroup analysis by cancer type, significantly increased risk was observed in breast cancer (additive model: OR, 1.24, 95%CI = 1.04–1.58, P heterogeneity  = 0.614; recessive model: OR, 1.24, 95%CI = 1.02–1.51, P heterogeneity  = 0.349) and lung cancer (recessive model: OR, 1.25, 95%CI = 1.04–1.49, P heterogeneity  = 0.090). Similarly, elevated cancer risk associated with Fas -1377 G/A polymorphism was revealed in Asians. Conclusions The combined results suggest that Fas -1377 G/A polymorphism might modulate cancer susceptibility in an Asian-specific manner.

Genetic polymorphisms in C-reactive protein increase cancer susceptibility

Elevated levels of C-reactive protein (CRP) partially induced by polymorphisms in the CRP gene have been associated with human cancer. The purpose of this study was to test the hypothesis that CRP gene polymorphisms (+942G>C, 1846C>T) modify inherited susceptibility to cancer. We systematically identified the publications addressing the association of CRP gene polymorphisms with cancer susceptibility. Studies that fulfilled all inclusion criteria were considered eligible in this meta-analysis. We analyzed a total of 8 case-control studies. Individuals with the CC genotype were found to have an almost 4 fold higher risk of cancer than those with the GG or GC and GG genotypes. A significant association was also indicated in subgroup of colorectal cancer. Meta-analysis of 1846C>T polymorphism showed increased cancer risk in relation to the 1846 TT genotype (TT vs. CC: OR = 1.15, 95% CI = 1.01–1.31; TT vs. CT + CC; OR = 1.17, 95% CI = 1.03–1.32). Similar results were suggested in Caucasian populations and colorectal cancer. These data suggest that both +942G>C and 1846C>T polymorphisms in the CRP gene may influence cancer susceptibility.