Peiliang Geng

Melatonin regulates PARP1 to control the senescence‐associated secretory phenotype (SASP) in human fetal lung fibroblast cells

Cellular senescence is an important tumor‐suppressive mechanism. However, acquisition of a senescence‐associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene‐induced senescence (OIS). Moreover, poly(ADP‐ribose) polymerase‐1 (PARP‐1), a sensor of DNA damage, was identified as a new melatonin‐dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat‐containing RNA (TERRA) and PARP‐1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP‐1 recruits CREB‐binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonins epigenetic role via modulating PARP‐1 in suppression of SASP gene expression in OIS‐induced senescent cells. Our studies identify melatonin as a novel anti‐SASP molecule, define PARP‐1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP‐1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin.

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.

Distinct Role of CD86 Polymorphisms (rs1129055, rs17281995) in Risk of Cancer: Evidence from a Meta-Analysis

Background and Purpose Previous studies concerning the role of CD86 polymorphisms (rs1129055 and rs17281995) in cancer fail to provide compelling evidence. The aim of this study was to investigate the role of common polymorphisms in the risk of cancer by meta-analysis. Methods By using the search terms Cluster of Differentiation 86/CD86/B7-2/polymorphism/polymorphisms/cancer, we searched PubMed, Embase, CNKI, and Wanfang and identified four studies for rs1129055 (2137 subjects) and rs17281995 (2856 subjects) respectively. Cancer risk was estimated by odds ratio (OR) and 95% confidence interval (95% CI). Major Findings Overall, we observed significant reduced risk of cancer in relation to rs1129055. Compared with the individuals with AA genotype, the individuals with GG genotype appeared to have 62% decreased risk to develop cancer (GG versus AA: OR, 0.62; 95% CI, 0.49–0.79; Phet., 0.996). Similar effects were indicated in the G versus A allele model and the GG versus GA+AA genetic model (OR, 0.83; 95% CI, 0.74–0.93; Phet., 0.987; OR, 0.63; 95% CI, 0.50–0.79; Phet., 0.973). In addition, we found genotypes of rs17281995 had a major effect on overall cancer risk (CC versus GG: OR, 2.38; 95% CI, 1.43–3.95; Phet., 0.433; C versus G: OR, 1.23; 95% CI, 1.06–1.43; Phet., 0.521; CC versus GC+GG: OR, 2.38; 95% CI, 1.45–3.93; Phet., 0.443). The association was also observed in Caucasians and colorectal cancer. No obvious publication bias was detected in this meta-analysis. Conclusions These data reveal that rs1129055 may have protective effects on cancer risk in Asians and that rs17281995 is likely to contribute to risk of cancer, particularly colorectal cancer in Caucasians.

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.

Increased Risk of Cutaneous Melanoma Associated with p53 Arg72Pro Polymorphism

Objective The objective of this study was to test the hypothesis that p53 Arg72Pro polymorphism may contribute to an increased risk of cutaneous melanoma (CM). Methods By searching the databases of PubMed, EMBASE, and Web of Science, a total of 8 eligible case-control studies with 1,957 CM cases and 2,887 controls were included in this meta-analysis. Stata software was used to analyze all the statistical data. Results The pooled data by a fixed-effects model suggested an increased risk of CM associated with p53 Arg72Pro polymorphism under the genetic model of Arg/Pro vs. Pro/Pro without heterogeneity (ORArg/Pro vs. Pro/Pro = 1.76, 95% CI = 1.55-1.99, P heterogeneity = 0.075). A similar trend was seen in subgroups of hospital-based studies and population-based studies. Conclusion Our meta-analysis based on all studies shows that the p53 Arg72Pro polymorphism may increase individual susceptibility to CM, particularly in Caucasians and could serve as a biomarker to predict the population at high risk of CM.

PSCA rs2294008 Polymorphism with Increased Risk of Cancer.

Background Published data on the association between PSCA rs2294008 polymorphism and cancer risk have implicated inconclusive results. To determine the relationship and to precisely assess the effect size estimate of the association, we performed a meta-analysis. Methods We searched published literature in Embase and PubMed databases using the search terms “PSCA”, “prostate stem cell antigen”, “variants”, “polymorphism”, “polymorphisms”, and “cancer”. A total of 21 eligible articles were retrieved, with 27, 197 cancer cases and 48, 237 controls. Results On the whole, we found the association between PSCA rs2294008 polymorphism and cancer risk was statistically significant: TT vs CC: OR = 1.18, 95% CI, 1.10 to 1.27; TT + CT vs CC: OR = 1.08, 95% CI, 1.05 to 1.10; TT vs CT + CC: OR = 1.14, 95% CI, 1.07 to 1.21; T vs C: OR = 1.10, 95% CI, 1.06 to 1.14; CT vs CC: OR = 1.10, 95% CI, 1.06 to 1.13. Stratified analyses in cancer type and ethnicity showed similar results. Conclusions Based on the statistical evidence, we can draw a conclusion that the rs2294008 polymorphism of PSCA gene is likely to play a role in cancer carcinogenesis, especially in gastric cancer and bladder 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.