XPD codon 312 and 751 polymorphisms, and AFB1 exposure, and hepatocellular carcinoma risk

<p>Abstract</p> <p>Background</p> <p>Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of hepatocellular carcinoma (HCC) related to the exposure of aflatoxin B1 (AFB1). In this study, we have focused on the polymorphisms of xeroderma pigmentosum complementation group D (XPD) codon 312 and 751 (namely Asp312Asn and Lys751Gln), involved in nucleotide excision repair.</p> <p>Methods</p> <p>We conducted a case-control study including 618 HCC cases and 712 controls to evaluate the associations between these two polymorphisms and HCC risk for Guangxi population by means of TaqMan-PCR and PCR-RFLP analysis.</p> <p>Results</p> <p>We found that individuals featuring the XPD genotypes with codon 751 Gln alleles (namely XPD-LG or XPD-GG) were related to an elevated risk of HCC compared to those with the homozygote of XPD codon 751 Lys alleles [namely XPD-LL, adjusted odds ratios (ORs) were 1.75 and 2.47; 95% confidence interval (CIs) were 1.30-2.37 and 1.62-3.76, respectively]. A gender-specific role was evident that showed an higher risk for women (adjusted OR was 8.58 for XPD-GG) than for men (adjusted OR = 2.90 for XPD-GG). Interestingly, the interactive effects of this polymorphism and AFB1-exposure information showed the codon 751 Gln alleles increase the risk of HCC for individuals facing longer exposure years (<it>P</it>_interaction= 0.011, OR = 0.85). For example, long-exposure-years (> 48 years) individuals who carried XDP-GG had an adjusted OR of 470.25, whereas long-exposure-years people with XDP-LL were at lower risk (adjusted OR = 149.12). However, we did not find that XPD codon 312 polymorphism was significantly associated with HCC risk.</p> <p>Conclusion</p> <p>These findings suggest that XPD Lys751Gln polymorphism is an important modulator of AFB1 related-HCC development in Guangxi population.</p

Effects of Common Polymorphisms rs11614913 in miR-196a2 and rs2910164 in miR-146a on Cancer Susceptibility: A Meta-Analysis

BACKGROUND: MicroRNAs regulate gene expression at the post-transcriptional level and involved in diverse biological and pathological processes, including tumorigenesis. Rs11614913 in miR-196a2 and rs2910164 in miR-146a are shown to associate with increased/decreased cancer risk. We performed a meta-analysis to systematically summarize the possible association. METHODOLOGY/PRINCIPAL FINDINGS: We assessed published studies of the association between these microRNA polymorphisms and cancer risk from eleven studies with 16,771 subjects for miR-196a2 and from ten studies with 15,126 subjects for miR-146a. As for rs11614913, the contrast of homozygote (TT vs CC: OR = 0.92, 95% CI = 0.85-0.99, P(heterogeneity) = 0.45), allele (T vs C: OR = 0.96, 95% CI = 0.92-0.99, P(heterogeneity) = 0.61) and recessive model (OR = 0.90, 95% CI = 0.84-0.97, P(heterogeneity) = 0.50) produced statistically association. Subgroup analysis by ethnicity, statistically significantly decreased cancer risks were found among Asians for allele contrast (OR = 0.95, 95% CI = 0.90-0.99, P(heterogeneity) = 0.74) and the recessive genetic model (OR = 0.90, 95% CI = 0.82-0.98, P(heterogeneity) = 0.85). According to subgroup analysis by tumor types, the protective effect of C/T polymorphism was only found in breast cancer under allele contrast (T vs C: OR = 0.94, 95% CI = 0.88-0.99, P(heterogeneity) = 0.26). For rs2910164, no significant associations were found among overall analysis model with relatively large heterogeneity. Through the stratified analysis, heterogeneity decreased significantly. In the subgroup analyses by cancer types, the C allele of rs2910164 was associated with protection from digestive cancer in allele contrast (C vs G: OR = 0.86, 95% CI = 0.77-0.96, P(heterogeneity) = 0.51). CONCLUSIONS/SIGNIFICANCE: Our meta-analysis suggests that the rs11614913 most likely contributes to decreased susceptibility to cancer, especially in Asians and breast cancer. Besides, the C allele of the rs2910164 might be associated with a protection from digestive cancer

Overexpression of ZEB2 in Peritumoral Liver Tissue Correlates with Favorable Survival after Curative Resection of Hepatocellular Carcinoma

BACKGROUND: ZEB2 has been suggested to mediate EMT and disease aggressiveness in several types of human cancers. However, the expression patterns of ZEB2 in hepatocellular carcinoma (HCC) and its effect on prognosis of HCC patients treated with hepatectomy are unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the methods of tissue microarray and immunohistochemistry (IHC) were utilized to investigate ZEB2 expression in HCC and peritumoral liver tissue (PLT). Receiver operating characteristic (ROC), spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Up-regulated expression of cytoplasmic/nuclear ZEB2 protein was observed in the majority of PLTs, when compared to HCCs. Further analysis showed that overexpression of cytoplasmic ZEB2 in HCCs was inversely correlated with AFP level, tumor size and differentiation (P<0.05). Also, overexpression of cytoplasmic ZEB2 in PLTs correlated with lower AFP level (P<0.05). In univariate survival analysis, a significant association between overexpression of cytoplasmic ZEB2 by HCCs/PLTs and longer patients' survival was found (P<0.05). Importantly, cytoplasmic ZEB2 expression in PLTs was evaluated as an independent prognostic factor in multivariate analysis (P<0.05). Consequently, a new clinicopathologic prognostic model with cytoplasmic ZEB2 expression (including HCCs and PLTs) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P = 0.002). CONCLUSIONS/SIGNIFICANCE: Our findings provide a basis for the concept that cytoplasmic ZEB2 expressed by PLTs can predict the postoperative survival of patients with HCC. The combined cytoplasmic ZEB2 prognostic model may become a useful tool for identifying patients with different clinical outcomes

Avoiding Loss of Catalytic Activity of Pd Nanoparticles Partially Embedded in Nanoditches in SiC Nanowires

Nanoditches from selective etching of periodically twinned SiC nanowires were employed to hinder the migration and coalescence of Pd nanoparticles supported on the nanowires, and thus to improve their catalytic stability for total combustion of methane. The results show that the etched Pd/SiC catalyst can keep the methane conversion of almost 100% while the unetched one has an obvious decline in the catalytic activity from 100 to 82% after ten repeated reaction cycles. The excellent catalytic stability originates from the limitation of the nanoditches to the migration and growth of Pd nanoparticles

An Ultra-High Discrimination Y Chromosome Short Tandem Repeat Multiplex DNA Typing System

In forensic casework, Y chromosome short tandem repeat markers (Y-STRs) are often used to identify a male donor DNA profile in the presence of excess quantities of female DNA, such as is found in many sexual assault investigations. Commercially available Y-STR multiplexes incorporating 12–17 loci are currently used in forensic casework (Promega's PowerPlex® Y and Applied Biosystems' AmpFlSTR® Yfiler®). Despite the robustness of these commercial multiplex Y-STR systems and the ability to discriminate two male individuals in most cases, the coincidence match probabilities between unrelated males are modest compared with the standard set of autosomal STR markers. Hence there is still a need to develop new multiplex systems to supplement these for those cases where additional discriminatory power is desired or where there is a coincidental Y-STR match between potential male participants. Over 400 Y-STR loci have been identified on the Y chromosome. While these have the potential to increase the discrimination potential afforded by the commercially available kits, many have not been well characterized. In the present work, 91 loci were tested for their relative ability to increase the discrimination potential of the commonly used ‘core’ Y-STR loci. The result of this extensive evaluation was the development of an ultra high discrimination (UHD) multiplex DNA typing system that allows for the robust co-amplification of 14 non-core Y-STR loci. Population studies with a mixed African American and American Caucasian sample set (n = 572) indicated that the overall discriminatory potential of the UHD multiplex was superior to all commercial kits tested. The combined use of the UHD multiplex and the Applied Biosystems' AmpFlSTR® Yfiler® kit resulted in 100% discrimination of all individuals within the sample set, which presages its potential to maximally augment currently available forensic casework markers. It could also find applications in human evolutionary genetics and genetic genealogy

Nonadhesive Culture System as a Model of Rapid Sphere Formation with Cancer Stem Cell Properties

BACKGROUND: Cancer stem cells (CSCs) play an important role in tumor initiation, progression, and metastasis and are responsible for high therapeutic failure rates. Identification and characterization of CSC are crucial for facilitating the monitoring, therapy, or prevention of cancer. Great efforts have been paid to develop a more effective methodology. Nevertheless, the ideal model for CSC research is still evolving. In this study, we created a nonadhesive culture system to enrich CSCs from human oral squamous cell carcinoma cell lines with sphere formation and to characterize their CSC properties further. METHODS: A nonadhesive culture system was designed to generate spheres from the SAS and OECM-1 cell lines. A subsequent investigation of their CSC properties, including stemness, self-renewal, and chemo- and radioresistance in vitro, as well as tumor initiation capacity in vivo, was also performed. RESULTS: Spheres were formed cost-effectively and time-efficiently within 5 to 7 days. Moreover, we proved that these spheres expressed putative stem cell markers and exhibited chemoradiotherapeutic resistance, in addition to tumor-initiating and self-renewal capabilities. CONCLUSIONS: Using this nonadhesive culture system, we successfully established a rapid and cost-effective model that exhibits the characteristics of CSCs and can be used in cancer research

Small Molecule Amiloride Modulates Oncogenic RNA Alternative Splicing to Devitalize Human Cancer Cells

Alternative splicing involves differential exon selection of a gene transcript to generate mRNA and protein isoforms with structural and functional diversity. Abnormal alternative splicing has been shown to be associated with malignant phenotypes of cancer cells, such as chemo-resistance and invasive activity. Screening small molecules and drugs for modulating RNA splicing in human hepatocellular carcinoma cell line Huh-7, we discovered that amiloride, distinct from four pH-affecting amiloride analogues, could “normalize” the splicing of BCL-X, HIPK3 and RON/MISTR1 transcripts. Our proteomic analyses of amiloride-treated cells detected hypo-phosphorylation of splicing factor SF2/ASF, and decreased levels of SRp20 and two un-identified SR proteins. We further observed decreased phosphorylation of AKT, ERK1/2 and PP1, and increased phosphorylation of p38 and JNK, suggesting that amiloride treatment down-regulates kinases and up-regulates phosphatases in the signal pathways known to affect splicing factor protein phosphorylation. These amiloride effects of “normalized” oncogenic RNA splicing and splicing factor hypo-phosphorylation were both abrogated by pre-treatment with a PP1 inhibitor. Global exon array of amiloride-treated Huh-7 cells detected splicing pattern changes involving 584 exons in 551 gene transcripts, many of which encode proteins playing key roles in ion transport, cellular matrix formation, cytoskeleton remodeling, and genome maintenance. Cellular functional analyses revealed subsequent invasion and migration defects, cell cycle disruption, cytokinesis impairment, and lethal DNA degradation in amiloride-treated Huh-7 cells. Other human solid tumor and leukemic cells, but not a few normal cells, showed similar amiloride-altered RNA splicing with devitalized consequence. This study thus provides mechanistic underpinnings for exploiting small molecule modulation of RNA splicing for cancer therapeutics

Dissecting Epigenetic Silencing Complexity in the Mouse Lung Cancer Suppressor Gene Cadm1

Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and complex, involving the interplay of several effectors including nucleosome positioning, DNA methylation, histone variants and histone modifications. We investigated the epigenetic silencing complexity in the tumor suppressor gene Cadm1 in mouse lung cancer progenitor cell lines, exhibiting promoter hypermethylation associated with transcriptional repression, but mostly unresponsive to demethylating drug treatments. After predicting nucleosome positions and transcription factor binding sites along the Cadm1 promoter, we carried out single-molecule mapping with DNA methyltransferase M.SssI, which revealed in silent promoters high nucleosome occupancy and occlusion of transcription factor binding sites. Furthermore, M.SssI maps of promoters varied within and among the different lung cancer cell lines. Chromatin analysis with micrococcal nuclease also indicated variations in nucleosome positioning to have implications in the binding of transcription factors near nucleosome borders. Chromatin immunoprecipitation showed that histone variants (H2A.Z and H3.3), and opposing histone modification marks (H3K4me3 and H3K27me3) all colocalized in the same nucleosome positions that is reminiscent of epigenetic plasticity in embryonic stem cells. Altogether, epigenetic silencing complexity in the promoter region of Cadm1 is not only defined by DNA hypermethylation, but high nucleosome occupancy, altered nucleosome positioning, and ‘bivalent’ histone modifications, also likely contributed in the transcriptional repression of this gene in the lung cancer cells. Our results will help define therapeutic intervention strategies using epigenetic drugs in lung cancer