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Yue Jiang, Jiaping Chen,
Jiangping Wu,
Zhibin Hu,
Zhenzhen Qin,
Xiao'an Liu,
Xiaoxiang Guan,
Yanru Wang,
Jing Han,
Tao Jiang,
Guangfu Jin,
Mingfeng Zhang,
Hongxia Ma,
Shui Wang,
Hongbing Shen
[show abstract]
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ABSTRACT: MicroRNAs (miRNA) are a class of small, noncoding RNA molecules involved in a diversity of cellular functions. Single nucleotide polymorphisms (SNPs) in miRNA biosynthesis genes may affect the biogenesis of miRNAs and consequently affect the miRNAs regulation. In this study, we systematically selected 24 functional SNPs located in 8 key biosynthesis genes of miRNA (DROSHA, DGCR8, RAN, DICER, AGO2, GEMIN3, GEMIN4 and HIWI) and investigated the association between these SNPs and the risk of breast cancer in a Chinese population. All 24 SNPs were firstly genotyped in stage 1 (878 cases and 900 controls) and three promising SNPs (DROSHA rs2291109, RAN rs7301722 and DGCR8 rs417309) were selected for further validation in stage 2 (914 cases and 967 controls). We found that only one SNP (rs417309) located in the 3'-UTR of DGCR8 was consistently associated with an increased breast cancer risk in two stages with a combined odds ratio (OR) of 1.59 [95% confidence interval (CI) = 1.09-2.33]. Based on the bioinformatics prediction, rs417309 is located at the binding sites of miR-106b and miR-579 in the 3'UTR of DGCR8. To evaluate whether rs417309 variant affects the binding capacity of miRNAs, we cotransfected luciferase reporter plasmids of DGCR8 3'UTR and miR-106b/miR-579 in three cell lines. Luciferase activity assay showed a higher expression level with rs417309 A allele compared with G allele in MCF-7 cell lines (P = 3.31×10(-) (7) , 9.29×10(-) (7) for miR-106b and miR-579, respectively). Our findings suggested that DGCR8 rs417309 G>A might affect breast cancer risk through the interruption of miRNA binding. © 2013 Wiley Periodicals, Inc.
International Journal of Cancer 04/2013; · 5.44 Impact Factor
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Yue Jiang,
Zhenzhen Qin,
Zhibin Hu,
Xiaoxiang Guan,
Yanru Wang,
Yisha He,
Jialei Xue,
Xiao'an Liu, Jiaping Chen,
Juncheng Dai,
Guangfu Jin,
Hongxia Ma,
Shui Wang,
Hongbing Shen
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[hide abstract]
ABSTRACT: Genetic variants may influence miRNA-mRNA interaction through modulate binding affinity, creating or destroying miRNA binding sites. Twenty-four single nucleotide polymorphisms (SNPs) that were predicted to affect the binding affinity of breast cancer related miRNAs to 3'-UTR of known genes were genotyped in 878 breast cancer cases and 900 controls in Chinese women. Three promising SNPs (rs10494836, rs10857748 and rs7963551) were further validated in additional 914 breast cancer cases and 967 controls. The variant allele (C) of rs7963551 at 3'-UTR of RAD52 showed a consistently reduced breast cancer risk in two stages with a combined odds ratio (OR) of 0.84 [95% confidence interval (CI) = 0.75-0.95], which was more prominent among women with early age at first live birth (OR = 0.71, 95% CI = 0.58-0.87). A significant interaction was observed between rs7963551 and age at first live birth on breast cancer risk (P for interaction = 0.04). Luciferase activity assay showed a higher expression level for rs7963551 C allele as compared with A allele (P = 5.19×10(-3) for MCF-7 cell lines), which might be due to a reduced inhibition from a weakened binding capacity of miRNA to 3'-UTR of RAD52 harboring C allele. These findings indicate that rs7963551 located at hsa-let-7 binding site may alter expression of RAD52 through modulating miRNA-mRNA interaction and contribute to the development of breast cancer in Chinese women.
Carcinogenesis 11/2012; · 5.70 Impact Factor
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Guangfu Jin,
Hongxia Ma,
Chen Wu,
Juncheng Dai,
Ruyang Zhang,
Yongyong Shi,
Jiachun Lu,
Xiaoping Miao,
Meilin Wang,
Yifeng Zhou, [......],
Wen Tan,
Baosen Zhou,
Daru Lu,
Tangchun Wu,
Zhengdong Zhang,
Feng Chen,
Xinru Wang,
Zhibin Hu,
Dongxin Lin,
Hongbing Shen
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ABSTRACT: Cancer susceptibility loci identified in reported genome-wide association studies (GWAS) are often tumor-specific; however, evidence of pleiotropy of some genes/loci has also been observed and biologically plausible. We hypothesized that there are important regions in the genome harboring genetic variants associated with risk of multiple types of cancer. In the current study, we attempted to map genetic variants that have consistent effects on risk of multiple cancers using our existing genome-wide scan data of lung cancer, noncardia gastric cancer, and esophageal squamous-cell carcinoma with overall 5,368 cases and 4,006 controls (GWAS stage), followed by a further evaluation in additional 9,001 cases with one of these cancer types and 11,436 controls (replication stage). Five variants satisfying the criteria of pleiotropy with p values from 1.10 × 10(-8) to 8.96 × 10(-6) for genome-wide scans of three cancer types were further evaluated in the replication stage. We found consistent associations of rs2494938 at 6p21.1 and rs2285947 at 7p15.3 with these three cancers in both GWAS and replication stages. In combined samples of GWAS and replication stages, the minor alleles of rs2494938 and rs2285947 were significantly associated with an increased risk of the cancers (odds ratio [OR] = 1.15, 95% confidence interval [CI], 1.10-1.19 and OR = 1.17, 95% CI, 1.12-1.21), with the p values being 1.20 × 10(-12) and 1.26 × 10(-16), respectively, which are at a genome-wide significance level. Our findings highlight the potential importance of variants at 6p21.1 and 7p15.3 in the susceptibility to multiple cancers.
The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
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ABSTRACT: Recently, it has been shown that ectopic expression of several germ line genes, such as piwi, vasa, nos and aub, drives the growth of malignant brain tumors in Drosophila. A genome-wide association study (GWAS) of ∼18 000 subjects indicated that genetic variation at 22q12.2, the location of the conserved meiotic gene HORMAD2, may contribute to the risk of lung cancer in Han Chinese individuals. The expression pattern of human HORMAD2 in multiple human tissues was determined by RT-PCR. HORMAD2 protein expression and localization were analyzed in the human testis using immunohistochemistry. The expression of HORMAD2 in lung cancer and normal tissues was studied using quantitative RT-PCR and immunohistochemistry. HORMAD2 is predominantly expressed in human testis and weakly expressed in liver. HORMAD2 is ectopically expressed in nearly 10% of lung cancer samples from Chinese Han individuals. In conclusion, HORMAD2 is a novel cancer/testis gene discovered by GWAS, which may provide a new target for lung cancer research.
Molecular Human Reproduction 08/2012; · 3.85 Impact Factor
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Jingjing Ben,
Guangfu Jin,
Yan Zhang,
Bingqing Ma,
Hui Bai, Jiaping Chen,
Hanze Zhang,
Qixing Gong,
Xiaodan Zhou,
Hanwen Zhang,
Lingling Qian,
Xudong Zhu,
Xiaoyu Li,
Qing Yang,
Zhibin Hu,
Yong Xu,
Hongbing Shen,
Qi Chen
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ABSTRACT: Rationale: Genetic alterations on 8p22 have been implicated in multiple cancers, including lung cancer. In this region, genetic variants of the class A scavenger receptor (SR-A) gene have been associated with prostate cancer risk and have been highlighted as a potential susceptibility gene of cancer. Objectives: To determine whether common polymorphisms in the SR-A gene are associated with human lung cancer risk and to clarify the role of SR-A in lung carcinogenesis. Methods: The relationship of three potentially functional polymorphisms (T-365C, T+25C, and Ala275Pro) in the SR-A gene with lung cancer risk was evaluated in 1287 lung cancer case subjects and 1261 control subjects from the Chinese population. At the same time, SR-A null mice were used to investigate its role in lung cancer development. Measurements and Main Results: The T+25C polymorphism was independently associated with lung cancer risk and significantly correlated with decreased expression of SR-A. The decreased SR-A expression was also found in tumor tissues as compared with normal tissues. Depletion of SR-A boosted the growth and angiogenesis of implanted Lewis lung carcinoma in mice. The cancer-suppressing capability of SR-A was attributable to its expression in bone marrow-derived cells as evidenced by bone marrow transplantation. Further analysis revealed augmented expression of proangiogenic factors including matrix metalloproteinase-9 (MMP9) in SR-A-deficient mice, indicative of a more procarcinogenic microenvironment. Last, zoledronate, an MMP9 inhibitor, abrogated acceleration of tumor growth conferred by SR-A loss-of-function. Conclusions: Evidence from the population study and mouse model strongly indicates that SR-A may function as a tumor modulator to inhibit lung cancer growth through affecting the tumor microenvironment.
American Journal of Respiratory and Critical Care Medicine 08/2012; 186(8):763-72. · 11.08 Impact Factor
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Hongxia Ma,
Huizhang Li,
Guangfu Jin,
Juncheng Dai,
Jing Dong,
Zhenzhen Qin, Jiaping Chen,
Shui Wang,
Xinru Wang,
Zhibin Hu,
Hongbing Shen
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ABSTRACT: A single nucleotide polymorphism (SNP) rs999737 at 14q24.1 was identified as a susceptibility marker of breast cancer in a genome-wide association study of the European population, which was also confirmed by some of the following studies in populations of European descent. However, rs999737 is very rare or nonpolymorphic in non-Europeans including Chinese, and the role of other genetic variants at 14q24.1 has not been evaluated in populations of non-European descent. In this study, we first selected 21 common tagging SNPs (minor allele frequency [MAF] >0.05 in the Chinese population) by searching the Hapmap database, covering a linage disequilibrium region of more than 70 Kb at 14q24.1, and then conducted a two-stage study (stage I: 878 cases and 900 controls; stage II: 914 cases and 967 controls) to investigate the associations between these tagging SNPs and risk of breast cancer in a Chinese population. In stage I, two SNPs (rs2842346 and rs17828907) were identified to be significantly associated with breast cancer risk (p=0.030 and 0.027 for genotype distributions, respectively). However, no significant associations were found between these two SNPs and breast cancer risk in either stage II or the combined dataset. These findings suggest that common variants at 14q24.1 might not be associated with the risk of breast cancer in the Chinese population, which will need the replication in additional larger studies.
DNA and cell biology 02/2012; 31(6):1114-20. · 2.28 Impact Factor
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Jiaping Chen,
Yue Jiang,
Xiaoan Liu,
Zhenzhen Qin,
Juncheng Dai,
Guangfu Jin,
Hongxia Ma,
Shui Wang,
Xinru Wang,
Zhibin Hu,
Hongbing Shen
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ABSTRACT: A recent genome-wide association study (GWAS) has identified a new subset of breast cancer susceptibility loci on chromosomes 9, 10, and 11 in populations of European descent. However, because of the genetic heterogeneity, the role of these loci in non-European descent populations is still unclear. To evaluate the relationships between genetic variants in these regions identified by GWAS and breast cancer risk in Chinese women, we genotyped four common SNPs at 9p21(rs1011970 and rs10757278), 10p15 (rs2380205), and 10q22 (rs1250009) in a two-stage case-control study with a total of 1792 breast cancer cases and 1,867 controls. We found that rs1250009 at 10q22 was consistently associated with risk of breast cancer in stage 1 and stage 2, with a per-allele OR of 1.13 (95% CI 1.02-1.25) after two stages combined (P = 0.023). However, no significant associations were observed between the other three SNPs and breast cancer risk. Our results suggest that the genetic variants at 10q22 may play an important role in breast cancer development in Chinese women, and rs1250009 may be a candidate marker for breast cancer susceptibility.
Breast Cancer Research and Treatment 12/2011; 132(2):741-6. · 4.43 Impact Factor
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Yongyong Shi,
Zhibin Hu,
Chen Wu,
Juncheng Dai,
Huizhang Li,
Jing Dong,
Meilin Wang,
Xiaoping Miao,
Yifeng Zhou,
Feng Lu, [......],
Zhiqiang Li,
Minjie Chu,
Hongxia Ma, Jiaping Chen,
Guangfu Jin,
Wen Tan,
Tangchun Wu,
Zhengdong Zhang,
Dongxin Lin,
Hongbing Shen
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ABSTRACT: Gastric cancer, including the cardia and non-cardia types, is the second leading cause of cancer-related deaths worldwide. To identify genetic risk variants for non-cardia gastric cancer, we performed a genome-wide association study in 3,279 individuals (1,006 with non-cardia gastric cancer and 2,273 controls) of Chinese descent. We replicated significant associations in an additional 6,897 subjects (3,288 with non-cardia gastric cancer and 3,609 controls). We identified two new susceptibility loci for non-cardia gastric cancer at 5p13.1 (rs13361707 in the region including PTGER4 and PRKAA1; odds ratio (OR) = 1.41; P = 7.6 × 10(-29)) and 3q13.31 (rs9841504 in ZBTB20; OR = 0.76; P = 1.7 × 10(-9)). Imputation analyses also confirmed previously reported associations of rs2294008 and rs2976392 on 8q24, rs4072037 on 1q22 and rs13042395 on 20p13 with non-cardia gastric cancer susceptibility in the Han Chinese population.
Nature Genetics 12/2011; 43(12):1215-8. · 35.53 Impact Factor
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Zhibin Hu,
Chen Wu,
Yongyong Shi,
Huan Guo,
Xueying Zhao,
Zhihua Yin,
Lei Yang,
Juncheng Dai,
Lingmin Hu,
Wen Tan, [......],
Zhengdong Zhang,
Feng Chen,
Xinru Wang,
Li Jin,
Jiachun Lu,
Baosen Zhou,
Daru Lu,
Tangchun Wu,
Dongxin Lin,
Hongbing Shen
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ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide. To identify genetic factors that modify the risk of lung cancer in individuals of Chinese ancestry, we performed a genome-wide association scan in 5,408 subjects (2,331 individuals with lung cancer (cases) and 3,077 controls) followed by a two-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10(-8)) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10(-26)), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10(-20) and P = 1.0 × 10(-27), respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10(-12)) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10(-11) and P = 6.2 × 10(-13), respectively). Two of these loci (13q12.12 and 22q12.2) were newly identified in the Chinese population. These results suggest that genetic variants in 3q28, 5p15.33, 13q12.12 and 22q12.2 may contribute to the susceptibility of lung cancer in Han Chinese.
Nature Genetics 07/2011; 43(8):792-6. · 35.53 Impact Factor
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ABSTRACT: Chemokines play an important role in the pathogenesis of non-small cell lung cancer (NSCLC). Although the deregulations of chemokines have been reported to be associated with the development and progression of many human cancers including lung cancer, polymorphisms of chemokine genes have not been examined with the survival of NSCLC. We systematically investigated associations of 23 common potentially functional SNPs in the key chemokine genes (CCL2, CCL5, CCL8, CCL20, CCL22, CXCL1, CXCL6, CXCL9 and CXCL12) with the survival of NSCLC in a case cohort of 568 NSCLC patients in a Chinese population. The results showed that variant genotypes of CCL2 rs3760396 and CCL8 rs3138035 were associated with a significantly decreased risk of death for NSCLC (dominant model: adjusted HR=0.65, 95% CI=0.48-0.89 for rs3760396; dominant model: adjusted HR=0.65, 95% CI=0.49-0.86 for rs3138035), while CXCL12 rs1804429 was associated with an increased risk of death for NSCLC (CC vs AA: adjusted HR=6.03, 95% CI=1.44-25.24). Further stepwise regression analysis suggested that only rs3138035, a SNP located at 5'-flanking region of CCL8, was an independently favorable factor for the prognosis of NSCLC and the protective effect was more evident in smokers (adjusted HR=0.61, 95% CI=0.42-0.87), patients with squamous cell cancer (adjusted HR=0.58, 95% CI=0.35-0.96), patients with early stage (adjusted HR=0.32, 95% CI=0.15-0.67) and patients treated with surgical operation (adjusted HR=0.47, 95% CI=0.31-0.71). In addition, the interaction analysis demonstrated that stage and surgical operation interacted with the genetic effect of rs3138035 in relation to NSCLC survival (adjusted P(interaction)=0.02 and 0.01, respectively). These findings suggest that CCL8 rs3138035 may be one of the candidate biomarkers for NSCLC survival and may modify death risk associated with stage and surgical operation. Larger studies incorporating functional evaluations are warranted to validate our findings.
Lung cancer (Amsterdam, Netherlands) 04/2011; 74(2):164-9. · 3.14 Impact Factor
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ABSTRACT: The exopolysaccharide (EPS) is a polysaccharide from cultivated Cordyceps sinensis, which possesses immunomodulatory and antitumor effects, was purified by DEAE-32 cellulose and Sephadex G-200 gel. The preliminary characters of EPS were analyzed by IR and GC, and the molecular weight was estimated by gel filtration. The effect of EPS on proliferation ability of lymphocytes from ICR mice was assayed by MTT method. The mRNA and protein expression levels of several cytokines in spleen and thymus cells were detected by RT-PCR and ELISA. The results showed that EPS consists of mannose, glucose, and galactose in a ratio of 23:1:2.6. Its molecular weight is about 1.04 × 10(5). EPS elevated proliferation ability of spleen lymphocytes only at 100 μg/ml after 48 h treatment. Tumor necrosis factor alpha (TNF-α), interferon-α (IFN-γ), and interleukin-2 (IL-2) mRNA levels in splenocytes and thymocytes were increased after EPS treatment for 2, 4, 8, or 20 h. EPS also significantly elevated splenic TNF-α and IFN-γ protein expressions at 100 μg/ml and increased thymic TNF-α and IFN-γ protein levels at 50 and 100 μg/ml. These data indicated that EPS may stimulate cytokine expressions of immunocytes.
Applied biochemistry and biotechnology 03/2011; 163(5):669-78. · 1.94 Impact Factor
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Yue Jiang,
Hao Shen,
Xiao'an Liu,
Juncheng Dai,
Guangfu Jin,
Zhenzhen Qin, Jiaping Chen,
Shui Wang,
Xinru Wang,
Zhibin Hu,
Hongbing Shen
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have identified several breast cancer susceptibility loci, and one genetic variant, rs11249433, at 1p11.2 was reported to be associated with breast cancer in European populations. To explore the genetic variants in this region associated with breast cancer in Chinese women, we conducted a two-stage fine-mapping study with a total of 1792 breast cancer cases and 1867 controls.
Seven single nucleotide polymorphisms (SNPs) including rs11249433 in a 277 kb region at 1p11.2 were selected and genotyping was performed by using TaqMan® OpenArray™ Genotyping System for stage 1 samples (878 cases and 900 controls). In stage 2 (914 cases and 967 controls), three SNPs (rs2580520, rs4844616 and rs11249433) were further selected and genotyped for validation. The results showed that one SNP (rs2580520) located at a predicted enhancer region of SRGAP2 was consistently associated with a significantly increased risk of breast cancer in a recessive genetic model [Odds Ratio (OR) = 1.66, 95% confidence interval (CI) = 1.16-2.36 for stage 2 samples; OR = 1.51, 95% CI = 1.16-1.97 for combined samples, respectively]. However, no significant association was observed between rs11249433 and breast cancer risk in this Chinese population (dominant genetic model in combined samples: OR = 1.20, 95% CI = 0.92-1.57).
Genotypes of rs2580520 at 1p11.2 suggest that Chinese women may have different breast cancer susceptibility loci, which may contribute to the development of breast cancer in this population.
PLoS ONE 01/2011; 6(6):e21563. · 4.09 Impact Factor
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ABSTRACT: Murine double minute 2 (MDM2) is a negative regulator of the tumor suppressor gene p53. Single nucleotide polymorphisms in MDM2 and p53 can affect patient's response to chemotherapy as well as overall survival of many cancers. This study aimed to assess the associations between polymorphisms in MDM2 and p53 and survival of non-small cell lung cancer (NSCLC) patients in Chinese. We selected and genotyped both potentially functional SNPs and tagging SNPs in MDM2 and p53 using Illumina Golden Gate platform in a cohort of 568 NSCLC patients. Associations between genotypes and NSCLC median survival time (MST) were assessed using the Kaplan-Meier method. Cox proportional hazard models were performed with the adjustment for age, stage, smoking, histology, surgical operation, and chemo- or radiotherapy status. We found that the MDM2 SNP309 (rs2279744) GT/TT genotypes were associated with a significantly worse survival (MST: 23.0 mo for GT/TT vs. 33.0 mo for GG; log-rank P = 0.028). In the multivariate Cox regression analyses, the MDM2 SNP309GT/TT genotypes were associated with a 1.42-fold [HR = 1.42, 95% confidence interval (CI), 1.09-1.84] increased risk of death of NSCLC, compared with SNP309GG genotype. MDM2 SNP309 may be used as one of the candidate biomarkers to predict NSCLC survival.
Molecular Carcinogenesis 01/2011; 50(6):433-8. · 3.16 Impact Factor
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ABSTRACT: The cell cycle governs the proliferation and growth of cells and is strictly controlled by some regulators including cyclins, CDKs and CKIs. Germ-line and somatic mutations in cell cycle genes were frequently observed in a subset of cancers including non-small cell lung cancer (NSCLC). In this study, we hypothesized that potentially functional single nucleotide polymorphisms (SNPs) in cell cycle genes may contribute to the prognosis of NSCLC in China. 54 potentially functional polymorphisms in key cell cycle genes (CDK1, CDK2, CDK4, CDK6, CDK7, CCND1, CCND2, CCND3, CCNE1, CCNA1, CCNA2, CCNB1, CCNH, p15, p16, p18, p19, p21, p27, Cdc25A and Cdc25B) were genotyped by using Illumina SNP genotyping platform to evaluate their associations with survival of NSCLC in a clinical cohort of 568 patients. We found that p18 rs3176447 variant genotypes were significantly associated with the decreased risk of death of NSCLC patients (adjusted HR=0.74, 95% CI=0.57-0.97 in an additive model; adjusted HR=0.76, 95% CI=0.55-0.97 in a dominant model); however, p21 rs2395655 variant genotypes were significantly associated with the increased risk of death (adjusted HR=1.21, 95% CI=1.02-1.42 in an additive model; adjusted HR=1.38, 95% CI=1.07-1.78 in a recessive model). Furthermore, the combined effect of unfavorable genotypes for these two SNPs was more prominent in patients with squamous cell carcinoma, late stage and without chemo- or radio-therapy. Although the exact biological function remains to be explored, our findings suggest possible association of polymorphisms of p18 and p21 with the prognosis of NSCLC in a Chinese population. Further large and functional studies are needed to confirm our findings.
Lung cancer (Amsterdam, Netherlands) 12/2010; 73(1):32-7. · 3.14 Impact Factor
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Zhibin Hu,
Yongqian Shu,
Yijiang Chen, Jiaping Chen,
Jing Dong,
Yao Liu,
Shiyang Pan,
Lin Xu,
Jing Xu,
Yi Wang,
Juncheng Dai,
Hongxia Ma,
Guangfu Jin,
Hongbing Shen
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ABSTRACT: Previously, we reported that common variants in precursor microRNA (pre-miRNA) sequences played a role in the prediction of non-small cell lung cancer (NSCLC) survival.
To assess whether variants in the pre-miRNA flanking region can influence the clinical behavior of NSCLC.
We conducted a two-stage study to examine the impact of a panel of 85 single-nucleotide polymorphisms on the overall survival of 923 patients with NSCLC (568 in the screening set and 355 in the validation set) in China.
Eleven single-nucleotide polymorphisms were primarily associated with NSCLC survival in the univariate analysis. However, in the validation set, only miR-30c-1 rs928508 was consistently an NSCLC survival predictor and the protective role of rs928508 AG/GG genotypes was more pronounced among early-stage (stage I/II) patients and patients treated with surgery. The area under the curve at Year 5 was significantly increased from 0.658 to 0.741 after adding the miR-30c-1 rs928508 risk score to the traditional clinical risk score (stage and surgery). Furthermore, in the genotype-phenotype correlation analysis, rs928508 AG/GG genotypes were associated with a significantly decreased expression of precursor and mature miR-30c (P = 0.009 and 0.011), but not with that of its primary miRNA. The expression of the host nuclear transcription factor Y gene was correlated with pri-mir-30c-1, but not with rs928508 genotypes, implicating the coregulation of the transcription of nuclear transcription factor Y and pri-mir-30c-1.
Our data indicated, for the first time, that genetic polymorphisms in the pre-miRNA flanking region may be prognostic biomarkers of NSCLC, and rs928508 is such a potential candidate.
American Journal of Respiratory and Critical Care Medicine 10/2010; 183(5):641-8. · 11.08 Impact Factor
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Jing Xu,
Zhibin Hu,
Zhengfeng Xu,
Haiyong Gu,
Long Yi,
Hailong Cao, Jiaping Chen,
Tian Tian,
Jie Liang,
Ying Lin,
Wanshan Qiu,
Hongxia Ma,
Hongbing Shen,
Yijiang Chen
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ABSTRACT: Hox gene clusters play an important role during cardiac septation to valve formation in different species, and the miR-196a-HOXB8-Sonic hedgehog signaling pathway is of particular interest. Recently, we found that a genetic variant of rs11614913 in the miR-196a2 sequence could alter mature miR-196a expression and target mRNA binding; this observation led us to hypothesize that rs11614913 might influence susceptibility to sporadic congenital heart disease (CHD). We conducted a three-stage case-control study of CHD in Chinese to test our hypothesis by genotyping miR-196a2 rs11614913 and three other pre-miRNA SNPs (miR-146a rs2910164, miR-149 rs2292832, and miR-499 rs3746444) in 1,324 CHD cases and 1,783 non-CHD controls. We found that rs11614913 CC was associated with a significantly increased risk of CHD in all three stages combined (P=6.81 x 10(-6)). In a genotype-phenotype correlation analysis using 29 cardiac tissue samples of CHD, rs11614913 CC was associated with significantly increased mature miR-196a expression (P=0.001). In vitro binding assays further revealed that the rs11614913 variant affects HOXB8 binding to mature miR-196a. This is the first study to indicate that miR-196a2 rs11614913 plays a role in sporadic CHD susceptibility.
Human Mutation 06/2009; 30(8):1231-6. · 5.69 Impact Factor
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Tian Tian,
Yongqian Shu, Jiaping Chen,
Zhibin Hu,
Lin Xu,
Guangfu Jin,
Jie Liang,
Ping Liu,
Xiaoyi Zhou,
Ruifen Miao,
Hongxia Ma,
Yijiang Chen,
Hongbing Shen
[show abstract]
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ABSTRACT: microRNAs (miRNA) are a new class of non-protein-coding, small RNAs that function as tumor suppressors or oncogenes. They participate in diverse biological pathways and function as gene regulators. Recently, we conducted a survey of common single nucleotide polymorphisms (SNP) in miRNA sequences and reported that, among four SNPs (rs2910164, rs2292832, rs11614913, and rs3746444) in pre-miRNAs, rs11614913 in miR-196a2 might affect mature miR-196a expression and target mRNA-binding activity and was significantly associated with non-small cell lung cancer survival. However, it remains largely unknown whether miRNA SNPs may alter lung cancer susceptibility. In the current study, we evaluated associations between the above four SNPs in pre-miRNAs and lung cancer susceptibility in a case-control study of 1,058 incident lung cancer patients and 1,035 cancer-free controls in a Chinese population. We found that miR-196a2 rs11614913 variant homozygote CC was associated with approximately 25% significantly increased risk of lung cancer compared with their wild-type homozygote TT and heterozygote TC (odds ratio, 1.25; 95% confidence interval, 1.01-1.54). However, no significant effects were observed on the association between the other three SNPs and lung cancer risk. These findings suggest that functional SNP rs11614913 in miR-196a2 could also contribute to lung cancer susceptibility.
Cancer Epidemiology Biomarkers & Prevention 05/2009; 18(4):1183-7. · 4.12 Impact Factor
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ABSTRACT: Small, noncoding RNA molecules, called microRNAs (miRNAs), are thought to function as either tumor suppressors or oncogenes. Common single-nucleotide polymorphisms (SNPs) in miRNAs may change their property through altering miRNA expression and/or maturation, and thus they may have an effect on thousands of target mRNAs, resulting in diverse functional consequences. However, it remains largely unknown whether miRNA SNPs may alter cancer susceptibility. We evaluated the associations of selected four SNPs (rs2910164, rs2292832, rs11614913, and rs3746444) in pre-miRNAs (hsa-mir-146a, hsa-mir-149, hsa-mir-196a2, and hsa-mir-499) with breast cancer risk in a case-control study of 1,009 breast cancer cases and 1,093 cancer-free controls in a population of Chinese women and we found that hsa-mir-196a2 rs11614913:T>C and hsa-mir-499 rs3746444:A>G variant genotypes were associated with significantly increased risks of breast cancer (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.02-1.48 for rs11614913:T>C; and OR, 1.25; 95% CI, 1.02-1.51 for rs3746444:A>G in a dominant genetic model) in a dose-effect manner (P for trend was 0.010 and 0.037, respectively). These findings suggest, for the first time, that common SNPs in miRNAs may contribute to breast cancer susceptibility. Further functional characterization of miRNA SNPs and their influences on target mRNAs may provide underlying mechanisms for the observed associations and disease etiology.
Human Mutation 01/2009; 30(1):79-84. · 5.69 Impact Factor
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Zhibin Hu, Jiaping Chen,
Tian Tian,
Xiaoyi Zhou,
Haiyong Gu,
Lin Xu,
Yi Zeng,
Ruifen Miao,
Guangfu Jin,
Hongxia Ma,
Yijiang Chen,
Hongbing Shen
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ABSTRACT: Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non-small cell lung cancer (NSCLC). When we assumed that disease susceptibility was inherited as a recessive phenotype, we found that the rs11614913 SNP in hsa-mir-196a2 was associated with survival in individuals with NSCLC. Specifically, survival was significantly decreased in individuals who were homozygous CC at SNP rs11614913. In the genotype-phenotype correlation analysis of 23 human lung cancer tissue samples, rs11614913 CC was associated with a statistically significant increase in mature hsa-mir-196a expression but not with changes in levels of the precursor, suggesting enhanced processing of the pre-miRNA to its mature form. Furthermore, binding assays revealed that the rs11614913 SNP can affect binding of mature hsa-mir-196a2-3p to its target mRNA. Therefore, the rs11614913 SNP in hsa-mir-196a2 may be a prognostic biomarker for NSCLC. Further characterization of miRNA SNPs may open new avenues for the study of cancer and therapeutic interventions.
Journal of Clinical Investigation 07/2008; 118(7):2600-8. · 15.39 Impact Factor
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ABSTRACT: In order to explore the effects of exopolysaccharide fraction (EPSF) from one of the anamorph strains of Cordyceps sinensis on immunocyte activity of H22 tumor bearing mice, ICR mice were treated with EPSF for 7 days by intraperitoneal injection at doses of 15 mg/kg (low-dose), 30 mg/kg (mid-dose) and 60 mg/kg (high-dose) after H22 tumor cells were implanted. At the end of the experiments, the tumor weight of each mouse was measured. Phagocytosis of mouse peritoneal macrophages was tested by neutral red uptake. The TNF-alpha expression of macrophages was assayed by ELISA. Proliferation ability and cytotoxicity of spleen lymphocytes were determined by MTT methods. The mRNA levels of cytokine TNF-alpha and IFN-gamma mRNA of spleen lymphocytes were detected by RT-PCR. The results indicated that EPSF not only significantly inhibited the H22 tumor growth, but also significantly elevated immunocytes' activity. It significantly enhanced the phagocytosis capacity of peritoneal macrophages and proliferation ability of spleen lymphocytes at all the three doses; it significantly promoted macrophages' TNF-alpha expression and spleen lymphocytes' cytotoxicity. EPSF also significantly elevated TNF-alpha and IFN-gamma mRNA expression of splenic lymphocytes. This experimental finding suggests that EPSF could elevate the immunocytes' activity in H22 tumor bearing mice.
Fitoterapia 05/2008; 79(3):168-73. · 1.85 Impact Factor
