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1.
J Cell Biochem ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31898364

RESUMO

The study aimed to investigate the expression and function of bladder cancer (BC) long noncoding RNAs (lncRNAs) using a high-throughput platform. High-throughput sequencing was used to compare the expression profiles of lncRNA in BC and adjacent normal tissues. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), in situ hybridization, gene ontology, and Kyoto Encyclopedia of Genes and Genomes analysis were performed to verify differential expression of lncRNA. The effect of lncRNA overexpression on cellular proliferation, apoptosis, migration, and invasion was analyzed following the transfection of lncRNA overexpressing lentivirus into 5637 and T24 cell lines. The overexpressing cells were subcutaneously injected into nude mice to evaluate their effects on tumor growth. Tumor-associated RNA-binding proteins of lncRNA were analyzed by RNA pull-down combined with mass spectrometry. A total of 93 lncRNA genes were upregulated and 352 lncRNA genes were downregulated in the tissues of patients with BC. Of which, we investigated the function of downregulated lnc-MUC20-9. Overexpression of lnc-MUC20-9 in 5637 and T24 cells resulted in decreased tumor cell viability and cell clones, decreased migration and invasion, and increased apoptosis. Similarly, nude mice bearing lnc-MUC20-9 overexpressing tumor cells exhibited smaller tumor size and volume than that of mice bearing control cells. Mass spectrometry analysis showed that lnc-MUC20-9 binds to ROCK1, an oncogene whose expression was decreased in lnc-MUC20-9 overexpressing cells. The study revealed that lnc-MUC20-9 has the function of inhibiting tumor growth, migration, and invasion. In BC cells, lnc-MUC20-9 binds to ROCK1 and may be involved in lnc-MUC20-9-mediated tumor suppressor function, which might be potential therapeutic targets for BC.

2.
Int J Cancer ; 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31837001

RESUMO

The missing heritability of breast cancer could be partially attributed to rare variants (MAF < 0.5%). To identify breast cancer-associated rare coding variants, we conducted whole-exome sequencing (~50×) in genomic DNA samples obtained from 831 breast cancer cases and 839 controls of Chinese females. Using burden tests for each gene that included rare missense or predicted deleterious variants, we identified 29 genes showing promising associations with breast cancer risk. We replicated the association for two genes, OGDHL and BRCA2, at a Bonferroni-corrected p < 0.05, by genotyping an independent set of samples from 1,628 breast cancer cases and 1,943 controls. The association for OGDHL was primarily driven by three predicted deleterious variants (p.Val827Met, p.Pro839Leu, p.Phe836Ser; p < 0.01 for all). For BRCA2, we characterized a total of 27 disruptive variants, including 18 nonsense, six frameshift and three splicing variants, whereas they were only detected in cases, but none of the controls. All of these variants were either very rare (AF < 0.1%) or not detected in >4,500 East Asian women from the genome Aggregation database (gnomAD), providing additional support to our findings. Our study revealed a potential novel gene and multiple disruptive variants of BRCA2 for breast cancer risk, which may identify high-risk women in Chinese populations.

3.
BMC Med Genomics ; 12(1): 131, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533728

RESUMO

BACKGROUND: Although APOBEC-mutational signature is found in tumor tissues of multiple cancers, how a common germline APOBEC3A/B deletion affects the mutational signature remains unclear. METHODS: Using data from 10 cancer types generated as part of TCGA, we performed integrative genomic and association analyses to assess inter-relationship of expressions for isoforms APOBEC3A and APOBEC3B, APOBEC-mutational signature, germline APOBEC3A/B deletions, neoantigen loads, and tumor infiltration lymphocytes (TILs). RESULTS: We found that expression level of the isoform uc011aoc transcribed from the APOBEC3A/B chimera was associated with a greater burden of APOBEC-mutational signature only in breast cancer, while germline APOBEC3A/B deletion led to an increased expression level of uc011aoc in multiple cancer types. Furthermore, we found that the deletion was associated with elevated APOBEC-mutational signature, neoantigen loads and relative composition of T cells (CD8+) in TILs only in breast cancer. Additionally, we also found that APOBEC-mutational signature significantly contributed to neoantigen loads and certain immune cell abundances in TILs across cancer types. CONCLUSIONS: These findings reveal new insights into understanding the genetic, biological and immunological mechanisms through which APOBEC genes may be involved in carcinogenesis, and provide potential genetic biomarker for the development of disease prevention and cancer immunotherapy.

4.
Am J Hum Genet ; 105(3): 477-492, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31402092

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer-colorectal, lung, ovary, prostate, pancreas, and melanoma-by using transcriptome data from the Genotype-Tissue Expression (GTEx) Project, the Cancer Genome Atlas (TCGA), and other public data sources. By using integrative analysis strategies, we identified 270 candidate target genes, including 99 with previously unreported associations, for six cancer types. By analyzing functional genomic data, our results indicate that 180 genes (66.7% of 270) had evidence of cis-regulation by putative functional variants via proximal promoter or distal enhancer-promoter interactions. Together with our previously reported associations for breast cancer risk, our results show that 24 genes are shared by at least two cancer types, including four genes for both breast and ovarian cancer. By integrating mutation data from TCGA, we found that expression levels of 33 and 66 putative susceptibility genes were associated with specific mutational signatures and TMB of cancer-driver genes, respectively, at a Bonferroni-corrected p < 0.05. Together, these findings provide further insight into our understanding of how genetic risk variants might contribute to carcinogenesis through the regulation of susceptibility genes that are related to the biogenesis of somatic mutations.

5.
Cancer Epidemiol Biomarkers Prev ; 28(8): 1308-1315, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31160347

RESUMO

BACKGROUND: Pathogenic variants in susceptibility genes lead to increased breast cancer risk. METHODS: To identify coding variants associated with breast cancer risk, we conducted whole-exome sequencing in genomic DNA samples from 831 breast cancer cases and 839 controls of Chinese women. We also genotyped samples, including 4,580 breast cancer cases and 6,695 controls, using whole exome-chip arrays. We further performed a replication study using a Multi-Ethnic Global Array in samples from 1,793 breast cases and 2,059 controls. A single marker analysis was performed using the Fisher exact test. RESULTS: We identified a missense variant (rs139379666, P2974L; AF = 0.09% for breast cancer cases, but none for controls) in the ATM gene for breast cancer risk using combing data from 7,204 breast cancer cases and 9,593 controls (P = 1.7 × 10-5). To investigate the functionality of the variant, we first silenced ATM and then transfected the overexpression vectors of ATM containing the risk alleles (TT) or reference alleles (CC) of the variant in U2OS and breast cancer SK-BR3 cells, respectively. Our results showed that compared with the reference allele, the risk allele significantly disrupts the activity of homologous recombination-mediated double-strand breaks repair efficiency. Our results further showed that the risk allele may play a defected regulation role in the activity of the ATM structure. CONCLUSIONS: Our findings identified a novel mutation that disrupts ATM function, conferring to breast cancer risk. IMPACT: Functional investigation of genetic association findings is necessary to discover a pathogenic variant for breast cancer risk.

6.
Front Plant Sci ; 9: 1636, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498503

RESUMO

The ubiquitin C-terminal hydrolase (UCH) and ubiquitin-specific processing protease (UBP) protein families both function in protein deubiquitination, playing important roles in a wide range of biological processes in animals, fungi, and plants. Little is known about the functions of these proteins in rice (Oryza sativa), and the numbers of genes reported for these families have not been consistent between different rice database resources. To further explore their functions, it is necessary to first clarify the basic molecular and biochemical nature of these two gene families. Using a database similarity search, we clarified the numbers of genes in these two families in the rice genome, examined the enzyme activities of their corresponding proteins, and characterized the expression patterns of all OsUCH and representative OsUBP genes. Five OsUCH and 44 OsUBP genes were identified in the rice genome, with four OsUCH proteins and 10 of 16 tested representative OsUBP proteins showing enzymatic activities. Two OsUCHs and five OsUBPs were found to be preferentially expressed in the early development of rice stamens. This work thus lays down a reliable bioinformatic foundation for future investigations of genes in these two families, particularly for exploring their potential roles in rice stamen development.

7.
Plant Physiol ; 176(1): 819-835, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29158333

RESUMO

This study aimed at elucidating regulatory components behind floral organ identity determination and tissue development. It remains unclear how organ identity proteins facilitate development of organ primordia into tissues with a determined identity, even though it has long been accepted that floral organ identity is genetically determined by interaction of identity genes according to the ABC model. Using the chromatin immunoprecipitation sequencing technique, we identified OsTGA10, encoding a bZIP transcription factor, as a target of the MADS box protein OsMADS8, which is annotated as an E-class organ identity protein. We characterized the function of OsTGA10 using genetic and molecular analyses. OsTGA10 was preferentially expressed during stamen development, and mutation of OsTGA10 resulted in male sterility. OsTGA10 was required for tapetum development and functioned by interacting with known tapetum genes. In addition, in ostga10 stamens, the hallmark cell wall thickening of the endothecium was defective. Our findings suggest that OsTGA10 plays a mediator role between organ identity determination and tapetum development in rice stamen development, between tapetum development and microspore development, and between various regulatory components required for tapetum development. Furthermore, the defective endothecium in ostga10 implies that cell wall thickening of endothecium is dependent on tapetum development.


Assuntos
Flores/crescimento & desenvolvimento , Flores/metabolismo , Proteínas de Domínio MADS/metabolismo , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Parede Celular/metabolismo , DNA de Plantas/metabolismo , Epistasia Genética , Flores/citologia , Flores/ultraestrutura , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Oryza/genética , Fenótipo , Homologia de Sequência de Aminoácidos
8.
Mol Plant ; 8(7): 1069-89, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25684654

RESUMO

Stamen is a unique plant organ wherein germ cells or microsporocytes that commit to meiosis are initiated from somatic cells during its early developmental process. While genes determining stamen identity are known according to the ABC model of floral development, little information is available on how these genes affect germ cell initiation. By using the Affymetrix GeneChip Rice Genome Array to assess 51 279 transcripts, we established a dynamic gene expression profile (GEP) of the early developmental process of rice (Oryza sativa) stamen. Systematic analysis of the GEP data revealed novel expression patterns of some developmentally important genes including meiosis-, tapetum-, and phytohormone-related genes. Following the finding that a substantial amount of nuclear genes encoding photosynthetic proteins are expressed at the low levels in early rice stamen, through the ChIP-seq analysis we found that a C-class MADS box protein, OsMADS58, binds many nuclear-encoded genes participated in photosystem and light reactions and the expression levels of most of them are increased when expression of OsMADS58 is downregulated in the osmads58 mutant. Furthermore, more pro-chloroplasts are observed and increased signals of reactive oxygen species are detected in the osmads58 mutant anthers. These findings implicate a novel link between stamen identity determination and hypoxia status establishment.


Assuntos
Flores/crescimento & desenvolvimento , Flores/genética , Perfilação da Expressão Gênica , Oryza/crescimento & desenvolvimento , Oryza/genética , Fotossíntese/genética , Proteínas de Plantas/genética , Núcleo Celular/genética , Cloroplastos/genética , Cloroplastos/metabolismo , Flores/citologia , Flores/metabolismo , Genômica , Oryza/citologia , Oryza/metabolismo , Oxigênio/metabolismo , Proteínas de Plantas/metabolismo
9.
Zhonghua Wei Chang Wai Ke Za Zhi ; 13(5): 354-6, 2010 May.
Artigo em Chinês | MEDLINE | ID: mdl-20499304

RESUMO

OBJECTIVE: To evaluate the effect of Sapylin combined with intraperitoneal and systemic chemotherapy for advanced colon cancer following radical operation on local recurrence, hepatic metastasis, and overall survival rate. METHODS: From Jan. 2004 to Dec. 2005,132 patients with stage II or III colon carcinoma after radical operation were randomly divided into two groups: Sapylin combined with chemotherapy(Sapylin) group and the control group. Toxic reaction, local recurrence, hepatic metastasis, and overall survival rate between two groups were compared. RESULTS: Both groups successfully completed the trial. There was no significant difference in toxic reaction between two groups, the recurrence and hepatic metastasis rate in Sapylin group were lower than those in the control group(9/60, 15.0% vs. 22/72, 30.6%; 11/60,18.3% vs. 22/72, 34.7%, respectively), which were statistically significant (P<0.05 respectively). The 3- year survival rate in Sapylin group was higher than that in control group(73.3% vs. 54.2%), which was statistically significant (P<0.05). CONCLUSION: Sapylin combined with intraperitoneal and systemic chemotherapy can effectively decrease local recurrence and hepatic metastasis,and improve the survival in patients with advanced colon cancer following radical operation.


Assuntos
Produtos Biológicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Streptococcus pyogenes , Adulto , Idoso , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pós-Operatório , Estudos Prospectivos , Taxa de Sobrevida
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