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1.
Int J Biol Markers ; : 1724600819897079, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031046

RESUMO

OBJECTIVE: Abundant evidence has illustrated that long non-coding RNA (lncRNA) plays a vital role in the regulation of tumor development and progression. Ectopic expression of a novel lncRNA, termed lnc-AGER-1, has been discovered in cancers, and this lncRNA was reported to exert an anti-tumor effect. However, its biological mechanism remains unelucidated in colorectal cancer. METHODS: A total of 159 paired colorectal cancer specimens and adjacent tissues was applied to detect the expression of lnc-AGER-1 by the quantitative Real-time PCR (qRT-PCR), and a series of functional assays was executed to uncover the role of this lncRNA on colorectal cancer. RESULTS: We found that the expression of lnc-AGER-1 in the tumor tissues was significantly down-regulated, while compared with adjacent normal tissues (0.0115 ± 0.0718 vs. 0.0347 ± 0.157; P < 0.0001). Also, lnc-AGER-1 was observably associated with clinical T status (r = -0.184, P = 0.024). Patients with advanced T status exerted a significantly lower level of lnc-AGER-1 than those with early T status (20.0% vs. 40.7%, P = 0.021). Over-expression of lnc-AGER-1 inhibited cell proliferation and migration efficiency, and induced cell cycle arrest at the G0/G1 phase, and promoted cell apoptosis. Further research proved that lnc-AGER-1 altered the expression of its neighbor gene, AGER, through acting as a competing endogenous RNA for miR-182 in colorectal cancer. CONCLUSION: lnc-AGER-1 has a suppressive role in colorectal cancer development via modulating AGER, which may serve as a target for colorectal cancer diagnosis and treatment.

2.
Aging (Albany NY) ; 12(1): 462-480, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31901898

RESUMO

Lnc-BMP1-1 is a lncRNA transcribed from SFTPC (surfactant associated protein C), a lung tissue specific gene encoding pulmonary-associated surfactant protein C (SPC) that is solely secreted by alveolar typeⅡ epithelial cells, among which the ones with SFTPC+ might be transformed into lung adenocarcinoma cells. Caveolin-1 (Cav-1) is a candidate tumor suppressor gene and is vital for coping with oxidative stress induced by cigarette smoke. When comparing lung cancer tissues with their adjacent normal tissues, the expression of lnc-BMP1-1 were decreased, especially in patients with cigarette smoking history (P=0.027), and positively associated with the expression of Cav-1 (P<0.001). When comparing to A549 cells transfected with empty vector (A549-NC cells), the expression level of Cav-1 in A549 cells with over-expressed lnc-BMP1-1 (A549-BMP cells) was increased along with the decreased level of HDAC2 protein. The drug sensitivity of A549-BMP cells to Doxorubicin hydrochloride (DOX) was increased; the growth and migration capability of A549-BMP cells were inhibited along with the decreased protein level of Bcl-2 and DNMT3a; the growth of tumor in nude mice injected with A549-BMP cells were inhibited, too. Furthermore, the lnc-BMP1-1 and Cav-1 expression was also down-regulated in the human bronchial epithelial (16HBE) cells treated with cigarette smoke extract (CSE).

3.
J Colloid Interface Sci ; 565: 70-76, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31935586

RESUMO

Fluorinated graphene (F-GNS) was synthesized using commercial graphene (GNS) as starting material and introduced in sodium batteries, which exhibited good rate performance, but large voltage gap between discharge and charge process. Ag nanoparticles were employed in freestanding and binder-free F-GNS electrode (the composite film electrode was labeled as FGA) as catalyst, which were shown to strongly facilitate the decomposition of NaF during charge process in sodium/carbon fluorides (Na/CFx) secondary batteries. During discharge process, the discharge voltage with Ag was about the same as that of Na/F-GNS cell. During charge process, the charge voltage of Na/FGA cell was substantially lower (by 480 mV) than that of Na/F-GNS cell, thus leading to a lower overpotential and a higher electric efficiency. Nanosized amorphous discharge products of NaF formed in Na/FGA cells were ascribed as the key role in reducing the polarization.

4.
EMBO J ; 39(1): e102190, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31755573

RESUMO

TGF-ß signaling pathway plays a key role in breast cancer metastasis. Recent studies suggest that TGF-ß regulates tumor progression and invasion not only via transcriptional regulation, but also via translational regulation. Using both bioinformatics and experimental tools, we identified a micropeptide CIP2A-BP encoded by LINC00665, whose translation was downregulated by TGF-ß in breast cancer cell lines. Using TNBC cell lines, we showed that TGF-ß-activated Smad signaling pathway induced the expression of translation inhibitory protein 4E-BP1, which inhibited eukaryote translation initiation factor elF4E, leading to reduced translation of CIP2A-BP from LINC00665. CIP2A-BP directly binds tumor oncogene CIP2A to replace PP2A's B56γ subunit, thus releasing PP2A activity, which inhibits PI3K/AKT/NFκB pathway, resulting in decreased expression levels of MMP-2, MMP-9, and Snail. Downregulation of CIP2A-BP in TNBC patients was significantly associated with metastasis and poor overall survival. In the MMTV-PyMT model, either introducing CIP2A-BP gene or direct injection of CIP2A-BP micropeptide significantly reduced lung metastases and improved overall survival. In conclusion, we provide evidence that CIP2A-BP is both a prognostic marker and a novel therapeutic target for TNBC.

5.
J Exp Med ; 217(3)2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31816634

RESUMO

Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with the most aggressive phenotype and poor overall survival. Using bioinformatics tools, we identified LINC00908 encoding a 60-aa polypeptide and differentially expressed in TNBC tissues. We named this endogenously expressed polypeptide ASRPS (a small regulatory peptide of STAT3). ASRPS expression was down-regulated in TNBCs and associated with poor overall survival. We showed that LINC00908 was directly regulated by ERα, which was responsible for the differential down-regulation of LINC00908 in TNBCs. ASRPS directly bound to STAT3 through the coiled coil domain (CCD) and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. In human endothelial cells, a mouse xenograft breast cancer model, and a mouse spontaneous BC model, ASRPS expression reduced angiogenesis. In a mouse xenograft breast cancer model, down-regulation of ASRPS promoted tumor growth, and ASRPS acted as an antitumor peptide. We presented strong evidence that LINC00908-encoded polypeptide ASRPS represented a TNBC-specific target for treatment.

6.
Carcinogenesis ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31630191

RESUMO

Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and noncoding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used FUMA to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5×10-8) identified by GWAS. The original GWAS melanoma study included 15,990 cases and 26,409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2, and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE, and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5×10-6. The genes associated with melanoma risk were DEF8 (P = 1.09×10-57), DBNDD1 (P = 2.19×10-42), SPATA33 (P = 3.54×10-38), and MC1R (P = 1.04×10-36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.

7.
Med Sci Monit ; 25: 6805-6811, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31503552

RESUMO

BACKGROUND The prevalence of bronchiectasis with comorbid chronic obstructive pulmonary disease (COPD) is rising, which causes extremely high risk of exacerbation and mortality. We aimed to evaluate the differences in clinicopathological manifestations, immune function, and inflammation in bronchiectasis patients with comorbid COPD vs. patients who only have COPD. MATERIAL AND METHODS Clinicopathological characteristics, including common potentially pathogenic microorganisms, lung function, immune function, and inflammation were assessed in bronchiectasis patients with comorbid COPD and in patients who only had COPD. RESULTS Compared to patients who only had COPD, patients with bronchiectasis with comorbid COPD had a higher positive rate of sputum bacteria (45.27% vs. 28.03%, P<0.01). Among them, Pseudomonas aeruginosa (P. aeruginosa) accounted for 25.19% in COPD (4.37%) (P<0.01). Likewise, patients with bronchiectasis with comorbid COPD had worse lung function, worse COPD assessment test scores, and worse Modified Medical Research Council scores. Moreover, compared with COPD only cases, patients with bronchiectasis with comorbid COPD had higher levels of white blood cells (WBC), neutrophils, C-reactive protein (CRP), and procalcitonin (PCT) (all P<0.05). Interestingly, the expression levels of Treg in patients with bronchiectasis with comorbid COPD were lower than in patients with COPD only (P<0.05). Th17 and Th17/Treg levels were higher (P<0.05). Furthermore, remarkable increased level of IL17 and IL-6 and decreased level of IL-10 and TGF-ß were observed in the bronchiectasis combined COPD than in pure COPD (All P<0.05). CONCLUSIONS Our findings suggest that P. aeruginosa is the main pathogen of bacterial infection in bronchiectasis patients with comorbid COPD. These patients have more serious clinical manifestations and immune imbalance, which should be considered when providing clinical treatment.


Assuntos
Bronquiectasia/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Biomarcadores/metabolismo , Bronquiectasia/imunologia , Bronquiectasia/patologia , Bronquiectasia/fisiopatologia , China/epidemiologia , Comorbidade , Progressão da Doença , Feminino , Humanos , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Escarro
8.
Int J Mol Sci ; 20(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374807

RESUMO

Many long non-coding RNAs (lncRNAs) have emerged as good biomarkers and potential therapeutic targets for various cancers. We aimed to get a detailed understanding of the lncRNA landscape that is associated with lung cancer survival. A comparative analysis between our RNA sequencing (RNA-seq) data and TCGA datasets was conducted to reveal lncRNAs with significant correlations with lung cancer survival and then the association of the most promising lncRNA was validated in a cohort of 243 lung cancer patients. Comparing RNA-seq data with TCGA ones, 84 dysregulated lncRNAs were identified in lung cancer tissues, among which 10 lncRNAs were significantly associated with lung cancer survival. LINC01537 was the most significant one (p = 2.95 × 10-6). Validation analysis confirmed the downregulation of LINC01537 in lung cancer. LINC01537 was observed to inhibit tumor growth and metastasis. It also increased cellular sensitivity to nilotinib. PDE2A (phosphodiesterase 2A) was further identified to be a target of LINC01537 and it was seen that LINC01537 promoted PDE2A expression via RNA-RNA interaction to stabilize PDE2A mRNA and thus echoed effects of PDE2A on energy metabolism including both Warburg effect and mitochondrial respiration. Other regulators of tumor energy metabolism were also affected by LINC01537. These results elucidate a suppressed role of LINC01537 in lung cancer development involving tumor metabolic reprogramming, and we believe that it might be a biomarker for cancer survival prediction and therapy.


Assuntos
Metabolismo Energético , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Células A549 , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Progressão da Doença , Feminino , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade
9.
Mol Cancer ; 18(1): 22, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736860

RESUMO

BACKGROUND: Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female. METHODS: We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1, TLR7 and NFκB. RESULTS: We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients. CONCLUSIONS: Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , NF-kappa B/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Receptor 7 Toll-Like/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Camundongos Nus , NF-kappa B/metabolismo , Células-Tronco Neoplásicas , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Análise de Sobrevida , Receptor 7 Toll-Like/metabolismo , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Gene ; 697: 57-66, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30796966

RESUMO

Oncogenes can potentially cause uncontrolled cell growth, leading to cancer development, and these genes are normally mutated and over-expressed in tumor cells. Genomic alteration of oncogenes might result in oncogenesis and promotion of cancer progression. To date, researchers have focused mainly on the roles of oncogenes in particular cancers, but investigation of oncogenes with gain-of-function mutations in multiple cancer types are less represented in the literature. Furthermore, the effect of those gain-of-function are not validated in gene expression level. To meet this demand, we performed a systematic analysis of gene expression in oncogenes to identify the occurrence of gain-of-function mutations in pan-cancer. We identified 33,551 oncogenic mutations in 5000 samples. From our analysis, we identified three tissues with the highest frequency of gain-of-functional oncogenic mutations in hundreds of samples: breast (739 samples), central nervous system (646 samples) and large intestine (498 samples). By further counting the number of occurrences of oncogenes across cancer types, we identified a list cross-cancer mutational signatures of 99 oncogenes highly mutated in >400 samples in breast, central nervous system and large intestine samples. By further overlapping with gene expression data in the matched tumor samples, we further identified 1875 gain-of-functional mutations/events with consistent gene up-regulation in 1031 samples from multiple cancers. This result may offer additional insight into the relationship between gene dosage and oncogenesis and maybe useful in targeted cancer therapy. In summary, this study provides the first globally examining on the genetic alteration of oncogenes across cancer types. Clinical association analysis has shown that these 99 genes have a significant effect on survival.


Assuntos
Mutação com Ganho de Função/genética , Neoplasias/genética , Oncogenes/genética , Carcinogênese , Bases de Dados Genéticas , Dosagem de Genes/genética , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Genômica , Humanos , Mutação , Transcriptoma/genética
11.
Int J Cancer ; 145(4): 927-940, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30698832

RESUMO

LncRNAs (long noncoding RNAs) are noncoding transcripts that are more than 200 nt long and have been described as the largest subclass in the noncoding transcriptome in humans. Although studies of lncRNAs in cancer have been continuing for a long time, no much has been known about X chromosome-linked lncRNAs. Here, by using RNA-seq we report the identification of a new X chromosome-linked lncRNA (lnc-XLEC1) that is aberrantly downregulated during the development of endometrial carcinoma (EC). The overexpression of lnc-XLEC1 reduces the migration and proliferation of EC cells. Flow cytometry analysis indicated that lnc-XLEC1 overexpression resulted in a substantial accumulation of EC cells in the G1 phase. In addition, lnc-XLEC1 had inhibitive effects that may result from its collaboration with MBP-1 during the suppression of the c-Myc expression and the negative regulating of the Cdk/Rb/E2F pathway. The anti-tumor effects of lnc-XLEC1 on EC progression suggest that lnc-XLEC1 has some potential value in anti-carcinoma therapies and deserves further investigation. Our study reported for the first time that the lnc-XLEC1 might be related to the incidence and prognosis of EC. Moreover, we discovered that this process might be related to somatic X dosage compensation and skewed X chromosome inactivation (SXCI).


Assuntos
Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Cromossomo X/genética , Animais , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo/genética , Neoplasias do Endométrio/patologia , Feminino , Fase G1/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transcriptoma/genética
12.
Cancer Med ; 8(2): 761-772, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30652414

RESUMO

Long noncoding RNAs have been proved to play essential roles in tumor development and progression. In this study, we focused on DNAJC3-AS1 and investigated its biological function and clinical significance in osteosarcoma. We detected the expression of DNAJC3-AS1 in 30 pairs of matched osteosarcoma and adjacent nontumorous specimens and osteosarcoma cell lines and analyzed association between DNAJC3-AS1 levels and clinicopathological factors. We found that DNAJC3-AS1 expression was up-regulated in osteosarcoma. High level of DNAJC3-AS1 was correlated with high differentiated degree (P = 0.018) and advanced Enneking stage (P = 0.016). Mechanistically, DNAJC3-AS1 enhanced cell proliferation, migration, and invasion in vitro and in vivo and reduced sensitivity of osteosarcoma to cisplatin. These effects of DNAJC3-AS1 were reversed by down-regulation of its sense-cognate gene DNAJC3. Thus, DNAJC3-AS1 promotes osteosarcoma development and progression by regulating DNAJC3 and might be a biomarker and therapeutic target for osteosarcoma.

13.
Brief Funct Genomics ; 18(1): 1-12, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30462154

RESUMO

The application of third-generation sequencing (TGS) technology in genetics and genomics have provided opportunities to categorize and explore the individual genomic landscapes and mutations relevant for diagnosis and therapy using whole genome sequencing and de novo genome assembly. In general, the emerging TGS technology can produce high quality long reads for the determination of overlapping reads and transcript isoforms. However, this technology still faces challenges such as the accuracy for the identification of nucleotide bases and high error rates. Here, we surveyed 39 TGS-related tools for de novo assembly and genome analysis to identify the differences among their characteristics, such as the required input, the interaction with the user, sequencing platforms, type of reads, error models, the possibility of introducing coverage bias, the simulation of genomic variants and outputs provided. The decision trees are summarized to help researchers to find out the most suitable tools to analyze the TGS data. Our comprehensive survey and evaluation of computational features of existing methods for TGS may provide a valuable guideline for researchers.


Assuntos
Biologia Computacional/métodos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Algoritmos , Humanos , Mutação , Software
14.
Carcinogenesis ; 40(1): 70-83, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30407486

RESUMO

Variants in the prostate stem cell antigen (PSCA) gene have been linked with risk of multiple cancers and other diseases. But results have been inconclusive and no systematic research synopsis has been available. We did a comprehensive meta-analysis to investigate associations between variants in this gene and risk of nine cancers and four nonneoplastic diseases based on data from 55 publications including 81 961 cases and 442 932 controls. We graded levels of cumulative epidemiological evidence of a significant association using the Venice criteria and false-positive report probability tests. We performed functional annotation for these variants using data from the Encyclopedia of DNA Elements Project and other public databases. We found that six variants were nominally significantly associated with an increased or reduced risk of three cancers and three nonneoplastic diseases (P < 0.05). Cumulative evidence of an association was graded as strong for rs2294008 [odds ratio (OR) = 1.32, P = 5.1 × 10-33], rs2976392 (OR = 1.29, P = 1.8 × 10-8), rs9297976 (OR = 0.75, P = 1.4 × 10-7), rs2976391 (OR = 1.38, P = 6.1 × 10-5) and rs138377917 (OR = 0.53, P = 0.008) with gastric cancer, rs2294008 with bladder cancer (OR = 1.15, P = 8.0 × 10-19), gastritis (OR = 1.35, P = 1.2 × 10-5), duodenal ulcer (OR = 0.68, P = 2.4 × 10-57) and gastric ulcer (OR = 0.88, P = 1.7 × 10-7). Data from the Encyclopedia of DNA Elements Project and other databases showed that these variants and other variants correlated with them might fall in putative functional regions. In conclusion, this study provides summary evidence that variants in the PSCA gene are associated with risk of gastric and bladder cancer, gastritis, as well as duodenal and gastric ulcer and highlights the significant role of this gene in the pathogenesis of these diseases.


Assuntos
Antígenos de Neoplasias/genética , Proteínas de Neoplasias/genética , Neoplasias/etiologia , Úlcera Duodenal/etiologia , Proteínas Ligadas por GPI/genética , Predisposição Genética para Doença , Humanos , Neoplasias/genética , Risco , Neoplasias Gástricas/etiologia , Úlcera Gástrica/etiologia , Neoplasias da Bexiga Urinária/etiologia
15.
DNA Cell Biol ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30362823

RESUMO

There is a perception that long noncoding RNA (lncRNA) has relationship with carcinogenesis. Many studies have previously identified and validated that the section of chromosome 11p13 is associated with high incidence of tumor. In this study, we investigated a new lncRNA, named lncPRRG4-4, mapped to 11p13 and suspected that lncPRRG4-4 was a potential lung cancer-related gene. To explore its role in carcinogenesis, we first demonstrated that lncPRRG4-4 was upregulated in lung cancer tissues compared with adjacent nontumor tissues and functioned as an oncogene in lung cancer cells. The lncPRRG4-4 was significantly upregulated in lung cancer tissues compared with adjacent normal counterparts (mean ± standard deviation: 0.12 ± 0.84 vs. 0.05 ± 0.22; p < 0.001). Patients with metastasis exhibited high levels of lncPRRG4-4 expression than those without metastasis in both the southern samples (p = 0.045) and eastern samples (p = 0.030), total samples (p = 0.004). In addition, downregulation of lncPRRG4-4 expression inhibited lung cancer proliferation, viability, migration, and invasion ability, arrested cell cycle, facilitated apoptosis, and vice versa. Taken together, these observations suggested that the lncPRRG4-4 functions as an oncogene in lung cancer cells.

16.
Cancer Lett ; 438: 116-125, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217564

RESUMO

The chromosomal locations of lncRNAs (long non-coding RNAs, lncRNAs) infer their biological functions in cancer. Lnc-RAB1A-2, a Ras-related protein Rab-1A (RAB1A) upstream lncRNA, was chosen for assessment of its impact on lung cancer prognosis in a case-based analysis and investigation of its biological function though a series of functional assays. Lnc-RAB1A-2 was significantly upregulated in 276 lung cancer tissues compared with corresponding non-tumor tissues, and its expression level was significantly correlated with clinical stage and metastasis status in lung cancer patients. Patients with high expression levels of this lncRNA had a shorter median survival time (16.0 months vs. 23.0 months, P = 0.011 in southern samples; 8.0 months vs. 19.0 months, P = 0.020 in eastern samples; 13.0 months vs. 19.0 months, P = 0.002 in merged samples) and a higher risk of death than those with lower levels (HR = 1.52; 95% CI = 1.01-2.26, in merged samples). Additionally, overexpression of lnc-RAB1A-2 significantly promoted lung cancer cell proliferation in vitro and in vivo. Further analyses using digital gene expression tag profiling revealed that lnc-RAB1A-2 could affect the expression of fibroblast growth factor 1 (FGF1), a gene involved in the PI3K/AKT/mTOR pathway that is largely activated by RAB1A. FGF1 was confirmed to be a down-stream gene of lnc-RAB1A-2. Collectively, our study demonstrated that lnc-RAB1A-2 is associated with poor lung cancer prognosis by promoting lung cancer development.


Assuntos
Fator 1 de Crescimento de Fibroblastos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Regulação para Cima , Células A549 , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Fator 1 de Crescimento de Fibroblastos/metabolismo , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais/genética , Análise de Sobrevida , Transplante Heterólogo , Carga Tumoral/genética
17.
Curr Genomics ; 19(5): 375-383, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30065613

RESUMO

Background: Musashi1 (MSI1) is a characteristic stem cell marker that regulates the balance between cell self-renewal and differentiation. Evidence has identified MSI1 as a pivotal oncogenic regulator in diverse malignancies. However, little evidence uncovers the role of genetic variations of MSI1 gene in cancer etiology. Objective: The aim of this study was to investigate the association between genetic variants in the MSI1 gene and lung cancer risk. Methods: Based on a two-stage retrospective study with a total of 1559 patients with lung cancer and 1667 healthy controls, we evaluated the relevance between three putative functional SNPs in the MSI1 promoter (i.e., -2696T>C[rs7959801], -2297T>C[rs3742038] and -1081C>T[rs34570155]) and lung cancer risk. Results: We found that the SNP rs7959801T>C was significantly associated with lung cancer susceptibility. Compared to those with rs7959801TT wild-genotype, individuals with CT/CC variant genotypes exerted consistently beneficial roles in lung cancer risk in the discovery set (adjusted odd ratios [OR] = 0.67; 95% confidence interval [CI] = 0.57-0.80), and in the validation set (OR=0.69; 95%CI=0.54-0.88). Functional assays indicated that the allele transformation from T to C in rs7959801 of MSI1 gene arrestingly decreased its transcription activity in vitro. Furthermore, the expression levels of MSI1 were significantly lower in the patients with CT/CC variants than in those who were with TT genotype. Conclusion: Our findings suggested that the rs7959801T>C polymorphism in the MSI1 promoter conferred a decreased risk to lung cancer by reducing the expression of MSI1 and it may be a promising indicator for lung cancer predisposition.

18.
BMC Genomics ; 19(1): 552, 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30045691

RESUMO

BACKGROUND: Cancer initiation genes (CIGs) are genes that can directly promote cell proliferation or induce cancer. There are thousands of published studies identifying various CIGs; however, no systematic collection or description is available. RESULTS: To construct a CIG reference for genetic screening, we have collected 177 human genes curated from 1507 PubMed abstracts. To facilitate data queries and browsing, the identified CIGs along with extensive bioinformatic annotations were stored in an online database called CIGene. Initial functional analysis revealed an overlooked role for cell motility in cancer initiation. Subsequent cross-referencing of known tumor suppressor genes and oncogenes against the 177 CIGs identified 96 and 81 CIGs with and without known oncogenic roles, respectively. Successive network analyses of all 177 CIGs determined that the two groups of genes were more likely to link within their group. The distinct molecular functions for these groups were also confirmed with functional studies. While the 96 known oncogenic genes had fundamental roles in gene regulation and signaling, the remaining 81 genes possessed more ancillary functions, such enhancer binding. Further network and mutational analysis of the 96 known oncogenic genes revealed that mutations in these genes were highly prevalent in multiple cancers. By focusing on breast cancer, we found that 32 of the 96 genes with mutations in breast cancers were significantly associated with patient survival. CONCLUSIONS: As the first literature-based online resource for CIGs, CIGene will serve as a useful gateway for the systematic analysis of cancer initiation. CIGene is freely available to all academic users at http://soft.bioinfo-minzhao.org/cigene/ .


Assuntos
Bases de Dados Genéticas , Genes Neoplásicos , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Feminino , Genes Supressores de Tumor , Humanos , Internet , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Oncogenes , Publicações Periódicas como Assunto
19.
J Cell Physiol ; 233(11): 8862-8873, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29856480

RESUMO

Cigarettes contain various chemicals with the potential to influence metabolic health. Exposure to cigarette smoke causes a dysfunction in pancreatic ß-cells and impairs insulin production. However, the mechanisms for cigarette smoke-induced reduction of insulin remain largely unclear. Data from 558 patients with diabetes showed that, with smoking pack-years, homeostatic model assessment (HOMA)-ß (a method for assessing ß-cell function) decreased and that HOMA of insulin resistance increased. For ß-cells (MIN6), cigarette smoke extract (CSE) increased the levels of thioredoxin-interacting protein (TXNIP) and the long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and downregulated the levels of the transcription factor, mafA, and microRNA (miR)-17. MALAT1, one of four lncRNAs predicted to regulate miR-17, was knocked down by small interfering RNA (siRNA). For these cells, an miR-17 mimic inhibited TXNIP and enhanced the production of insulin. Knockdown of MALAT1 induced an increase in miR-17, which suppressed TXNIP and promoted the production of insulin. In the sera of patients with diabetes who smoked, there were higher MALAT1 levels and lower miR-17 levels than in the sera of nonsmokers. Thus, CSE inhibits insulin production by upregulating TXNIP via MALAT1-mediated downregulation of miR-17, which provides an understanding of the processes involved in the reduced ß-cells function caused by cigarette smoke.


Assuntos
Adenocarcinoma de Pulmão/genética , Proteínas de Transporte/genética , Fumar Cigarros/efeitos adversos , MicroRNAs/genética , RNA Longo não Codificante/genética , Adenocarcinoma de Pulmão/induzido quimicamente , Adenocarcinoma de Pulmão/patologia , Apoptose/genética , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Fumar Cigarros/epidemiologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hemoglobina A Glicada/genética , Humanos , Insulina/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Produtos do Tabaco/toxicidade
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