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1.
Hum Mol Genet ; 33(1): 64-77, 2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-37756636

RESUMEN

GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. However, the molecular mechanism responsible for poly-PR-induced cell toxicity remains incompletely understood. Here, we found that poly-PR overexpression triggers severe DNA damage in cultured cells, primary cortical neurons, and the motor cortex of a poly-PR transgenic mouse model. Interestingly, we identified a linkage between poly-PR and RNA-binding protein fused in sarcoma (FUS), another ALS-related gene product associated with DNA repair. Poly-PR interacts with FUS both in vitro and in vivo, phase separates with FUS in a poly-PR concentration-dependent manner, and impairs the fluidity of FUS droplets in vitro and in cells. Moreover, poly-PR impedes the recruitment of FUS and its downstream protein XRCC1 to DNA damage foci after microirradiation. Importantly, overexpression of FUS significantly decreased the level of DNA damage and dramatically reduced poly-PR-induced cell death. Our data suggest the severe DNA damage caused by poly-PR and highlight the interconnection between poly-PR and FUS, enlightening the potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Animales , Ratones , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Expansión de las Repeticiones de ADN , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Proteínas/genética , Daño del ADN/genética , Arginina/genética , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Dipéptidos/genética
2.
J Biol Chem ; 298(3): 101623, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35074427

RESUMEN

Arabidopsis LHP1 (LIKE HETEROCHROMATIN PROTEIN 1), a unique homolog of HP1 in Drosophila, plays important roles in plant development, growth, and architecture. In contrast to specific binding of the HP1 chromodomain to methylated H3K9 histone tails, the chromodomain of LHP1 has been shown to bind to both methylated H3K9 and H3K27 histone tails, and LHP1 carries out its function mainly via its interaction with these two epigenetic marks. However, the molecular mechanism for the recognition of methylated histone H3K9/27 by the LHP1 chromodomain is still unknown. In this study, we characterized the binding ability of LHP1 to histone H3K9 and H3K27 peptides and found that the chromodomain of LHP1 binds to histone H3K9me2/3 and H3K27me2/3 peptides with comparable affinities, although it exhibited no binding or weak binding to unmodified or monomethylated H3K9/K27 peptides. Our crystal structures of the LHP1 chromodomain in peptide-free and peptide-bound forms coupled with mutagenesis studies reveal that the chromodomain of LHP1 bears a slightly different chromodomain architecture and recognizes methylated H3K9 and H3K27 peptides via a hydrophobic clasp, similar to the chromodomains of human Polycomb proteins, which could not be explained only based on primary structure analysis. Our binding and structural studies of the LHP1 chromodomain illuminate a conserved ligand interaction mode between chromodomains of both animals and plants, and shed light on further functional study of the LHP1 protein.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Histonas , Factores de Transcripción , Animales , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Metilación , Péptidos/química
3.
Biochem Biophys Res Commun ; 569: 199-206, 2021 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-34271259

RESUMEN

The NSD proteins, namely NSD1, NSD2 and NSD3, are lysine methyltransferases, which catalyze mono- and di-methylation of histone H3K36. They are multi-domain proteins, including two PWWP domains (PWWP1 and PWWP2) separated by some other domains. These proteins act as potent oncoproteins and are implicated in various cancers. However the biological functions of these PWWP domains are still largely unknown. To better understand the functions of these proteins' PWWP domains, we cloned, expressed and purified all the PWWP domains of these NSD proteins to characterize their interactions with methylated histone peptides and dsDNA by quantitative binding assays and crystallographic analysis. Our studies indicate that all these PWWP domains except NSD1_PWWP1 bind to trimethylated H3K36, H3K79 peptides and dsDNA weakly. Our crystal structures uncover that the NDS3_PWWP2 and NSD2_PWWP1 domains, which hold an extremely long α-helix and α-helix bundle, respectively, need a conformation adjustment to interact with nucleosome.


Asunto(s)
ADN/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Dominios Proteicos , Proteínas Represoras/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Sitios de Unión/genética , Cristalografía por Rayos X , ADN/química , ADN/genética , N-Metiltransferasa de Histona-Lisina/química , N-Metiltransferasa de Histona-Lisina/genética , Histonas/química , Humanos , Lisina/química , Lisina/metabolismo , Metilación , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/genética , Conformación de Ácido Nucleico , Unión Proteica , Proteínas Represoras/química , Proteínas Represoras/genética , Homología de Secuencia de Aminoácido
4.
Dis Markers ; 2020: 1245645, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33149790

RESUMEN

[This corrects the article DOI: 10.1155/2017/1202710.].

5.
Am J Transl Res ; 9(10): 4652-4672, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29118925

RESUMEN

Chronic myeloid leukemia (CML) treatment remains a challenge due to drug resistance and severe side effect, rendering the need on the development of novel therapeutics. CDDO-Me (Bardoxolone methyl), a potent Nrf2 activator and NF-κB inhibitor, is a promising candidate for cancer treatment including leukemia. However, the underlying mechanism for CDDO-Me in CML treatment is unclear. This study aimed to evaluate the molecular interactome of CDDO-Me in K562 cells using the quantitative proteomics approach stable-isotope labeling by amino acids in cell culture (SILAC) and explore the underlying mechanisms using cell-based functional assays. A total of 1,555 proteins responded to CDDO-Me exposure, including FANCI, SRPK2, XPO5, HP1BP3, NELFCD, Na+,K+-ATPase 1, etc. in K562 cells. A total of 246 signaling pathways and 25 networks regulating cell survival and death, cellular function and maintenance, energy production, protein synthesis, response to oxidative stress, and nucleic acid metabolism were involved. Our verification experiments confirmed that CDDO-Me down-regulated Na+,K+-ATPase α1 in K562 cells, and significantly arrested cells in G2/M and S phases, accompanied by remarkable alterations in the expression of key cell cycle regulators. CDDO-Me caused mitochondria-, death receptor-dependent and ER stress-mediated apoptosis in K562 cells, also induced autophagy with the suppression of PI3K/Akt/mTOR signaling pathway. p38 MAPK/Erk1/2 signaling pathways contributed to both apoptosis- and autophagy-inducing effects of CDDO-Me in K562 cells. Taken together, these data demonstrate that CDDO-Me is a potential anti-cancer agent that targets cell cycle, apoptosis, and autophagy in the treatment of CML.

6.
J Exp Clin Cancer Res ; 36(1): 131, 2017 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-28938919

RESUMEN

BACKGROUND: As a disease with extremely complex molecular mechanisms, many deregulated miRNAs have been identified in colon cancer. Few studies have been performed by using Ingenuity Pathways Analysis (IPA) to predict miRNAs specifically expressed in colon cancer. METHODS: A characteristic microRNA-target network of colon cancer was explored using IPA. Then the clinical significance of miR-19b-3p was evaluated in 211 colon cancer patients. The roles of miR-19b-3p and its candidate target gene, SMAD4, in colon cancer progression were examined both in vitro and in vivo. RESULTS: Bioinformatics analysis showed that 15 microRNAs screened by IPA were significantly correlated with malignant biological behaviors of colon cancer. miR-19b-3p was the most significantly upregulated candidate based on the validation experiment using 211 colon cancer samples. High expression of miR-19b-3p was significantly associated with high N stage (P < 0.001), high AJCC stage (P < 0.001), poor histologic grade (P = 0.032), frequent venous and lymphatic invasion (P = 0.027), and liver metastasis (P < 0.001). Survival analysis revealed that miR-19b-3p was an independent prognostic factor associated with colon cancer patient's overall survival (OS) and disease-free survival (DFS). miR-19b-3p promoted proliferation and chemoresistance of colon cancer cells, but had no effect on invasion in vitro, along with tumorigenesis in vivo. In addition, we confirmed that miR-19b-3p mediates resistance to oxaliplatin-based chemotherapy via SMAD4. CONCLUSIONS: Our findings demonstrate the role of miR-19b-3p-SMAD4 axis in colon cancer progression, which may become a potential therapeutic target against chemotherapy resistance.


Asunto(s)
Neoplasias Colorrectales/patología , Biología Computacional/métodos , Resistencia a Antineoplásicos , MicroARNs/genética , Proteína Smad4/genética , Animales , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HT29 , Humanos , Masculino , Ratones , Estadificación de Neoplasias , Trasplante de Neoplasias , Compuestos Organoplatinos/farmacología , Oxaliplatino , Regulación hacia Arriba
7.
J Genet ; 96(4): 687-693, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28947718

RESUMEN

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect due to abnormal orofacial development. Previous studies report abnormal sonic hedgehog (SHH) signalling activity during NSCL/P pathogenesis and propose several genes in the SHH pathway as candidate risk genes. As such, we focussed on GLI3, a downstream modulator of the SHH pathway. In the present study,we genotyped 34 tag SNPs covering GLI3 and performed association analysis with NSCL/P in 504 cases and 455 healthy controls. Our preliminary results identified risk variants of GLI3 that are associated with NSCL/P susceptibility in a Chinese population. In particular, rs3801161 and its haplotypes rs3801161-rs7785287 displayed significant association with NSCL/P and survived Bonferroni correction for multiple comparisons. The robustness of the association between GLI3 and NSCL/P is worth further examination in the future across different populations.


Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Proteínas del Tejido Nervioso/genética , Proteína Gli3 con Dedos de Zinc/genética , Alelos , Estudios de Casos y Controles , Femenino , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple
8.
Biofactors ; 43(6): 812-820, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28817203

RESUMEN

Digoxin is a member of cardiac glycosides and recent studies show that digoxin plays anticancer role in several types of cancer. However, the anticancer effects and mechanism of digoxin in leukemia is largely unknown. Her, our data show that digoxin treatment significantly inhibits leukemia cell viability. In addition, digoxin treatment significantly induced apoptosis and G2/M cell cycle arrest in leukemia cells. Furthermore, we demonstrated that digoxin treatment inactivate that oncogenic pathway Akt/mTOR signaling in leukemia cells. In addition, our data show that digoxin treatment induces activation of unfolded protein response (UPR) signaling in leukemia cells. Interestingly, our in vitro and in vivo experiments show that combination treatment of digoxin and UPR inhibitor can synergistically suppress leukemia growth and induces apoptosis and cell cycle arrest compared to single drug treatment. In summary, our findings indicate that digoxin has potential anticancer effects on leukemia. The combination of digoxin and UPR signaling inhibitor can exerts synergistic anticancer activity against leukemia. © 2017 BioFactors, 43(6):812-820, 2017.


Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/farmacología , Digoxina/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Indoles/farmacología , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Adenina/farmacología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Humanos , Células K562 , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patología , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células THP-1 , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Chem Biol Interact ; 271: 59-66, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28450041

RESUMEN

Psoriasis vulgaris is a chronic inflammatory skin disease, stubbornly intractable, with substantial consequences for patient physical and mental welfare. Approaches currently available to treat psoriasis are not satisfactory due to undesirable side-effects or expense. Psoriasis is characterized by hyperproliferation and inflammation. Oxymatrine, an active component extracted from Sophora flavescens, has been demonstrated to possess anti-proliferation, anti-inflammatory, anti-tumorigenic, immune regulation and pro-apoptotic properties. This investigation presents a detailed retrospective review examining the effect of Oxymatrine on psoriasis and investigates the mechanisms underlying patient responses to Oxymatrine. We confirm that Oxymatrine administration significantly reduced the Psoriasis Area Severity Index score, with high efficacy compared to the control group. In addition, we have found that Oxymatrine significantly inhibits the viability, proliferation and differentiation of human keratinocyte in vitro. Immunohistochemical analysis indicates Oxymatrine significantly suppresses the expression of Pan-Cytokeratin, p63 and keratin 10. The results indicate that the suppression of p63 expression may lead to the anti-proliferation effect of Oxymatrine on human skin keratinocytes. Oxymatrine does not affect the formation of basement membrane, which is very important to maintain the normal function of human skin keratinocytes. In summary, Oxymatrine offers an effective, economical, and safe treatment for patients presenting with intractable psoriasis vulgaris.


Asunto(s)
Alcaloides/uso terapéutico , Psoriasis/tratamiento farmacológico , Quinolizinas/uso terapéutico , Adolescente , Adulto , Anciano , Alcaloides/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Queratinocitos/efectos de los fármacos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Modelos Biológicos , Quinolizinas/farmacología , Estudios Retrospectivos , Piel/efectos de los fármacos , Piel/patología
10.
Am J Transl Res ; 9(3): 845-873, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28386317

RESUMEN

Glioblastoma (GBM) is the most common brain tumor with poor response to current therapeutics. Alisertib (ALS), a second-generation selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects on solid tumors in animal studies. This study aimed to investigate the killing effect of ALS on GBM cell line DAOY and the possible underlying mechanisms using both bioinformatic and cell-based approaches. Our molecular docking showed that ALS preferentially bound AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS also bound key regulating proteins of cell cycle, apoptosis and autophagy, such as cyclin-dependent kinase 1 (CDK1/CDC2), CDK2, cyclin B1, p27 Kip1, p53, cytochrome C, cleaved caspase 3, Bax, Bcl-2, Bcl-xl, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 5'-adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK), beclin 1, phosphatase and tensin homolog (PTEN), and microtubule-associated protein light chain 3 (LC3). ALS exhibited potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects on DAOY cells in a concentration-dependent manner. Notably, ALS remarkably induced G2/M arrest mainlyvia regulating the expression of CDK1/CDC2, CDK2, cyclin B1, p27 Kip1, and p53 in DAOY cells. ALS significantly induced the expression of mitochondria-mediated pro-apoptotic proteins such as Baxbut inhibited the expression of anti-apoptotic proteins such as Bcl-2 and Bcl-xl, with a significant increase in the release of cytochrome C and the activation of caspases 3 and 9. ALS also induced PI3K/Akt/mTOR and p38 MAPK signaling pathways while activating the AMPK signaling pathway. Taken together, these findings indicate that ALS exerts a potent inhibitory effect on cell proliferation and induces mitochondria-dependent apoptosis and autophagy with the involvement of PI3K/Akt/mTOR- and p38 MAPK-mediated signaling pathways in DAOY cells. ALS is a promising anticancer agent for GBM treatment.

11.
J Cancer ; 8(2): 220-226, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28243326

RESUMEN

Cutaneous squamous cell carcinoma (cSCC) contributes to one of most common types of skin cancer. Epidermal growth factor receptor (EGFR) activation has been investigated to be associated with the development of cSCC. Lapatinib is an inhibitor targeting HER2/neu and EGFR pathway. We found that lapatinib can inhibit proliferation by enhancing apoptosis of human cSCC cell lines. The cSCC cell cycle distribution could be arrested in G2/M phase after lapatinib treatment. In the in vitro experiment, we found that lapatinib interrupted PI3K/AKT/mTOR signaling pathway in human cSCC cells. Furthermore, lapatinib could suppress epithelial to mesenchymal transition (EMT) via Wnt/ErK/PI3K-AKT signaling pathway to represent a promising anticancer drug for cSCC treatment.

12.
Dis Markers ; 2017: 1202710, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29445249

RESUMEN

Deregulation of G protein-coupled receptor kinase 3 (GRK3), which belongs to a subfamily of kinases called GRKs, acts as a promoter mechanism in some cancer types. Our study found that GRK3 was significantly overexpressed in 162 pairs of colon cancer tissues than in the matched noncancerous mucosa (P < 0.01). Based on immunohistochemistry staining of TMAs, GRK3 was dramatically stained positive in primary colon cancer (130/180, 72.22%), whereas it was detected minimally or negative in paired normal mucosa specimens (50/180, 27.78%). Overexpression of GRK3 was closely correlated with AJCC stage (P = 0.001), depth of tumor invasion (P < 0.001), lymph node involvement (P = 0.004), distant metastasis (P = 0.016), and histologic differentiation (P = 0.004). Overexpression of GRK3 is an independent prognostic indicator that correlates with poor survival in colon cancer patients. Consistent with this, downregulation of GRK3 exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate, and impaired colon tumorigenicity in a xenograft model. Hence, a specific overexpression of GRK3 was observed in colon cancer, GRK3 potentially contributing to progression by mediating cancer cell proliferation and functions as a poor prognostic indicator in colon cancer and potentially represent a novel therapeutic target for the disease.


Asunto(s)
Neoplasias del Colon/patología , Quinasa 3 del Receptor Acoplado a Proteína-G/genética , Quinasa 3 del Receptor Acoplado a Proteína-G/metabolismo , Regulación hacia Arriba , Animales , Apoptosis , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Células HT29 , Humanos , Masculino , Ratones , Metástasis de la Neoplasia , Estadificación de Neoplasias , Trasplante de Neoplasias , Pronóstico , Análisis de Supervivencia
13.
Sci Rep ; 6: 38872, 2016 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-28008912

RESUMEN

Orofacial clefts are among the most common birth defects in humans worldwide. A large-scale, genome-wide association study (GWAS) in the Chinese population recently identified several genetic risk variants for nonsyndromic cleft lip with or without cleft palate (NSCL/P). We selected 16 significant SNPs from the GWAS I stage (P < 1.00E-5) that had not been replicated to validate their association with NSCL/P in 1931 NSCL/P cases and 2258 controls. Ultimately, we identified a NSCL/P susceptibility loci (rs17095681 at 10q25.3, intron of SHTN1 and 27.2 kb downstream of VAX1, Pmeta = 3.80E-9, OR = 0.64) in Chinese Han and Hui populations. This locus was not high LD with the reported loci in 10q25.3. It was a newly identified independent locus in 10q25.3 associated with NSCL/P. These results imply that SHTIN1 may involve in the pathogenesis of NSCL/P advance our understanding of the genetic susceptibility to NSCL/P.


Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Pueblo Asiatico , China/epidemiología , Labio Leporino/epidemiología , Fisura del Paladar/epidemiología , Femenino , Proteínas de Homeodominio/genética , Humanos , Masculino , Factores de Transcripción/genética
14.
Oncotarget ; 7(43): 70194-70210, 2016 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-27661126

RESUMEN

Colorectal cancer (CRC) is one of the most common prevalent cancer types worldwide. MicroRNAs (miRNAs or miRs) have been demonstrated to play crucial roles in the development, metastasis and drug resistance of CRC. In the present study, a strikingly elevated expression of miR-552 was determined in CRC tumor tissues and cells by a miRNA profiling analysis. Importantly, the gene of A Disintegrin And Metalloprotease (ADAM) family member 28 (ADAM28) was identified as a target of miR-552, which was further validated in terms of genetic dual luciferase report assay. Furthermore, an inhibition of miR-552 in LOVE and LS174T CRC cells by transducing miR-552 inhibitor (antagomiR-552) with a lentiviral vector exhibited an ability to reduce cell proliferation, migration and clonogenicity. Moreover, both LOVO and LS174T cells stably expressing miR-552 inhibitor displayed a decreased ability to develop tumors in a murine xenograft model in vivo. In contrast, a knockdown of ADAM28 by short hairpin RNA could reverse the antagomiR-552-induced inhibition of metastatic features of CRC cells in vitro. These results suggested that miR-552 is an oncomir able to promote CRC metastasis in part through a mechanism of targeting ADAM28, which may be a novel target for CRC treatment and warrants for further investigation.


Asunto(s)
Proteínas ADAM/genética , Neoplasias Colorrectales/patología , MicroARNs/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia
15.
Adv Exp Med Biol ; 937: 19-51, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27573893

RESUMEN

Colorectal cancer (CRC) is one of the most common diagnosed cancers worldwide. The metastasis and development of resistance to anti-cancer treatment are major challenges in the treatment of CRC. Understanding mechanisms underpinning the pathogenesis is therefore critical in developing novel agents for CRC treatments. A large number of evidence has demonstrated that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs have functional roles in both the physiological and pathological processes by regulating the expression of their target genes. These molecules are engaged in the pathobiology of neoplastic diseases and are targets for the diagnosis, prognosis and therapy of a variety of cancers, including CRC. In this regard, ncRNAs have emerged as one of the hallmarks of CRC pathogenesis and they also play key roles in metastasis, drug resistance and the stemness of CRC stem cell by regulating various signaling networks. Therefore, a better understanding the ncRNAs involved in the signaling pathways of CRC may lead to the development of novel strategy for diagnosis, prognosis and treatment of CRC. In this chapter, we summarize the latest findings on ncRNAs, with a focus on miRNAs and lncRNAs involving in signaling networks and in the regulation of pathogenic signaling pathways in CRC.


Asunto(s)
Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica/genética , ARN Neoplásico/genética , ARN no Traducido/genética , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Humanos , MicroARNs/genética , Metástasis de la Neoplasia , Proteínas de Neoplasias/fisiología , ARN/genética , ARN Circular , ARN Largo no Codificante/genética , Transducción de Señal/genética
16.
Tumour Biol ; 37(9): 12889-12896, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27449042

RESUMEN

There is increasing evidence supporting the cancer stem cell (CSC) hypothesis, which suggests that a population of tumor cells with stem cell characteristics is responsible for tumor growth, resistance, and recurrence as well as drug resistance. In colorectal cancer, the CD133 antigen defines distinct cell subpopulations that are rich in tumor-initiating cells; however, the drug resistance properties of these CD133-positive cells have not been well defined. The breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is present on the plasma membrane of many types of human cancer cells and contributes to multidrug resistance during chemotherapy. The results of the present study showed that ABCG2 is expressed in CD133-positive CSCs from human colorectal tumors. Furthermore, the downregulation of ABCG2 expression inhibited the self-renewal capacity of these cells, and significantly enhanced the efficacy of chemotherapy-induced apoptosis in LS174T colon adenocarcinoma cells and CD133-positive colorectal carcinoma cells. Together, these data show that ABCG2 expression correlates with the presence of CD133-positive cancer cells, and thus is a possible therapeutic target for colorectal cancer.


Asunto(s)
Antígeno AC133/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Autorrenovación de las Células , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Antígeno AC133/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/farmacología , Western Blotting , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Femenino , Fluorouracilo/farmacología , Células HCT116 , Células HT29 , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Compuestos Organoplatinos/farmacología , Oxaliplatino , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Int J Mol Sci ; 17(7)2016 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-27367670

RESUMEN

The human cytochrome P450 (CYP) superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs. The functional implications and implications in drug discovery and evolutionary biology were then discussed. GeneCards and Ensembl were used to identify the paralogs of human CYPs. We have used a panel of online databases to identify the orthologs of human CYP genes: NCBI, Ensembl Compara, GeneCards, OMA ("Orthologous MAtrix") Browser, PATHER, TreeFam, EggNOG, and Roundup. The results show that each human CYP has various numbers of paralogs and orthologs using GeneCards and Ensembl. For example, the paralogs of CYP2A6 include CYP2A7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 2R1, 2S1, 2U1, and 2W1; CYP11A1 has 6 paralogs including CYP11B1, 11B2, 24A1, 27A1, 27B1, and 27C1; CYP51A1 has only three paralogs: CYP26A1, 26B1, and 26C1; while CYP20A1 has no paralog. The majority of human CYPs are well conserved from plants, amphibians, fishes, or mammals to humans due to their important functions in physiology and xenobiotic disposition. The data from different approaches are also cross-validated and validated when experimental data are available. These findings facilitate our understanding of the evolutionary relationships and functional implications of the human CYP superfamily in drug discovery.


Asunto(s)
Biología Computacional/métodos , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Descubrimiento de Drogas , Humanos , Relación Estructura-Actividad
18.
Gene ; 588(1): 69-73, 2016 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-27129939

RESUMEN

Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects worldwide and is characterized by abnormalities of the orofacial structure. Syndromic CL/P is mainly caused by Mendelian disorders such as Van der Woude Syndrome (VWS). However, >70% of CL/P cases are nonsyndromic, characterized by isolated orofacial cleft without any known syndrome. The etiology of nonsyndromic CL/P (NSCL/P) remains elusive, but it has been suggested that causative genes of syndromic CL/P might also contribute to NSCL/P. As such, the VWS causative gene IRF6 has been extensively studied in NSCL/P. Recently, GRHL3 was identified as another VWS causative gene. Thus, it may be a novel candidate gene for NSCL/P. In the present study, we genotyped 10 tag SNPs covering GRHL3 and performed association analysis with NSCL/P in 504 cases and 455 healthy controls. Our preliminary results identified rs10903078, rs4638975, and a haplotype rs10903078-rs6659209 of GRHL3 that exceeded the significance threshold (p<0.05), though none survived Bonferroni correction for multiple comparisons. As the first study between GRHL3 and NSCL/P, the contribution of this gene to NSCL/P etiology should be interpreted with caution based on existing evidence. Further, the robustness of association between GRHL3 and NSCL/P should be further validated in expanded cohorts.


Asunto(s)
Anomalías Múltiples/genética , Labio Leporino/genética , Fisura del Paladar/genética , Quistes/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Labio/anomalías , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética , Anomalías Múltiples/patología , Pueblo Asiatico/genética , Estudios de Casos y Controles , Labio Leporino/patología , Fisura del Paladar/patología , Quistes/patología , Humanos , Labio/patología , Modelos Estadísticos
19.
Expert Opin Ther Targets ; 20(7): 771-82, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27167185

RESUMEN

OBJECTIVE: A microRNA (miRNA) that functionally downregulates the expression of tumor suppressors can be defined as an oncomir. Here, we interrogate the biological significance of miR-592 in colorectal cancer (CRC). RESEARCH DESIGN AND METHODS: The expression of miR-592 in CRC tissues and cell lines was ascertained by qRT-PCR assay, and the expression of its target gene was determined by immunohistochemistry staining. The oncogenic role of miR-592 was assessed in terms of cell proliferation, migration, and clonogenicity in vitro, whereas the tumorigenicity was assessed by inhibiting endogenous miR-592 in CRC cells in vivo. RESULTS: A striking upregulation of miR-592 was observed in CRC tissues and cell lines compared to the matched adjacent non-tumor tissues and normal colon cells. Importantly, Forkhead Box O3A (FoxO3A) was identified as a novel target of miR-592. miR-592 inhibitor exhibited a significant reduction of migration, proliferation, and clonogenicity in CRC cells. These cells also displayed a decreased tumorigenicity in SCID mice relative to the control cells. CONCLUSION: These data suggest that miR-592 may promote the progression and metastasis, in part, by targeting FoxO3A in CRC. miR-592 may be a novel target for CRC treatment and antagomir-592 may inhibit the proliferation and metastasis of CRC cells.


Asunto(s)
Neoplasias Colorrectales/patología , Proteína Forkhead Box O3/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Humanos , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba
20.
Curr Drug Metab ; 17(6): 520-7, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26892731

RESUMEN

BACKGROUND: Non-human primates are valuable animal models in drug discovery and biomedical research. Human CYP2D6 accounts for 1.3-4.3% of total hepatic CYP content in the liver, but is involved in the metabolism of more than 150 drugs. With the advancement of genomic sequencing and annotation, a panel of CYP2D genes have been cloned from non-human primates. This review highlights the similarities and differences of these CYP2D genes non-human primates. METHODS: We conducted a structured PubMed search using a focused review question and proper inclusion/exclusion criteria. The quality of retrieved papers was assessed and briefed using standard tools and expert knowledge. RESULTS: Most studies on CYP expression in non-human primates have been carried out in the cynomolgus and Rhesus monkeys. Deduced amino acid sequences of primate CYP2D cDNAs share high sequence identity (93-96%) with human CYP2D6. The chimpanzee genome has CYP2D6 and 2D7 but bonobos only contain CYP2D6. The CYP2D6 gene is located on chromosome 22 in the chimpanzee genome (human CYP2D6 maps to chromosome 22q13.1), and on chromosome 10 in the genome of the Rhesus monkey. Cynomolgus monkey CYP2D17 and Japanese monkey 2D29 metabolize bufuralol and dextromethorphan. CYP2D17 metabolizes bufuralol and dextromethorphan, whereas CYP2D29 metabolizes bufuralol and debrisoquine. In addition, quinidine inhibits both cynomolgus monkey CYP2D17 and Japanese monkey 2D29. CONCLUSION: The CYP2D members from non-human primates show differential genomic contexts, catalytic activities toward substrates and inhibitory profiles. Further studies are warranted to elucidate the structural and functional features of CYP2D members in non-human primates and thus offer a solid base for the application of these animals in drug discovery.


Asunto(s)
Familia 2 del Citocromo P450/metabolismo , Descubrimiento de Drogas/métodos , Hígado/enzimología , Primates/metabolismo , Xenobióticos/metabolismo , Animales , Familia 2 del Citocromo P450/química , Familia 2 del Citocromo P450/genética , Isoenzimas , Modelos Animales , Primates/genética , Conformación Proteica , Especificidad de la Especie , Relación Estructura-Actividad , Especificidad por Sustrato
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