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1.
Artículo en Ruso | MEDLINE | ID: mdl-32119223

RESUMEN

The colorectal cancer is considered as the third most common malignant disease in the world. During last decade, the problem of colorectal cancer became especially urgent conditioned not only by increasing of number of metastatic tumors of colon and rectum, but also by implementation of high-tech methods of treatment that significantly improved the results of five-year survival period. Along with success of therapy, understanding of genomics of colorectal cancer and owing to extensive application of next generation sequencing, the opportunity of optimal choice of treatment options was offered. METHODS: The sampling included tumor material of 332 patients diagnosed with colorectal cancer, fixed in formalin and enclosed in paraffin, and treated in oncology dispensaries and centers and in the Kazakh Research Institute of Oncology and Radiology in 2010-2014. After morphological evaluation of the material quality, the molecular genetic analysis was applied to establish mutation of the KRAS gene using polymerase chain reaction in real-time. RESULTS: The study established that KRAS mutation rate in patients with colorectal cancer had no reliable dependency with the region of their residence, since statistical analysis of pair "region of residence - all KRAS mutations" had value of correlation coefficient rp = 0.1 (p = 0.05). CONCLUSIONS: colorectal cancer It was established that there is no reliable dependence of rate of KRAS gene mutation in patients with colorectal cancer in the region of their residence. The high rate of occurrence of mutated type of gene was detected in 3 regions (Kyzyl-Orda, North Kazakhstan and Almaty) within the range of 58.3-76.5% of cases. The wild type of KRAS gene was most frequently detected in patients from the Karaganda region (65.5%), South Kazakhstan (71.4%) and Almaty (60.7%).


Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias Colorrectales/genética , Humanos , Kazajstán , Mutación , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas p21(ras)/genética
2.
J Cancer Res Clin Oncol ; 146(4): 809-820, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32146564

RESUMEN

PURPOSE: MicroRNAs (miRNAs) participate in a variety of biological processes, including tumorigenesis, progression, invasion, and drug resistance to multiple cancers. Phosphatase and tensin homolog (PTEN) is a cancer suppressor gene that has been certified to be regulated by miRNAs in various tumors, including colorectal cancer (CRC). In this review, we screened articles focusing on low PTEN expression in CRC, observed the expression of related miRNAs, analyzed their correlation and relationship with clinicopathological features, and discussed the possibility of these miRNAs as prognostic molecules. METHODS: We conducted a systematic search for articles published in the Web of Science, PubMed and EBSCO databases between January 1, 2002, and July 18, 2019. We identified these studies by using combinations of the following index entries and key words: 'colorectal tumor OR colorectal neoplasm OR colorectal carcinoma OR colorectal cancer OR CRC', 'protein tyrosine phosphatase OR PTEN', and 'microRNA OR MiRNA OR miRNA OR MicroRNA'. Moreover, we evaluated the underlying association between alterations in PTEN and CRC prognosis. RESULTS: PTEN expression was obviously lower in CRC tissues than in normal mucosa. However, PTEN expression did not differ significantly between adenoma and normal tissues. PTEN tends to be negatively associated with tumor size and metastasis. MiR-21, miR-200a, miR-543, miR-32, miR-92a, miR-26a, miR-106a and miR-181a were correlated with the downregulation of PTEN. MiR-26a, miR-106a and miR-181a were obviously higher in CRC tissues than in normal tissues, while PTEN was downregulated in CRC tissues. Additionally, miRNAs were mainly positively correlated with distant metastasis, followed by TNM stage. The relationship between miRNAs and tumor differentiation is controversial. However, there were no significant differences between miRNAs and either sex or age. CONCLUSIONS: The loss of PTEN may be a diagnostic factor for CRC patients. The above-mentioned miRNAs may function as oncogenes in CRC and represent potential targets for CRC therapy. However, further prospective clinical studies are necessary.


Asunto(s)
Neoplasias Colorrectales/genética , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/enzimología , Humanos , MicroARNs/metabolismo , Fosfohidrolasa PTEN/metabolismo
3.
Medicine (Baltimore) ; 99(7): e19066, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32049807

RESUMEN

Previous work suggests that the long noncoding RNA HCC associated long non-coding RNA (HANR) is associated with hepatocellular carcinoma (HCC) progression, but its significance in the context of colorectal cancer (CRC) remains to be determined. Therefore, in this study we assessed the prognostic and diagnostic value of HANR in patients suffering from CRC.The HANR expression in 165 pairs of CRC cancer and adjacent non-cancerous prostate tissues was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Student t test was conducted for intergroup comparison. Pearson correlation test was used for correlation analysis. Survival curves were carried out by the Kaplan-Meier method and evaluated using the log-rank test. Multivariable Cox proportional hazard risk regression model was performed to screen the independent factor affected the prognosis of CRC patients.In this study, levels of HANR were significantly higher in CRC tumor samples relative to adjacent normal tissue samples (P < .001). A ROC analysis suggested HANR expression could be reliably used to differentiate between normal and CRC tumor tissue. In addition, elevated HANR expression was positively correlated with more advanced and aggressive CRC features, such as a larger tumor size (P = .003), increased invasion depth (P = .012), and more advanced TNM stage (P = .011). Survival analyses revealed that elevated HANR expression was correlated with worse overall survival (P = .002) and disease-free survival (P = .003). A multivariate analysis further confirmed the relevance of HANR as an independent predictor of CRC patient outcomes.In summary, these results indicate that the lncRNA HANR is a promising prognostic indicator in CRC patients.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Colorrectales/diagnóstico , ARN Largo no Codificante/genética , Regulación hacia Arriba , Adulto , Anciano , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Detección Precóz del Cáncer , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Pronóstico , Análisis de Supervivencia
4.
Medicine (Baltimore) ; 99(8): e19189, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32080102

RESUMEN

Studies on the relationship between ABCB1 3435C>T polymorphism (rs1045642) and colorectal cancer (CRC)susceptibility have yielded inconclusive results. To clarify this issue, we undertook a meta-analysis to investigate the relationship between rs1045642 and CRC risk.Three electronic scientific publication databases (Cochrane Library, Pubmed, Embase) were screened using specific search terms. Relevant literature was identified using literature traceability methods. Selected publications were evaluated according to the inclusion and exclusion criteria. Effect size information (odds ratio and the corresponding 95% confidence interval [CI]) was obtained following quality assessment and data extraction from the included publications, and a meta-analysis conducted. Statistical analysis was performed with the Stata sofz (Version 13.0) software.Overall, 17 case-control studies involving 7129 CRC patients and 7710 healthy control subjects satisfied the criteria for inclusion in the meta-analysis. There was no significant association between ABCB1 3435C>T polymorphism and CRC risk in any of the genetic models. In the CC versus CT model (I = 20.9%, Pheterogeneity = .276), CC versus CT + TT model (I = 45.6%, Pheterogeneity = .102) and CT versus CC + TT model (I = 17.8%, Pheterogeneity = .298) analyses, between-study heterogeneities were detected as significant in Asian populations. In the CT versus TT model (I = 24%, Pheterogeneity = .254) and CC + CT versus TT model (I = 0, Pheterogeneity = .55), between-study heterogeneities were found to be significant in groups of different populations.The meta-analysis described here suggests that the ABCB1 3435C>T polymorphism is not related to CRC susceptibility.


Asunto(s)
Neoplasias Colorrectales/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo
5.
Medicine (Baltimore) ; 99(5): e18924, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000405

RESUMEN

Adiponectin is an adipose tissue-derived cytokine that exerts its antiinflammatory effects by binding to 2 adiponectin receptors, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2). However, the role of these adiponectin receptors on inflammatory pain remains unclear. We investigated the association between single nucleotide polymorphisms (SNPs) of these genes and inflammatory pain, such as postoperative pain and cancer pain.We analyzed 17 SNPs of the ADIPOR1 gene and 27 SNPs of the ADIPOR2 gene in 56 adult patients with postlaparotomy pain. We compared these genotypes with pain intensity and opioid consumption, adjusting for multiple testing. We analyzed the genotypes of 88 patients with cancer pain and examined the association of the relevant SNP(s) with pain intensity and opioid consumption.One variant of the ADIPOR1 gene (rs12045862) showed significant association with postoperative pain intensity; patients with minor allele homozygote (n = 7) demonstrated significantly worse pain intensity than that of combined patient group exhibiting major allele homozygote or the heterozygote (n = 49; Mann-Whitney test, P < .00002), although their opioid consumptions were comparable. Cancer pain intensity between minor allele homozygote patients (n = 7) and other 2 genotype patients (n = 81) were comparable.The rs12045862 SNP of the ADIPOR1 gene was associated with postoperative pain but not cancer pain. This might result from functional alteration of the ADIPOR1 signalling pathways, which influence the inflammatory process. ADIPOR1 may be a novel potential target for developing analgesics of postoperative pain.


Asunto(s)
Dolor en Cáncer/genética , Dolor Postoperatorio/genética , Polimorfismo de Nucleótido Simple , Receptores de Adiponectina/genética , Analgésicos Opioides/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugía , Femenino , Estudios de Asociación Genética , Humanos , Inflamación/genética , Laparotomía , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Dolor Postoperatorio/tratamiento farmacológico
6.
Gene ; 734: 144391, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32001373

RESUMEN

OBJECTIVE: Several earlier reports implicated TP53 (rs1042522) and MDM2 (rs2279744) variants in outcome of colorectal cancer (CRC), but with inconclusive findings. This current meta-analysis designed to uncover the role of these variants in CRC risk. METHODOLOGY: Two independent investigators extracted 59 eligible case-control studies from different electronic databases involving Scopus, Web of Science and PubMed prior to June 2019. Pooled odds ratios (ORs) and "95% confidence intervals (CIs)" were computed for different hereditary models. Stratification and heterogeneity analyses, and "Begg's funnel plots" were conducted. In silico data analyses of the functional and structural properties of the study variants were applied. RESULTS: In general, 47 and 16 case-control reports for TP53 (11,589 patients and 13,622 controls) and MDM2 (6841 CRC patients and 8792 healthy controls), respectively were enrolled in this meta-analysis. A significant association of TP53 (rs1042522) variant with increased CRC risk in overall pooled subjects under recessive model [(CC vs. GC + GG, OR = 1.134, 95% CI = 1.006-1.278, P = 0.039)] was observed. Moreover, an evidence of MDM2 (rs2279744) association with increased CRC risk in overall pooled subjects under dominant and heterozygote models [(TG + GG vs. TT, OR = 1.120, 95% CI = 1.003-1.250, P = 0.044) and (TG vs. TT, OR = 1.189, 95% CI = 1.076-1.313, P = 0.001), respectively] was reported. Additionally, TP53 (rs1042522) and MDM2 (rs2279744) showed an association with CRC risk among Asians and Africans under a recessive model, and among Asians under different genetic models, respectively, by stratification analysis. CONCLUSION: TP53 (rs1042522) and MDM2 (rs2279744) variants might represent candidate risk factors for CRC susceptibility.


Asunto(s)
Neoplasias Colorrectales/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p53 Supresora de Tumor/genética , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple
7.
Zhonghua Yi Xue Za Zhi ; 100(4): 301-306, 2020 Feb 04.
Artículo en Chino | MEDLINE | ID: mdl-32075360

RESUMEN

Objective: To investigate the clinicopathological characteristics, MSI and K-ras mutation of double primary malignancies (DPM) associated with colorectal cancer (CRC). Methods: From January 2015 to December 2016, the clinicopathological data of CRC patients treated by surgery in the Affiliated Drum Tower Hospital of Nanjing University Medical School were collected, and the clinical data was analyzed. Multiplex real-time fluorescence quantitative PCR and amplification refractory mutation was performed to identify MSI and K-ras gene mutations. Results: Of all patients with CRC, 5.2% (55/1 066) were DPM. There was no significant difference in the male and female ratio, age, colorectal cancer site, T stage, N stage composition ratio between DPM patients with CRC and patients with single CRC (P>0.05). There were significant difference of TNM stage between the two group (P<0.05). The most frequent location of CRC was the colon in both DPM patients with CRC and patients with single CRC[35.5% (359/1 011) and 41.8% (23/55), respectively]. Of 55 DPM patients with CRC, 48 were metachronous DPM patients, 7 were synchronous DPM patients and 41 were colorectal cancer first. In extracolonic organ, digestive system (23/55) was the most commonly occurring system and stomach (11/55) was the most common lesion. DPM patients with CRC had higher incidence of MSI-H than patients with single CRC (P<0.05). There was no significant difference of K-ras gene mutation between DPM patients with CRC and patients with single CRC (P>0.05). MSI-H and K-ras mutation were present in only 2 patients of DPM patients with CRC. Conclusions: The rectum is the most common lesion site in CRC patients. The stomach is the most common extracolonic organ of DPM patients with CRC. DPM patients with CRC has high risk of MSI-H, but no significant difference in the incidence of K-ras mutation.


Asunto(s)
Neoplasias Colorrectales , Genes ras , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Colorrectales/genética , Femenino , Humanos , Masculino , Inestabilidad de Microsatélites , Mutación , Estadificación de Neoplasias
8.
Crit Rev Oncol Hematol ; 146: 102859, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31927392

RESUMEN

Lung and colorectal cancer are included in the most tremendously threatening diseases in terms of incidence and death. Although they are located in completely different organs and differ in various characteristics they do share some common features, especially regarding their molecular mutational profile. Among several commonly mutated genes KRAS and BRAF are spotted to be highly associated with patient's poor disease outcome and resistance to targeted therapies mostly in liaison with other mutant activated genes. Many studies have shed light in these mechanisms for disease progression and numerous preclinical models, clinical trials and meta-analysis reports investigate the impact of specific treatments or combination of therapies. The present review is an effort to compare the mutational imprint of these genes between the two diseases and their impact in prognosis, current therapy, mechanisms of therapy resistance and future therapeutic plans and provide a spherical perspective regarding the systemic molecular profile of cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas ras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/patología , Mutación/genética , Valor Predictivo de las Pruebas , Pronóstico , Resultado del Tratamiento
9.
Dis Colon Rectum ; 63(2): 183-189, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31914111

RESUMEN

BACKGROUND: Researchers are searching in vain for a coherent genetic explanation for serrated polyposis. We hypothesize that there is no consistent monogenetic inheritance. OBJECTIVE: The purpose of this study was to describe the serrated polyposis phenotype, assessing features of mendelian inheritance, and to compare these features with patients with a solitary sessile serrated lesion. DESIGN: This was a retrospective review of a prospectively maintained database comparing patients with serrated polyposis versus solitary sessile serrated lesions. SETTINGS: The study was conducted at a single-institution tertiary referral center. PATIENTS: Patients with serrated polyposis meeting World Health Organization criteria type I (≥5 serrated polyps proximal to the sigmoid, ≥2 of which are ≥10 mm in diameter) and isolated sessile serrated lesions were included MAIN OUTCOME MEASURES:: Disease phenotype was the main outcome measured. RESULTS: A total of 46 serrated polyposis patients were identified. Median age of first sessile serrated lesion was 66 years (interquartile range, 42-70 y). A total of 60.3% were current or past smokers (mean = 38.6 packs per year). Serrated polyposis patients had a higher number of all types of polyps (26.3 vs 4.4) and a higher rate of high-grade dysplasia (19.6% vs 3.7%) compared with patients with a solitary sessile serrated lesion. A total of 36.2% of patients had personal history of noncolorectal cancers, including skin, prostate, breast, thyroid, and renal cell cancers and leukemia. In addition, 32.6% had a family history of colorectal cancer in first- or second-degree relatives; these cancers were not young age of onset. Breast and prostate cancers were also common (family history of any cancer, 83.0%). Ten patients underwent genetic testing: 4 had negative panels, 1 had a pathogenic variant in MSH2, 1 an IVS7 deletion in PTEN, 2 negative APC sequencing (1 negative MYH), and 1 a pathogenic variant in Chek2. LIMITATIONS: RNF4 was not sequenced. Genetic analysis was performed on a subset of patients. CONCLUSIONS: The rate of associated cancers suggests an underlying genetic predisposition to disordered growth, but serrated polyposis does not have typical features of dominant inheritance. The association with smoking suggests that familial/environmental factors play a role. See Video Abstract at http://links.lww.com/DCR/B84. POLIPOSIS SERRADA SÉSIL: ¿NO ES UN SÍNDROME HEREDITARIO?: Los investigadores están buscando en vano una explicación genética coherente para la póliposis serrados. Suponemos que no existe una herencia monogenética consistente.1) Describir el fenotipo de póliposis serrada, evaluando las características de la herencia mendeliana, 2) comparar estas características con pacientes con una lesión serrada sésil solitaria.Revisión retrospectiva de una base de datos mantenida prospectivamente que compara pacientes con póliposis serrada versus lesiones serradas sésiles solitarias.Institución única, centro de referencia terciario.Pacientes con póliposis serrada que cumplen con los Criterios de la Organización Mundial de la Salud Tipo I (≥ 5 pólipos serrados proximales al sigmoideo, ≥2 de los cuales tienen ≥10 mm de diámetro) y lesiones serradas sésiles aisladas.Fenotipo de la enfermedad.Se identificaron un total de 46 pacientes con póliposis serrada. La edad mediana de la primera lesión serrada sésil fue de 66 años (RIC: 42-70 años). El 60.3% eran fumadores actuales o pasados (medio 38.6 paquetes / año). Los pacientes con póliposis serrada tuvieron un mayor número de todos los tipos de pólipos (26.3 versus 4.4) y una mayor tasa de displasia de alto grado (19.6% versus 3.7%) en comparación con los pacientes con una lesión serrada sésil solitaria. El 36.2% de los pacientes tenían antecedentes personales de cánceres no colorectales, incluyendo los cánceres de piel, próstata, mama, tiroides, células renales y leucemia. El 32.6% tenía antecedentes familiares de cáncer colorectal en familiares de primer o segundo grado; estos cánceres no eran de inicio de edad temprana. El cáncer de mama y próstata también fue frecuente (antecedentes familiares de cualquier tipo de cáncer: 83.0%). 10 pacientes se sometieron a pruebas genéticas: 4 tenían paneles negativos, 1 tenía una variante patogénica en MSH2, 1 una eliminación IVS7 en PTEN, 2 secuenciación APC negativa (1 MYH negativa) y 1 variante patogénica en Chek2.RNF4 no fue secuenciado. El análisis genético se realizó en un subconjunto de pacientes.La tasa de cánceres asociados sugiere una predisposición genética subyacente al crecimiento desordenado, pero la póliposis serrada no tiene características típicas de herencia dominante. La asociación con el tabaquismo sugiere que los factores familiares / ambientales juegan un papel. Consulte Video Resumen en http://links.lww.com/DCR/B84. (Traducción-Dr. Yesenia Rojas-Khalil).


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Pruebas Genéticas/métodos , Anamnesis/estadística & datos numéricos , Poliposis Adenomatosa del Colon/diagnóstico por imagen , Poliposis Adenomatosa del Colon/patología , Adulto , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Endoscopía Gastrointestinal/métodos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Estudios Retrospectivos , Fumar/efectos adversos
10.
Isr Med Assoc J ; 22(1): 32-36, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31927803

RESUMEN

BACKGROUND: Evaluation of mismatch repair (MMR) deficiency is conducted via immunohistochemistry or by microsatellite instability (MSI) analysis. Heterogeneous immunohistochemistry staining for MMR proteins may show different patterns; however, according to current guidelines, all of those patterns should be interpreted as MMR proficient. This conclusion might lead to false negative results because although most cases of heterogeneity stem from technical factors and biological variability, other types of heterogeneity represent true MMR deficiency. OBJECTIVES: To identify a unique heterogeneity pattern that is associated with true MMR loss. METHODS: We analyzed 145 cases of colorectal carcinoma. Immunohistochemistry staining for MLH1, PMS2, MSH2, and MSH6 were performed. We defined geographic heterogeneity as areas of tumor nuclear staining adjacent to areas of loss of tumor nuclear staining with intact staining in the surrounding stroma. All cases were evaluated for the presence of geographic heterogeneity. In addition, 24 cases were also evaluated by MSI testing. RESULTS: Of the 145 cases, 24 (16.5%) were MMR deficient. Of the 24 cases for which MSI analysis was also available, 10 cases (41.7%) demonstrated biological heterogeneity, 5 (20.8%) demonstrated technical heterogeneity, and 2 (8.3%) demonstrated geographic heterogeneity. Only the two cases with geographic heterogeneity were MSI-high via MSI analysis. In addition, a germline mutation in MSH-6 was identified in one of these cases. CONCLUSIONS: Geographic heterogeneity may raise a suspicion for a MMR-deficient case, which should be further analyzed using additional methodologies such as MSI analysis.


Asunto(s)
Reparación de la Incompatibilidad de ADN/genética , Proteínas MutS/genética , Adenoma/genética , Adenoma/patología , Adulto , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Colorantes , Heterogeneidad Genética , Humanos , Masculino
11.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892565

RESUMEN

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Fluorouracilo/farmacología , Xenoinjertos , Humanos , Receptores de Hialuranos/genética , Ratones
12.
Anticancer Res ; 40(1): 177-190, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892566

RESUMEN

BACKGROUND/AIM: The chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) regulates cancer cell proliferation and invasion via complex molecular mechanisms. We aimed to investigate whether COUP-TFII modulates proliferation and invasion of the colorectal adenocarcinoma cell line HT-29. MATERIALS AND METHODS: HT-29 cells were stably tranfected with COUP-TFII shRNA plasmid to knock-down COUP-TFII (COUP-TFII shRNA-HT-29 cells). Cell proliferation, colony formation assay, invasion assay, microarray assays and western blot analyses were performed. RESULTS: Cell proliferation and invasion were significantly enhanced in COUP-TFII shRNA-HT-29 cells. The protein levels of forkhead box C1 (FOXC1), p-Akt, p-glycogen synthase kinase-3ß (p-GSK-3ß), and ß-catenin, which are known to be involved in cell proliferation and invasion, were significantly increased in COUP-TFII shRNA-HT-29 cells. Akt inhibitor IV and dominant negative (DN)-Akt expression vector transfection reversed the increased proliferation and invasion, which was accompanied by decreased protein levels of p-Akt, p-GSK-3ß, ß-catenin and FOXC1. CONCLUSION: COUP-TFII knock-down promoted proliferation and invasion via activation of Akt/GSK-3ß/ß-catenin and up-regulation of FOXC1. Further studies on the molecular mechanism of interaction between ß-catenin and FOXC1 expression may reveal novel target molecules for metastatic colorectal cancer therapy.


Asunto(s)
Factor de Transcripción COUP II/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor de Transcripción COUP II/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/patología , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , ARN Interferente Pequeño/genética
13.
Gene ; 730: 144323, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-31917230

RESUMEN

The subjection of DNA to numerous lethal damages is threatening for the stability and integrity of the whole body genome. DNA damage response (DDR) is a critical phosphorylation-based signaling pathway developed for the maintaining of the genome against these threatens. Recent studies showed that various targets of DDR are involved in the activation of autophagy, as one of the important effectors of this signaling. The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies such as colorectal cancer, which can be a basement for the designing novel therapeutic strategies for combating this cancer type. On the other hand, autophagy is also demonstrated to be contributed to the regulation of DDR components. Therefore, in this review article, we will discuss the crosstalk between DDR and autophagy and their exact function in the pathogenesis of various human cancer types, with special attention on colorectal cancer.


Asunto(s)
Autofagia/genética , Neoplasias Colorrectales/metabolismo , Reparación del ADN/fisiología , Neoplasias del Colon/genética , Neoplasias Colorrectales/genética , Daño del ADN/fisiología , Inestabilidad Genómica/genética , Humanos , Transducción de Señal/genética
14.
BMC Med Genet ; 21(1): 3, 2020 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900123

RESUMEN

BACKGROUND: Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients. CASE PRESENTATION: In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19-9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed. CONCLUSION: As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.


Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/sangre , Proteína p53 Supresora de Tumor/sangre , Proteína de la Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Ácidos Nucleicos Libres de Células/sangre , ADN Tumoral Circulante/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Biopsia Líquida , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas p21(ras)/genética , Inducción de Remisión , Proteína p53 Supresora de Tumor/genética
15.
Gene ; 734: 144395, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-31987907

RESUMEN

Studies imply the FOXP3 gene polymorphisms are engaged in the occurrence of some cancers, but the relationship between FOXP3 rs2280883 polymorphism and the hazard of colorectal cancer (CRC) is unclear. For this reason, a case-control investigation involving 365 CRC patients and 411 healthy individuals (matched by both age and gender) was taken to illustrate the underlying association. FOXP3 rs2280883 polymorphism genotyped via PCR-RELP. Data revealed this polymorphism was significantly linked to increased risk for CRC (CC versus TT, OR, 1.75; 95%CI, 1.06-2.88; P = 0.030). Subgroup analyses uncovered FOXP3 rs2280883 polymorphism intensified the risk of CRC among smokers. As for the connection between rs2280883 and clinical data of CRC, this polymorphism corelated to lymph node metastasis (CC versus TT: OR, 2.75; 95%CI, 1.35-5.62; P = 0.004) and the TNM stage. In conclusion, FOXP3 rs2280883 polymorphism is related to higher risk of CRC in a Chinese individuals. Larger-sized studies involving other races are needed.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Neoplasias Colorrectales/genética , Factores de Transcripción Forkhead/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
16.
Life Sci ; 244: 117300, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31953162

RESUMEN

MiR-346-5p is overexpressed in several cancers, including colorectal cancer (CRC). However, the effects of miR-346-5p on CRC progression have not yet been clarified. In our study, miR-346-5p levels in four CRC cell lines and normal human colon epithelial cells were determined by real-time PCR. SW620 and HCT116 cells were selected and then transfected with miR-346-5p mimic, miR-346-5p inhibitor, or specific siRNAs targeting F-box/LRR-repeat protein 2 (FBXL2). Cell proliferation, cell cycle distribution and cell cycle regulators were examined by CCK-8 assay, flow cytometry, and western blot. The binding of miR-346-5p on 3' untranslated region (UTR) of FBXL2 were verified by dual-luciferase reporter assay. CRC cells were co-transfected with miR-346-5p inhibitor and siFBXL2 to investigate the involvement of FBXL2. Interaction of FBXL2 with forkhead box M1 (FoxM1) was examined by co-immunoprecipitation (Co-IP) assay. The effect of miR-346-5p knockdown on CRC tumorigenesis in vivo was investigated. Here, we found that miR-346-5p overexpression promoted, while miR-346-5p knockdown inhibited cell proliferation and G1-S transition. Inhibition of FBXL2 showed similar effects as miR-346-5p overexpression. Moreover, we verified that FBXL2 was a direct target of miR-346-5p. FBXL2 interacted with FoxM1, and then negatively regulated both FoxM1 and nuclear ß-catenin levels. Additionally, FBXL2 knockdown reversed the effects of miR-346-5p inhibitor. In xenograft models, miR-346-5p knockdown significantly inhibited tumor growth, increased FBXL2 expression, and downregulated the levels of FoxM1 and nuclear ß-catenin. In conclusion, miR-346-5p may promote CRC growth by targeting FBXL2 and activating the ß-catenin signaling pathway. MiR-346-5p may be a novel target in cancer therapy.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Proteínas F-Box/metabolismo , MicroARNs/genética , Animales , Apoptosis/genética , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Proteínas F-Box/genética , Proteína Forkhead Box M1/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Transducción de Señal/genética , Vía de Señalización Wnt/genética , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismo
17.
Cancer Invest ; 38(2): 85-93, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31939681

RESUMEN

The identification and quantification of actionable mutations are critical for guiding targeted therapy and monitoring drug response in colorectal cancer. Liquid biopsy (LB) based on plasma cell-free DNA analysis has emerged as a noninvasive approach with many clinical advantages over conventional tissue sampling. Here, we developed a LB protocol using ultra-deep massive parallel sequencing and validated its clinical performance for detection and quantification of actionable mutations in three major driver genes (KRAS, NRAS and BRAF). The assay showed a 92% concordance for mutation detection between plasma and paired tissues and great reliability in quantification of variant allele frequency.


Asunto(s)
ADN Tumoral Circulante/genética , Neoplasias Colorrectales/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biopsia Líquida/métodos , Neoplasias Colorrectales/sangre , GTP Fosfohidrolasas/genética , Humanos , Proteínas de la Membrana/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Reproducibilidad de los Resultados
19.
DNA Cell Biol ; 39(1): 16-24, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31808724

RESUMEN

Colorectal cancer (CRC) is a severe risk to public health, and there is growing evidence that alternative splicing (AS) plays a crucial role in cancer. However, the AS biomarkers in CRC are seldom reported. In this study, we perform transcriptome analysis of colorectal samples for cancer-specific AS and transcriptomic alterations. We identify 1577 splice events in 885 genes, enriched in CRC-associated pathways and functions. In parallel, we find 10 splicing factors (SFs) with transcriptome variation or significant differential expression. Based on co-expression and binding motif, we construct an SF-AS regulatory network, revealing the association between cancer-specific AS and aberrant SF. Integrating The Cancer Genome Atlas and published sources, we observed that some recurrent AS is an indicator of poor prognosis. Through further experimental verification, we found that the AS of six genes showed significant differences between the tumor sample and the normal sample, and AS of TCF7, COL12A1, GK, and UBA1 can be used as new potential biomarkers in CRC. Our study provides an important analysis of CRC-associated AS, which could act as a starting point for future functional explorations, the development of biomarkers and AS-based target therapy.


Asunto(s)
Empalme Alternativo , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Transcriptoma/genética , Adulto , Secuencia de Bases , Femenino , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Homología de Secuencia de Ácido Nucleico , Factor 1 de Transcripción de Linfocitos T/genética
20.
Life Sci ; 241: 117114, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31790687

RESUMEN

AIMS: Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide. Over-expression of tetraspanin 8 (TSPAN8) is related to the development and progression of CRC. Whether TSPAN8 plays a role in the growth of colorectal cancer and its epigenetic mechanisms regulated by Lysine Specific Demethylase 1 (LSD1) are still unknown. MAIN METHODS: In this study, RT-PCR and western blotting were used to analyze the mRNA and protein expression, respectively; cell viability was assayed with MTS analysis; cell migration was measured with Trans-well analysis. KEY FINDINGS: In the present study, the results indicated that the mRNA levels of LSD1 and TSPAN8 in CRC were significantly higher than that in corresponding adjacent non-tumor tissue. Down-regulation of LSD1 or TSPAN8 as well as LSD1 inhibitor Tranylcypromine hemisulfate inhibited the proliferation and migration of CRC cells, while over-expression of LSD1 exhibited opposite effects. LSD1 up-regulated TSPAN8 expression and reduced H3K9me2 occupancy on the TSPAN8 promoter in CRC cells. TSPAN8 promoted epithelial-mesenchymal transition (EMT) in CRC cells in LSD1-dependent manner. SIGNIFICANCE: TSPAN8 may be considered as a promising biomarker for the diagnosis and prognosis in patients with CRC. Furthermore, TSPAN8 could be a novel therapeutic target and potent LSD1 inhibitors could be designed and developed in the treatment of CRC.


Asunto(s)
Neoplasias Colorrectales/patología , Histona Demetilasas/metabolismo , Tetraspaninas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilación , Regiones Promotoras Genéticas , Tetraspaninas/genética
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