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1.
Braz J Med Biol Res ; 54(5): e9700, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33825780

RESUMEN

Lung adenocarcinomas are usually sensitive to radiation therapy, but some develop resistance. Radiation resistance can lead to poor patient prognosis. Studies have shown that lung adenocarcinoma cells (H1299 cells) can develop radioresistance through epithelial-mesenchymal transition (EMT), and this process is regulated by miRNAs. However, it is unclear which miRNAs are involved in the process of EMT. In our present study, we found that miR-183 expression was increased in a radioresistant lung adenocarcinoma cell line (H1299R cells). We then explored the regulatory mechanism of miR-183 and found that it may be involved in the regulation of zinc finger E-box-binding homeobox 1 (ZEB1) expression and mediate EMT in lung adenocarcinoma cells. qPCR results showed that miR-183, ZEB1, and vimentin were highly expressed in H1299R cells, whereas no difference was observed in E-cadherin expression. Western blot results showed that ZEB1 and vimentin were highly expressed in H1299R cells, while E-cadherin expression was decreased. When miR-183 expression was inhibited in H1299R cells, radiation resistance, proliferation, and cell migration were decreased. The expression of ZEB1 and vimentin in H1299R cells was decreased, while the expression of E-cadherin was increased. Moreover, miR-183 overexpression in H1299 cells enhanced radiation resistance, proliferative capacity, and cell migration ability. The expression of ZEB1 and vimentin in H1299 cells was increased, while that of E-cadherin was decreased. In conclusion, miR-183 may promote EMT and radioresistance in H1299 cells, and targeting the miR-183-ZEB1 signaling pathway may be a promising approach for lung cancer treatment.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , MicroARNs , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/radioterapia , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , MicroARNs/genética
2.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807876

RESUMEN

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal-epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809660

RESUMEN

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is "undruggable", (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically "cold" tumors into "hot" ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich's century-old "magic bullet" vision with Rudolf Virchow's cancer inflammation theory.


Asunto(s)
Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/terapia , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Microambiente Tumoral
4.
Drugs Today (Barc) ; 57(4): 265-275, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33851690

RESUMEN

Non-small cell lung cancer (NSCLC) is one of the most devastating cancers with high mortality worldwide. By inhibiting the activity of specific molecular targets in the cancer cells, tyrosine kinase inhibitors (TKIs) have become a standard treatment in combating NSCLC. Tepotinib hydrochloride is an orally bioavailable, mesenchymal-epithelial transition (MET) TKI developed mainly for selected NSCLC patients with METex14 skipping mutations. Tepotinib demonstrated durable clinical response in phase II clinical trials, which led to its approval for use in Japan and breakthrough therapy designation and accelerated approval in the U.S. These progresses highlighted tepotinib as a promising candidate for NSCLC patients. This review summarizes the pharmacological profile of tepotinib, preclinical studies and landmark clinical trials of tepotinib. In addition, we share our perspectives on the future direction of tepotinib as a novel anticancer drug.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos , Humanos , Japón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-met/genética , Piridazinas , Pirimidinas
6.
Nat Commun ; 12(1): 2038, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795683

RESUMEN

Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Largo no Codificante/genética , Células A549 , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
7.
J Environ Pathol Toxicol Oncol ; 40(2): 55-63, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33822517

RESUMEN

BACKGROUND: SET domain-containing protein 5 (SETD5) could promote non-small cell lung cancer (NS-CLC) cell invasion, but the effect of SETD5 on NSCLC cell stemness characteristics is unknown. Thus we attempted to evaluate the effect of SETD5 on NSCLC stemness and its mechanism. METHODS: The expressions of SETD5 and stemness-related genes (SOX2, OCT4, ABCG2) were detected in NSCLC tissues by immunohistochemistry assay, qRT-PCR, and western blot. A SETD5 knockdown cell model was constructed by siRNA transfection in A549 and H1299 cells. A CCK8 assay was used to examine cell viability. A sphere-forming assay and side population cell assay were conducted to measure the cancer cell stem properties. The cells with SETD5 deletion were treated with an activator of AKT, SC79, and the protein expressions of Akt, p-Akt, mTOR, and p-mTOR were assessed. RESULTS: SETD5 and cancer stem-related genes SOX2, OCT4, and ABCG2 were co-expressed and co-localized in tumor tissues and cell lines of NSCLC. The deletion of SETD5 significantly reduced the cell viability, cancer stem properties, and activity of the PI3K/Akt/mTOR pathway, while the decreased SETD5-induced effects were partially restored with SC79 treatment. CONCLUSION: In this study, SETD5 promoted the cancer stem cell property of NSCLC through mitigating the activation of the PI3K/Akt/mTOR pathway, suggesting a candidate target role for SETD5 in NSCLC treatment.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Metiltransferasas/genética , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Línea Celular , Humanos , Proteínas de Neoplasias/genética , Células Madre Neoplásicas , Factor 3 de Transcripción de Unión a Octámeros/genética , Factores de Transcripción SOXB1/genética , Transducción de Señal
8.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799513

RESUMEN

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome's distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Ensayos Clínicos como Asunto , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Femenino , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Medicina de Precisión/métodos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Análisis de Supervivencia , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/mortalidad
9.
Artículo en Inglés | MEDLINE | ID: mdl-33799753

RESUMEN

The aim of the current study is to investigate potential associations among Long Noncoding RNA (LncRNA) H19 single nucleotide polymorphism (SNP) and epidermal growth factor receptor (EGFR) phenotypes on the clinicopathological characteristics of lung adenocarcinoma (LADC). Five loci of LncRNA H19 SNPs (rs217727, rs2107425, rs2839698, rs3024270, and rs3741219) were genotyped by using TaqMan allelic discrimination in 223 LADC patients with wild-type EGFR phenotype and 323 LADC individuals with EGFR mutations. After the statistical analyses, patients with the EGFR mutation were related to a higher distribution frequency of rs217727 SNP CT heterozygote (p = 0.030), and the female population with EGFR mutation demonstrated a higher distribution frequency of rs217727 SNP CT heterozygote (p < 0.001) and rs2107425 CT heterozygote (p = 0.002). In addition, the presence of LncRNA H19 SNP rs217727 T allele (CT + TT) in patients with EGFR wild-type was associated to higher tumor T status (stage III or IV, p = 0.037) and poorer cell differentiation status (poor differentiation, p = 0.012) compared to those EGFR wild-type individuals with LncRNA H19 SNP rs217727 CC allele. Besides, a prominently higher tumor T status was found in subjects with LncRNA H19 SNP rs2107425 T allele (CT + TT) (stage III or IV, p = 0.007) compared to EGFR wild-type LADC individuals with LncRNA CC allele in EGFR wild-type patients. Our findings suggest that the presence of LncRNA H19 SNP rs217727 is related to the EGFR mutation in LADC patients, and the LncRNA H19 SNP rs217727 and rs2107425 are associated with progressed tumor status for LADC patients with EGFR wild-type.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , ARN Largo no Codificante , Adenocarcinoma del Pulmón/genética , Estudios de Casos y Controles , Receptores ErbB/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/genética , Fenotipo , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética
10.
Anticancer Res ; 41(4): 2059-2065, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813414

RESUMEN

BACKGROUND/AIM: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher's exact test. Overall (OS) and progression-free (PFS) survival were estimated by Kaplan-Meier method. RESULTS: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. CONCLUSION: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.


Asunto(s)
Afatinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , República Checa/epidemiología , Progresión de la Enfermedad , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
11.
Zhonghua Bing Li Xue Za Zhi ; 50(5): 447-452, 2021 May 08.
Artículo en Chino | MEDLINE | ID: mdl-33915649

RESUMEN

Objective: To investigate the value of chromosomes 7 and 8 polysomy in circulating tumor cells (CTCs) for the diagnosis of non-small cell lung cancer, and the correlation of CTCs with clinical pathological characteristics and epidermal growth factor receptor (EGFR) mutations in cancer tissue. Methods: Fifty-seven patients with non-small cell lung cancer and 21 patients with benign lung diseases were enrolled at Beijing Chaoyang Hospital, Capital Medical University, Beijing, China from November 2017 to October 2020. Negative enrichment combined with immunofluorescence in situ hybridization (imFISH) was used to identify CTCs polysomy on chromosomes 7 and 8. EGFR mutations in 56 lung cancer patients was detected using ARMS-PCR. Results: CTCs were detected in 93.0% (53/57) of non-small cell lung cancers and 28.6% (6/21) benign lung lesions. The difference between lung cancer patients and the control cohort was statistically significant (P<0.01). Receive operator curve (ROC) analyses showed that, when the cut-off value was 1 cell/3.2 mL, Youden index had the highest sensitivity of 93.0% and specificity of 71.4% (AUC=0.906, 95%CI:0.833-0.980, P<0.01). The positive rate of CTCs in stage Ⅲ-Ⅳ cancers was significantly higher than that in stage Ⅰ-Ⅱ (P=0.023). No significant correlation was observed between positive rate of CTCs or chromosome polysomy and age, gender, smoking status, pathologic types and EGFR mutation status. The number of CTCs in EGFR mutated group was higher than that in the non-mutated group (6.5±1.1 vs. 3.7±0.7, P=0.045). The detection rate for CTCs ≥5 in the EGFR mutated group was also higher than the EGFR non-mutated group (52.0% vs. 19.4%,P=0.010). Conclusion: Detection of CTCs with chromosomes 7 and 8 polysomy has potential value in auxiliary diagnosis of non-small cell lung cancer, and the number of CTCs is correlated to TNM stage and EGFR gene mutation status.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , China , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutación
12.
Medicine (Baltimore) ; 100(16): e25478, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879681

RESUMEN

BACKGROUND: Long noncoding RNAs play vital roles in development and progression of lung cancers. Nuclear paraspeckle assembly transcript 1 (NEAT1) polymorphisms were reported to be closely related to lung cancer susceptibility. Recently, numerous studies have been performed to detect the association between NEAT1 polymorphisms and lung cancer susceptibility. However, their results were inconsistent and controversial. So, we carried out a meta-analysis aiming to define the association exactly. METHODS: Appropriate studies were retrieved from searching Web of Science, PubMed, Scopus, and Google scholar databases, updated January 31, 2021. The pooled odds ratios with 95% confidence intervals were calculated to estimate the strength of the association between NEAT1 polymorphisms and lung cancer risk. All of the data were analyzed with Stata 16.0. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: This meta-analysis will summarize the relationship between NEAT1 polymorphism and lung cancer.


Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , ARN Largo no Codificante/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , Metaanálisis como Asunto , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Revisiones Sistemáticas como Asunto
13.
Sensors (Basel) ; 21(6)2021 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-33801002

RESUMEN

Machine learning (ML)-based algorithms are playing an important role in cancer diagnosis and are increasingly being used to aid clinical decision-making. However, these commonly operate as 'black boxes' and it is unclear how decisions are derived. Recently, techniques have been applied to help us understand how specific ML models work and explain the rational for outputs. This study aims to determine why a given type of cancer has a certain phenotypic characteristic. Cancer results in cellular dysregulation and a thorough consideration of cancer regulators is required. This would increase our understanding of the nature of the disease and help discover more effective diagnostic, prognostic, and treatment methods for a variety of cancer types and stages. Our study proposes a novel explainable analysis of potential biomarkers denoting tumorigenesis in non-small cell lung cancer. A number of these biomarkers are known to appear following various treatment pathways. An enhanced analysis is enabled through a novel mathematical formulation for the regulators of mRNA, the regulators of ncRNA, and the coupled mRNA-ncRNA regulators. Temporal gene expression profiles are approximated in a two-dimensional spatial domain for the transition states before converging to the stationary state, using a system comprised of coupled-reaction partial differential equations. Simulation experiments demonstrate that the proposed mathematical gene-expression profile represents a best fit for the population abundance of these oncogenes. In future, our proposed solution can lead to the development of alternative interpretable approaches, through the application of ML models to discover unknown dynamics in gene regulatory systems.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Algoritmos , Difusión , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(3): 329-335, 2021 Mar 25.
Artículo en Chino | MEDLINE | ID: mdl-33849822

RESUMEN

OBJECTIVE: To investigate the role and expression pattern of LIM-domain binding protein 2 (LDB2) in lung adenocarcinoma. OBJECTIVE: We studied the expression pattern of LDB2 in lung adenocarcinoma based on data from the online databases TCGA, GEO and CPTAC, and the results were verified in lung adenocarcinoma tissues and cells using immunohistochemistry, qRT-PCR and Western blotting. The relationship between LDB2 and the prognosis of patients with lung adenocarcinoma was analyzed using GEPIA and GEO databases. We further analyzed the role of LDB2 in regulating cell behaviors in a H1299 cell model over-expressing LDB2 using cell counting, soft agar colony forming assay and flow cytometry. The m6A binding sites on LDB2 were confirmed by bioinformatics analysis and MeRIP-qPCR assays. The effect of YTHDC2 on LDB2 was examined using qRT-PCR and Western blotting, and the binding of YTHDC2 to the transcript of LDB2 was verified with RIP-qPCR assays. Dual luciferase reporter assay was performed to verify YTHDC2 functioning via m6A sites. OBJECTIVE: LDB2 expression was significantly decreased in lung adenocarcinoma in comparison with normal tissues based on data from TCGA, GEPIA and CPTAC, and the same results were obtained from 80 lung adenocarcinoma tissues and 17 adjacent normal tissues. Similarly, LDB2 expression was decreased in lung adenocarcinoma cells as compared with 16HBE cells. The data from Prognoscan and GEPIA suggested that a high LDB2 expression was positively correlated with a more favorable outcome of lung adenocarcinoma patients. LDB2-overexpressing H1299 cells showed a significant inhibition of proliferative activity with cell cycle arrest in S phage. Bioinformatics analysis and MeRIP-qPCR assay confirmed the presence of m6A sites on LDB2. The m6A reader YTHDC2 was positively related with LDB2 in lung adenocarcinoma based on data from GEPIA (r=0.22). Overexpression YTHDC2 significantly enhanced LDB2 expression in H1299 cells by about 19.35 folds. Dual luciferase reporter assay showed that YTHDC2 enhanced the promoter activity in the wild-type group but not in deletion group. OBJECTIVE: LDB2 expression can be up-regulated by m6A reader YTHDC2 in lung adenocarcinoma to inhibit the proliferation of the tumor cells in vitro.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Proteínas Portadoras , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas con Dominio LIM , Neoplasias Pulmonares/genética , ARN Helicasas , Factores de Transcripción/genética
15.
Nat Commun ; 12(1): 2163, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846331

RESUMEN

γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Trials of adoptive γδ T cell transfer in solid tumors have had limited success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate surface molecules on cancer cells related to γδ T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells. Mechanistically, DNMTi enhances immune synapse formation and mediates cytoskeletal reorganization via coordinated alterations of DNA methylation and chromatin accessibility. Genetic depletion of adhesion molecules or pharmacological inhibition of actin polymerization abolishes the potentiating effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature stratifies lung cancer patients prognostically. These results support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management.


Asunto(s)
Citoesqueleto/metabolismo , Citotoxicidad Inmunológica/genética , Epigénesis Genética , Sinapsis Inmunológicas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Animales , Línea Celular Tumoral , Citoesqueleto/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Decitabina/farmacología , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Sinapsis Inmunológicas/efectos de los fármacos , Marcaje Isotópico , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/metabolismo , Masculino , Ratones Endogámicos NOD , Fosfotirosina/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Medicine (Baltimore) ; 100(16): e25246, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879658

RESUMEN

ABSTRACT: Lung adenocarcinoma (LUAD) is a lethal malignancy worldwide and a major public health concern. We explored the potential clinical significance for LUAD of ATP-binding cassette (ABC), sub-family C, consisting of ABCC1-6, 8-12, and cystic fibrosis transmembrane conductance regulator (CFTR).Five hundred LUAD patients from The Cancer Genome Atlas database were used for analysis, including differential expression and diagnostic and prognostic significance. Oncomine and MERAV databases were used to validate differential expression and diagnostic significance. A risk score model was constructed using prognosis-related ABCC members. Prognosis-related genes were further explored to correlate their expression with tumor stage progression. Interaction networks, including biological processes and metabolic pathways, were constructed using Cytoscape software and STRING website.ABCC1-3 consistently showed high expression in tumor tissues (all P ≤ 0.05). Most datasets indicated that ABCC5, 10, and 11 were highly expressed in tumor tissues whereas ABCC6, 9, and CFTR were highly expressed in nontumor tissues (all P ≤ 0.05). Diagnostic significance of ABCC3 and ABCC5 was consistently assessed and validated in three datasets (all area under the curve > 0.700) whereas ABCC6, 8, 10, 11, and CFTR were assessed in The Cancer Genome Atlas dataset and validated in one dataset (all area under the curve > 0.700). Prognostic analysis indicated that ABCC2, 6, and 8 mRNA expression was associated with survival of LUAD (all adjusted P ≤ .037). The risk score model constructed using ABCC2, 6, and 8 suggested prognostic significance for survival predictions. ABCC2 expression was associated with tumor stage, whereas ABCC6 and 8 were not. Interaction networks indicated that they were involved in establishment of localization, ion transport, plasma membrane, apical plasma membrane, adenylyl nucleotide binding, ABC transporters, ABC transporter disorders, ABC-family-protein-mediated transport, and bile secretion.Differentially expressed ABCC2 and ABCC5 might be diagnostic whereas ABCC2, 6, and 8 may be prognostic biomarkers for LUAD, possibly through ABC-family-mediated transporter disorders.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Anciano , Biomarcadores de Tumor/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Bases de Datos Genéticas , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Factores de Riesgo , Análisis de Supervivencia
17.
Nat Commun ; 12(1): 2357, 2021 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-33883548

RESUMEN

Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We perform the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n = 46], lung [n = 30]) and non-cancer (n = 89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) are not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identify tissue- and cancer-specific genes, defined as "dark channel biomarker" (DCB) genes, that are recurrently detected in individuals with cancer. DCB levels in plasma correlate with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Ácidos Nucleicos Libres de Células/genética , Neoplasias Pulmonares/genética , Transcriptoma , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Ácidos Nucleicos Libres de Células/sangre , Estudios de Cohortes , Bases de Datos de Ácidos Nucleicos , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/sangre , Anotación de Secuencia Molecular , Especificidad de Órganos/genética , ARN Mensajero/sangre , ARN Mensajero/genética
18.
Zhonghua Bing Li Xue Za Zhi ; 50(5): 458-464, 2021 May 08.
Artículo en Chino | MEDLINE | ID: mdl-33915651

RESUMEN

Objective: To observe the clinicopathological features of bronchiolar adenoma (BA) and mixed squamous cell and glandular papilloma (MSGP). The relationship between them was also analyzed. Methods: Clinical data of eight patients with BA and four patients with MSGP diagnosed in China-Japan Friendship Hospital were collected from January 2018 to January 2020. Hematoxylin-eosin staining and immunohistochemical staining (EnVision method) were used to compare their histopathological characteristics. The hotspots regions of cancer-associated driver genes in lung cancer, using real-time quantitative PCR, were detected in all the cases and the literatures were reviewed. Results: The clinical and imaging manifestations of BA and MSGP were analogous. Histologically they had a two-layer structure including bronchial or bronchiolar-type epithelium and a continuous layer of basal cells,similar to bronchial/bronchiole mucosae. P16 protein was highly expressed in 7/8 of BA and 1/4 of MSGP. Mutations of cancer-associated genes were detected in 4/8 of BA, but none in MSGP. Conclusions: BA and MSGP, derived from different parts of the respiratory tract in the lungs, are rare and benign. Their morphological features overlapped with each other, and some cases are accompanied by genetic changes. It is necessary to pay attention to the differential diagnosis between them and lung adenocarcinoma, especially during the intraoperative diagnosis; and be alert to the potentially malignant components in the tumor or combined cancers.


Asunto(s)
Adenoma , Neoplasias Pulmonares , Papiloma , Adenoma/genética , Bronquiolos , China , Células Epiteliales , Humanos , Neoplasias Pulmonares/genética , Papiloma/genética
20.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809929

RESUMEN

The occurrence of distant tumor metastases is a major barrier in non-small cell lung cancer (NSCLC) therapy, and seriously affects clinical treatment and patient prognosis. Recently, long non-coding RNAs (lncRNAs) have been demonstrated to be crucial regulators of metastasis in lung cancer. The aim of this study was to reveal the underlying mechanisms of a novel lncRNA LNC CRYBG3 in regulating NSCLC metastasis. Experimental results showed that LNC CRYBG3 was upregulated in NSCLC cells compared with normal tissue cells, and its level was involved in these cells' metastatic ability. Exogenously overexpressed LNC CRYBG3 increased the metastatic ability and the protein expression level of the metastasis-associated proteins Snail and Vimentin in low metastatic lung cancer HCC827 cell line. In addition, LNC CRYBG3 contributed to HCC827 cell metastasis in vivo. Mechanistically, LNC CRYBG3 could directly combine with eEF1A1 and promote it to move into the nucleus to enhance the transcription of MDM2. Overexpressed MDM2 combined with MDM2 binding protein (MTBP) to reduce the binding of MTBP with ACTN4 and consequently increased cell migration mediated by ACTN4. In conclusion, the LNC CRYBG3/eEF1A1/MDM2/MTBP axis is a novel signaling pathway regulating tumor metastasis and may be a potential therapeutic target for NSCLC treatment.


Asunto(s)
Proteínas Portadoras/metabolismo , Cristalinas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Factor 1 de Elongación Peptídica/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Unión Proteica , ARN Largo no Codificante/genética , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
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