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1.
Am J Hum Genet ; 104(3): 439-453, 2019 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-30773278

RESUMEN

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.


Asunto(s)
Fibroblastos/patología , Genes Letales , Mutación , FN-kappa B/genética , Osteocondrodisplasias/patología , Adolescente , Adulto , Animales , Células Cultivadas , Niño , Preescolar , Daño del ADN , Dermis/metabolismo , Dermis/patología , Femenino , Fibroblastos/metabolismo , Humanos , Lactante , Recién Nacido , Ratones , Ratones Endogámicos C57BL , Osteocondrodisplasias/genética , Secuenciación del Exoma/métodos , Adulto Joven
2.
J Biol Chem ; 293(2): 588-598, 2018 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-29167269

RESUMEN

Cells have evolved sophisticated mechanisms to maintain genomic integrity in response to DNA damage. Ionizing radiation (IR)-induced DNA damage results in the formation of IR-induced foci (iRIF) in the nucleus. The iRIF formation is part of the DNA damage response (DDR), which is an essential signaling cascade that must be strictly regulated because either the loss of or an augmented DDR leads to loss of genome integrity. Accordingly, negative regulation of the DDR is as critical as its activation. In this study, we have identified ring finger protein 126 (RNF126) as a negative regulator of the DDR from a screen of iRIF containing 53BP1. RNF126 overexpression abolishes not only the formation of 53BP1 iRIF but also of RNF168, FK2, RAP80, and BRCA1. However, the iRIF formation of γH2AX, MDC1, and RNF8 is maintained, indicating that RNF126 acts between RNF8 and RNF168 during the DDR. In addition, RNF126 overexpression consistently results in the loss of RNF168-mediated H2A monoubiquitination at lysine 13/15 and inhibition of the non-homologous end joining capability. Taken together, our findings reveal that RNF126 is a novel factor involved in the negative regulation of DDR, which is important for sustaining genomic integrity.


Asunto(s)
Radiación Ionizante , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Línea Celular , Línea Celular Tumoral , Daño del ADN/efectos de la radiación , Células HeLa , Histonas/metabolismo , Histonas/efectos de la radiación , Humanos , Inmunoprecipitación , Proteína 1 de Unión al Supresor Tumoral P53/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación/efectos de la radiación
3.
Gut ; 65(1): 19-32, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25410163

RESUMEN

BACKGROUND: Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. OBJECTIVE: To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. METHODS: We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. RESULTS: Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. CONCLUSIONS: Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate 'metabolic switch' characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.


Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 4 del Hepatocito/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias Gástricas/genética , Proteínas Wnt/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Adenocarcinoma/etnología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Pueblo Asiatico , Biomarcadores de Tumor/metabolismo , Western Blotting , Estudios de Casos y Controles , Línea Celular Tumoral , Regulación hacia Abajo , Femenino , Factor Nuclear 4 del Hepatocito/metabolismo , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas/metabolismo , Distribución Aleatoria , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/etnología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Regulación hacia Arriba , Población Blanca , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , Proteína Wnt-5a
4.
BMC Cancer ; 16: 200, 2016 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-26955870

RESUMEN

BACKGROUND: "Biomarker-driven targeted therapy," the practice of tailoring patients' treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance. METHOD: To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays. RESULTS: The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 - 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network. CONCLUSION: Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor "omics" profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse.


Asunto(s)
Neoplasias Gástricas/etiología , Neoplasias Gástricas/metabolismo , Animales , Antineoplásicos/farmacología , Biomarcadores , Línea Celular Tumoral , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Amplificación de Genes , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Ratones , Terapia Molecular Dirigida , Estadificación de Neoplasias , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transducción de Señal , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Biochem Biophys Res Commun ; 446(1): 218-23, 2014 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-24602614

RESUMEN

Piwi-interacting RNAs (piRNAs) are 26-31 nt small noncoding RNAs that are processed from their longer precursor transcripts by Piwi proteins. Localization of Piwi and piRNA has been reported mostly in nucleus and cytoplasm of higher eukaryotes germ-line cells, where it is believed that known piRNA sequences are located in repeat regions of nuclear genome in germ-line cells. However, localization of PIWI and piRNA in mammalian somatic cell mitochondria yet remains largely unknown. We identified 29 piRNA sequence alignments from various regions of the human mitochondrial genome. Twelve out 29 piRNA sequences matched stem-loop fragment sequences of seven distinct tRNAs. We observed their actual expression in mitochondria subcellular fractions by inspecting mitochondrial-specific small RNA-Seq datasets. Of interest, the majority of the 29 piRNAs overlapped with multiple longer transcripts (expressed sequence tags) that are unique to the human mitochondrial genome. The presence of mature piRNAs in mitochondria was detected by qRT-PCR of mitochondrial subcellular RNAs. Further validation showed detection of Piwi by colocalization using anti-Piwil1 and mitochondria organelle-specific protein antibodies.


Asunto(s)
Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN/genética , ARN/metabolismo , Línea Celular Tumoral , ADN Mitocondrial/genética , Etiquetas de Secuencia Expresada , Genoma Mitocondrial , Células HEK293 , Células HeLa , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , ARN Mitocondrial , ARN Neoplásico/genética , ARN Neoplásico/metabolismo
6.
Biomedicines ; 11(9)2023 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-37760968

RESUMEN

Ubiquitination is a post-translational modification (PTM) that is involved in proteolysis, protein-protein interaction, and signal transduction. Accumulation of mutations and genomic instability are characteristic of cancer cells, and dysfunction of the ubiquitin pathway can contribute to abnormal cell physiology. Because mutations can be critical for cells, DNA damage repair, cell cycle regulation, and apoptosis are pathways that are in close communication to maintain genomic integrity. Uncontrolled cell proliferation due to abnormal processes is a hallmark of cancer, and mutations, changes in expression levels, and other alterations of ubiquitination factors are often involved. Here, three E3 ubiquitin ligases will be reviewed in detail. RNF126, RNF168 and CUL1 are involved in DNA damage response (DDR), DNA double-strand break (DSB) repair, cell cycle regulation, and ultimately, cancer cell proliferation control. Their involvement in multiple cellular pathways makes them an attractive candidate for cancer-targeting therapy. Functional studies of these E3 ligases have increased over the years, and their significance in cancer is well reported. There are continuous efforts to develop drugs targeting the ubiquitin pathway for anticancer therapy, which opens up the possibility for these E3 ligases to be evaluated for their potential as a target protein for anticancer therapy.

7.
Biomolecules ; 11(2)2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33498235

RESUMEN

While Next-Generation Sequencing (NGS) and technological advances have been useful in identifying genetic profiles of tumorigenesis, novel target proteins and various clinical biomarkers, cancer continues to be a major global health threat. DNA replication, DNA damage response (DDR) and repair, and cell cycle regulation continue to be essential systems in targeted cancer therapies. Although many genes involved in DDR are known to be tumor suppressor genes, cancer cells are often dependent and addicted to these genes, making them excellent therapeutic targets. In this review, genes implicated in DNA replication, DDR, DNA repair, cell cycle regulation are discussed with reference to peptide or small molecule inhibitors which may prove therapeutic in cancer patients. Additionally, the potential of utilizing novel synthetic lethal genes in these pathways is examined, providing possible new targets for future therapeutics. Specifically, we evaluate the potential of TONSL as a novel gene for targeted therapy. Although it is a scaffold protein with no known enzymatic activity, the strategy used for developing PCNA inhibitors can also be utilized to target TONSL. This review summarizes current knowledge on non-oncogene addiction, and the utilization of synthetic lethality for developing novel inhibitors targeting non-oncogenic addiction for cancer therapy.


Asunto(s)
Neoplasias/genética , Neoplasias/terapia , Oncogenes , Animales , Biomimética , Ciclo Celular , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Daño del ADN , Reparación del ADN , Replicación del ADN , Genoma Humano , Histonas/química , Humanos , Terapia Molecular Dirigida , FN-kappa B/metabolismo , Péptidos/química , Medicina de Precisión , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Tirosina Quinasas/metabolismo
8.
Mutat Res ; 809: 99-107, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-28521962

RESUMEN

In the nucleus, there are several membraneless structures called nuclear bodies. Among them, promyelocytic leukemia nuclear bodies (PML-NBs) are involved in multiple genome maintenance pathways including the DNA damage response, DNA repair, telomere homeostasis, and p53-associated apoptosis. In response to DNA damage, PML-NBs are coalesced and divided by a fission mechanism, thus increasing their number. PML-NBs also play a role in repairing DNA double-strand breaks (DSBs) by homologous recombination (HR). Clinically, the dominant negative PML-RARα fusion protein expressed in acute promyelocytic leukemia (APL) inhibits the transactivation of downstream factors and disrupts PML function, revealing the tumor suppressor role of PML-NBs. All-trans retinoic acid and arsenic trioxide treatment has been implemented for promyelocytic leukemia to target the PML-RARα fusion protein. PML-NBs are associated with various factors implicated in genome maintenance, and are found at the sites of DNA damage. Their interaction with proteins such as p53 indicates that PML-NBs may play a significant role in apoptosis and cancer. Decades of research have revealed the importance of PML-NBs in diverse cellular pathways, yet the underlying molecular mechanisms and exact functions of PML-NBs remain elusive. In this review, PML protein modifications and the functional relevance of PML-NB and its associated factors in genome maintenance will be discussed.


Asunto(s)
Reparación del ADN , Inestabilidad Genómica , Espacio Intranuclear , Leucemia Promielocítica Aguda , Proteínas de Fusión Oncogénica/metabolismo , Proteína de la Leucemia Promielocítica/metabolismo , Animales , Apoptosis , Roturas del ADN de Doble Cadena , Humanos , Espacio Intranuclear/metabolismo , Espacio Intranuclear/patología , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Proteínas de Fusión Oncogénica/genética , Proteína de la Leucemia Promielocítica/genética , Homeostasis del Telómero
9.
Oncotarget ; 8(41): 69808-69822, 2017 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-29050243

RESUMEN

The recent creation of enormous, cancer-related "Big Data" public depositories represents a powerful means for understanding tumorigenesis. However, a consistently accurate system for clinically evaluating single/multi-biomarkers remains lacking, and it has been asserted that oft-failed clinical advancement of biomarkers occurs within the very early stages of biomarker assessment. To address these challenges, we developed a clinically testable, web-based tool, CANcer-specific single/multi-biomarker Evaluation System (CANES), to evaluate biomarker effectiveness, across 2,134 whole transcriptome datasets, from 94,147 biological samples (from 18 tumor types). For user-provided single/multi-biomarkers, CANES evaluates the performance of single/multi-biomarker candidates, based on four classification methods, support vector machine, random forest, neural networks, and classification and regression trees. In addition, CANES offers several advantages over earlier analysis tools, including: 1) survival analysis; 2) evaluation of mature miRNAs as markers for user-defined diagnostic or prognostic purposes; and 3) provision of a "pan-cancer" summary view, based on each single marker. We believe that such "landscape" evaluation of single/multi-biomarkers, for diagnostic therapeutic/prognostic decision-making, will be highly valuable for the discovery and "repurposing" of existing biomarkers (and their specific targeted therapies), leading to improved patient therapeutic stratification, a key component of targeted therapy success for the avoidance of therapy resistance.

10.
BMB Rep ; 50(6): 308-317, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28391780

RESUMEN

Bone morphogenetic protein type 2 receptor (BMPR2) is one of the transforming growth factor-ß (TGF-ß) superfamily receptors, performing diverse roles during embryonic development, vasculogenesis, and osteogenesis. Human BMPR2 consists of 1,038 amino acids, and contains functionally conserved extracellular, transmembrane, kinase, and C-terminal cytoplasmic domains. Bone morphogenetic proteins (BMPs) engage the tetrameric complex, composed of BMPR2 and its corresponding type 1 receptors, which initiates SMAD proteins-mediated signal transduction leading to the expression of target genes implicated in the development or differentiation of the embryo, organs and bones. In particular, genetic alterations of BMPR2 gene are associated with several clinical disorders, including representative pulmonary arterial hypertension, cancers, and metabolic diseases, thus demonstrating the physiological importance of BMPR2. In this mini review, we summarize recent findings regarding the molecular basis of BMPR2 functions in BMP signaling, and the versatile roles of BMPR2. In addition, various aspects of experimentally validated pathogenic mutations of BMPR2 and the linked human diseases will also be discussed, which are important in clinical settings for diagnostics and treatment. [BMB Reports 2017; 50(6): 308-317].


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Animales , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Humanos , Mutación/genética , Transducción de Señal/genética , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
11.
Oncotarget ; 7(49): 81435-81451, 2016 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-27806312

RESUMEN

Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer "Big Data" has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of "hit" compounds.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Gástricas/genética , Proteína de Unión al GTP rhoA/genética , Animales , Antineoplásicos/farmacología , Pueblo Asiatico/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular , Biología Computacional , Bases de Datos Genéticas , Inhibidores Enzimáticos/farmacología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Humanos , Ratones SCID , Terapia Molecular Dirigida , Interferencia de ARN , República de Corea , Transducción de Señal , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/etnología , Neoplasias Gástricas/patología , Factores de Tiempo , Transcriptoma , Transfección , Carga Tumoral , Regulación hacia Arriba , Población Blanca/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoB/genética , Proteína de Unión al GTP rhoB/metabolismo
12.
PLoS One ; 10(9): e0136879, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26332125

RESUMEN

Despite their clear T7-bacteriophage origin, mitochondrial RNA polymerases have evolved to require transcription factors. All mitochondrial polymerases contain an extra N-terminal domain that has no counterpart in the self-proficient phage enzyme, which is therefore hypothesized to interact with transcription factors. We studied a series of N-terminal deletion mutants of yeast mitochondrial RNA polymerase, Rpo41, and have found that the N-terminal region does not abolish the effects of Mtf1; rather it contributes directly to enzyme catalysis. Mtf1 can rescue the defective Rpo41 enzymes resulted from N-terminal domain deletions. Although Rpo41 appears to have retained all promoter recognition elements found in T7 RNAP, the elements are not independently functional, and Mtf1 is necessary and sufficient for holoenzyme promoter-directed transcription activity.


Asunto(s)
ARN Polimerasas Dirigidas por ADN/genética , ARN Polimerasas Dirigidas por ADN/metabolismo , Regulación Fúngica de la Expresión Génica , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Regiones Promotoras Genéticas , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , ARN Polimerasas Dirigidas por ADN/química , Proteínas Mitocondriales/química , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Alineación de Secuencia , Eliminación de Secuencia , Activación Transcripcional
13.
Cancer Lett ; 356(2 Pt B): 880-90, 2015 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-25449779

RESUMEN

Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Adulto , Anciano , Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trastuzumab , Células Tumorales Cultivadas
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