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1.
Sci Rep ; 9(1): 15771, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673071

RESUMO

Angiogenesis is involved in both normal physiological and pathological conditions. Vascular endothelial growth factor (VEGF) is a major factor for promoting angiogenesis. The current anti-VEGF therapies have limited efficacy and significant adverse effects. To find novel targets of VEGFA for angiogenesis inhibition, we performed yeast two-hybrid screening and identified calpain-6 as a novel VEGFA-interaction partner and confirmed the endogenous VEGFA-calpain-6 interaction in mammalian placenta. A domain mapping study revealed that the Gly321-Asp500 domain in calpain-6 is required for the interaction with the C-terminus of the VEGFA protein. The functional significance of the VEGFA-calpain-6 interaction was explored by assessing its effect on angiogenesis in vitro. Whereas forced overexpression of calpain-6 increased the secretion of the VEGF protein and tube formation, knockdown of calpain-6 expression abrogated the calpain-6-mediated VEGF secretion and tube formation in HUVECs. Consistent with the domain mapping result, overexpressing calpain-6 without the VEGFA-interacting domain III (Gly321-Asp500) failed to increase the secretion of VEGF protein. Our results identify calpain-6, an unconventional non-proteolytic calpain, as a novel VEGFA-interacting protein and demonstrate that their interaction is necessary to enhance VEGF secretion. Thus, calpain-6 might be a potential molecular target for angiogenesis inhibition in many diseases.

2.
Genome Biol ; 20(1): 253, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771620

RESUMO

BACKGROUND: Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. RESULTS: Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. CONCLUSIONS: Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.

3.
Anticancer Res ; 39(10): 5361-5367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570430

RESUMO

BACKGROUND/AIM: The mechanism responsible for B-cell translocation gene 1 (BTG1) down-regulation in breast carcinoma remains unknown. We examined the BTG1 expression status in breast carcinoma cells and investigated the mechanism underlying the observed alterations. MATERIALS AND METHODS: Four breast carcinoma cell lines (SK-BR-3, MDA-MB-231, T-47D, and MCF-7), and one normal mammary epithelial cell line (MCF-10A) were analyzed. BTG1 expression was examined using quantitative reverse transcription polymerase chain reaction (PCR) and western blot. Methylation status of the BTG1 promoter was analyzed using methylation-specific PCR (MSP). To investigate the effect of methylation on BTG1, the cells were treated with a demethylating agent. RESULTS: The carcinoma cells expressed significantly lower levels of BTG1 mRNA and protein than normal cells. The BTG1 promoter was highly methylated in the carcinoma cells. 5-aza-2-deoxycytidine significantly restored BTG1 expression. CONCLUSION: Down-regulation of BTG1 expression through epigenetic repression is involved in mammary carcinogenesis. BTG1 is a potential diagnostic marker and therapeutic target for breast carcinoma.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , RNA Mensageiro/genética
5.
Cancer Biomark ; 24(1): 1-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30614793

RESUMO

BACKGROUND: Both QKI and TMEFF2 genes are considered putative tumor suppressor genes (TSGs). In gastric (GC) and colorectal (CRC) cancers, downregulation of their expressions is known to be frequent. However, QKI and TMEFF2 mutations that could potentially inactivate their functions are not reported in cancers. METHODS: In a genome database, we observed that both QKI and TMEFF2 harbor mononucleotide repeats, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 79 GCs and 124 CRCs for the mutations and their intratumoral heterogeneity (ITH). RESULTS: Six of 34 GCs (17.6%) and 10 of 79 CRCs (12.7%) with MSI-H exhibited QKI frameshift mutations while five of 79 CRCs (6.3%) with high MSI (MSI-H) exhibited TMEFF2 frameshift mutations. However, we found no such mutation in microsatellite stable/low MSI (MSS/MSI-L) cancers within the mononucleotide repeats. We also studied ITH for the detected frameshift mutations in 16 cases of CRCs and detected that QKI and TMEFF2 frameshift mutations showed regional ITH in 2 (12.5%) and 1 (6.3%) cases, respectively. CONCLUSIONS: Our data show that candidate TSG genes QKI and TMEFF2 harbor mutational ITH as well as the frameshift mutations in GC and CRC with MSI-H. From this observation, frameshift mutations of QKI and TMEFF2 may play a role in tumorigenesis through their TSG inactivation in GC and CRC.


Assuntos
Neoplasias Colorretais/genética , Mutação da Fase de Leitura , Genes Supressores de Tumor , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas de Ligação a RNA/genética , Neoplasias Gástricas/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Heterogeneidade Genética , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Gástricas/patologia
6.
Nat Genet ; 50(10): 1399-1411, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30262818

RESUMO

Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive intertumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Towards this goal, we have established a compilation of pharmacological landscapes of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared with the traditional long-term cultured cancer cell line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. Here, we provide insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors, and the potential repurposing of ibrutinib (currently used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present a potential implementation of PDC-derived drug sensitivities for the prediction of clinical response to targeted therapeutics using retrospective clinical studies.

7.
Sci Rep ; 8(1): 13887, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30224753

RESUMO

The use of four groups of tumor immune microenvironments (TME) based on PD-L1 and tumor-infiltrating T lymphocytes (TIL) is a reliable biomarker for anti-PD-1/PD-L1 inhibitor therapy. We classified the TME in 241 gastric cancers which were subdivided according to 40 EBV+, 76 microsatellite instability-high (MSI-H), and 125 EBV-/microsatellite-stable (MSS) subtypes by quantitative image analysis (QIA) and correlated the results with mRNA expression levels. The mean PD-L1 ratio and CD8 ratio in EBV+, MSI-H, and EBV-/MSS GCs were significantly different (P < 0.006). The PD-L1 ratio and CD8 ratio obtained by QIA correlated well with the RNA levels of PD-L1 (r = 0.63) and CD8 (r = 0.67), respectively. The TME were type I (PD-L1H/CD8H) in 45, type II (PD-L1L/CD8L) in 106, type III (PD-L1H/CD8L) in 8, and type IV (PD-L1L/CD8H) in 82 cases. The type I TME was significantly associated with high TIL (P = 3.0E-11) and EBV+ status (P = 8.55E-08). In conclusion, QIA results correlated well with the mRNA expression levels and classified TME of gastric cancers.

8.
Exp Mol Med ; 50(2): e442, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29422544

RESUMO

Vulvar squamous cell carcinoma (SCC) consists of two different etiologic categories: human papilloma virus (HPV)-associated (HPV (+)) and HPV-non-associated (HPV (-)). There have been no genome-wide studies on the genetic alterations of vulvar SCCs or on the differences between HPV (+) and HPV (-) vulvar SCCs. In this study, we performed whole-exome sequencing and copy number profiling of 6 HPV (+) and 9 HPV (-) vulvar SCCs and found known mutations (TP53, CDKN2A and HRAS) and copy number alterations (CNAs) (7p and 8q gains and 2q loss) in HPV (-) SCCs. In HPV (+), we found novel mutations in PIK3CA, BRCA2 and FBXW7 that had not been reported in vulvar SCCs. HPV (-) SCCs exhibited more mutational loads (numbers of nonsilent mutations and driver mutations) than HPV (+) SCCs, but the CNA loads and mutation signatures between HPV (+) and HPV (-) SCCs did not differ. Of note, 40% and 40% of the 15 vulvar SCCs harbored PIK3CA and FAT1 alterations, respectively. In addition, we found that the SCCs harbored kataegis (a localized hypermutation) in 2 HPV (+) SCCs and copy-neutral losses of heterozygosity in 4 (one HPV (+) and 3 HPV (-)) SCCs. Our data indicate that HPV (+) and HPV (-) vulvar SCCs may have different mutation and CNA profiles but that there are genomic features common to SCCs. Our data provide useful information for both HPV (+) and HPV (-) vulvar SCCs and may aid in the development of clinical treatment strategies.

9.
Pathol Oncol Res ; 24(3): 477-481, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28664474

RESUMO

GLI1 is a transcription factor for hedgehog signaling that plays a crucial role in signaling pathways for controlling cell proliferation, alterations of which are known to contribute to tumorigenesis. Aim of this study was to explore whether GLI1 gene is mutated in gastric (GC) and colorectal cancers (CRC). In a public database, we found that GLI1 had a G7 mononucleotide repeat in the coding sequences that could be a mutation target in the cancers with microsatellite instability (MSI). In this study, we analyzed frameshift mutation of GLI1 in 79 GCs and 129 CRCs (high MSI (MSI-H) or microsatellite stable (MSS)) by single-strand conformation polymorphism analysis and DNA sequencing. We found 10 frameshift mutations in the repeat, nine for CRCs and one for GC. All of the mutations were detected in cancers with MSI-H and there was a statistical difference in the frameshift mutation frequencies between the cancers with MSI-H (10/113) and MSS (0/90). We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutation in 16 CRCs and found that the mutations exhibited regional ITH in three of the CRCs (18.8%). Our data indicate GLI1 harbored not only frameshift mutation but also its mutational ITH, which together could be a feature of GC and CRC with MSI-H.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , DNA de Neoplasias/genética , Mutação da Fase de Leitura , Neoplasias Gástricas/genética , Proteína GLI1 em Dedos de Zinco/genética , Neoplasias Colorretais/diagnóstico , Análise Mutacional de DNA , Humanos , Instabilidade de Microssatélites , Prognóstico , Neoplasias Gástricas/diagnóstico
10.
Biopreserv Biobank ; 16(1): 28-35, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29148824

RESUMO

BACKGROUND: The effects of preanalytical variables in tissue processing and storage periods on RNA quality of tissues have been well documented in each type of cancer. However, few studies have been performed on a comparative assessment of the impacts across different cancer tissues, even though it is well known that RNase activity is highly variable in various tissue types and RNase-rich tissues have been found to yield low-quality RNA. METHODS: We investigated the impacts of cold ischemia times and long-term storage on RNA integrity in various types of cancer tissue, which had been fresh-frozen and collected at the Samsung Medical Center Biobank. RNA quality was also evaluated with regard to histopathological variables. We analyzed RNA integrity number (RIN) data, which had been obtained from our quality control (QC) processes over the last 7 years. Approximately 2% of samples were randomly selected and processed to measure RIN quarterly and after 6 years of storage for QC purposes. RESULTS: Fresh-frozen tumor tissues yielded high-quality RNA regardless of tumor type and histopathological features. Up to 1-hour cold ischemia times and up to 6-year storage times did not adversely influence RNA integrity. Only 3 samples showed RIN of <7 out of a total of 396 analyzed tumor tissues. CONCLUSIONS: Tissue quality was not adversely affected by long-term storage or limited variations of cold ischemia times. The low-quality samples could be correlated with the structural composition or intratumoral heterogeneity of tissues. The strict application of standardized protocols for tissue collection is the key for high-quality biobanking.


Assuntos
Isquemia Fria/métodos , RNA Neoplásico/química , Bancos de Tecidos/normas , Preservação de Tecido/métodos , Criopreservação , Feminino , Humanos , Masculino , Neoplasias/genética , Neoplasias/patologia , Controle de Qualidade , Estabilidade de RNA
11.
Pathol Oncol Res ; 24(4): 827-832, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28844109

RESUMO

Both NRIP1 and DOK1 genes are considered candidate tumor suppressor genes (TSGs). Also, cell polarity-related genes PARD3, PRKCI and DLGAP3, and autophagy-related genes ULK1 and ULK2 genes are considered to play crucial roles in tumorigenesis. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 harbored 18 (22.8%), 2 (2.5%), 2 (2.5%), 2 (2.5%), 5 (6.3%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. We also studied ITH for the frameshift mutations in 16 cases of CRCs and detected that the frameshift mutations of NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 showed regional ITH in 5 (31.3%), 2 (12.5%), 0 (0%), 0 (0%), 1 (6.3%), 1 (6.3%) and 3 (18.8%) cases, respectively. Our data exhibit that candidate cancer-related genes NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.


Assuntos
Neoplasias do Colo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteínas de Ciclo Celular/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Isoenzimas/genética , Proteínas de Membrana/genética , Instabilidade de Microssatélites , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteína 1 de Interação com Receptor Nuclear , Fosfoproteínas/genética , Proteína Quinase C/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ligação a RNA/genética
13.
Sci Rep ; 7(1): 12177, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28939806

RESUMO

Local variations of superconductivity have been studied using scanning tunneling microscopy around nano-cavities formed by Ar ions embedded in Pb(111). Various factors including the density of states at Fermi energy, electron-phonon couplings, and quantum well states, which are known to affect superconductivity, have been examined. We show that the superconductivity is enhanced near the nano-cavities and propose that quantum effects such as quantum confinement, proximity effect and multi-gap effect are possibly involved in determining the superconducting gap of this system. These results have important implications for the characterization and understanding of superconductivity at a nanometer scale.

14.
BMC Cancer ; 17(1): 535, 2017 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-28806950

RESUMO

BACKGROUND: Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models. METHODS: We performed array-comparative genomic hybridization, microarray, and targeted next-generation sequencing analyses, in order to determine the oncogenic driver mutations. PDX cells were obtained from PDXs and subsequently screened in vitro with 17 targeted agents. RESULTS: PDX tumors recapitulated the histopathologic and genetic features of the patient tumors. Among the samples from lung cancer patients that were molecularly-profiled, copy number analysis identified unique focal MET amplification in one sample, 033 T, without RTK/RAS/RAF oncogene mutations. Although HER2 amplification in 033 T was not detected in the cancer panel, the selection of HER2-amplified clones was found in PDXs and PDX cells. Additionally, MET and HER2 overexpression were found in patient tumors, PDXs, and PDX cells. Crizotinib or EGFR tyrosine kinase inhibitor treatments significantly inhibited cell growth and impaired tumor sphere formation in 033 T PDX cells. CONCLUSIONS: We established PDX cell models using surgical samples from lung cancer patients, and investigated their preclinical and clinical implications for personalized targeted therapy. Additionally, we suggest that MET and EGFR inhibitor-based therapy can be used to treat MET and HER2-overexpressing lung cancers, without receptor tyrosine kinase /RAS/RAF pathway alterations.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Medicina de Precisão/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Crizotinibe , Modelos Animais de Doenças , Receptores ErbB/antagonistas & inibidores , Feminino , Amplificação de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Receptor ErbB-2/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Res Treat ; 49(4): 915-926, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28052650

RESUMO

PURPOSE: Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research. MATERIALS AND METHODS: We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues. RESULTS: Patients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor-overexpressing PDX with clear cell histology (p=0.023). CONCLUSION: PDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.


Assuntos
Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Adulto , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Biópsia , Carboplatina/farmacologia , Carcinoma Epitelial do Ovário , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Instabilidade Genômica , Xenoenxertos , Humanos , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Paclitaxel/farmacologia , Pesquisa Médica Translacional , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Gynecol Minim Invasive Ther ; 6(3): 108-112, 2017 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30254891

RESUMO

Objective: To examine the effectiveness of proximal tube destruction at the uterine cornu by additional application of a sealing device. Methods: A single-center randomized trial was conducted on 40 patients receiving a laparo-endoscopic single-site hysterectomy with opportunistic salpingectomy. We randomized patients into two groups at the time of admission to determine the laterality of additional thermal cauterization. Additional thermal cauterization for 10 seconds was applied on the right cornu in one group and on the left cornu in the other group. Three pieces of cornual tissue from each cornu were biopsied. One gynecological pathologist examined the cornual tissue to determine the residual tubal epithelium (TE) and thermal destruction of the specimens. Results: Of the 40 patients enrolled in this study between September 2012 and July 2014, samples of 26 patients were subjected to tissue analysis. Residual TE was found in the cornu in 73.1% (19/26) and 65.4 % (17/26) of tissues from the side of no additional cauterization (NO) and the side of additional cauterization (AD), respectively (p < 0.001). Residual TE was detected in 5.3% (1/19) and 94.1% (16/17) of the specimens from the NO and AD groups, respectively. Conclusion: We observed that a high incidence of residual TE and efficacious cauterization-induced thermal destruction was achieved following 10 seconds of additional cauterization. These results suggest that additional cauterization of the uterine cornu using the sealing device effectively destroys residual TE after salpingectomy.

17.
Pathol Oncol Res ; 23(1): 145-149, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27620344

RESUMO

MECOM gene, also known as EVI, encodes a transcriptional regulator involved in hematopoiesis, apoptosis, development and proliferation. In blood system, MECOM is considered an oncogene, but in solid tumors it has both oncogenic and tumor suppressor activities. Low frequent somatic mutations of MECOM have been detected in many cancers including colorectal cancers (CRC), but the mutation status with respect to the microsatellite instability (MSI) has not been studied. There is an A7 mononucleotide repeat in MECOM coding sequences that could be a mutation target in the cancers with MSI. We analyzed the A7 of MECOM in 79 CRCs with high MSI (MSI-H) and 65 microsatellite stable/low MSI (MSS/MSI-L) CRCs by single-strand conformation polymorphism analysis and DNA sequencing. Overall, we found MECOM frameshift mutations in 6 (7.6 %) CRCs with MSI-H, but not in MSS/MSI-L cancers (0/65) (p < 0.025). We also analyzed intratumoral heterogeneity (ITH) of the MECOM frameshift mutation in 16 CRCs and found that four CRCs (25.0 %) harbored regional ITH of the frameshift mutations. Our data indicate that MECOM gene harbors both somatic frameshift mutations and mutational ITH, which together may be features of CRC with MSI-H.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura/genética , Proto-Oncogenes/genética , Fatores de Transcrição/genética , Apoptose/genética , Carcinogênese/genética , Análise Mutacional de DNA/métodos , Humanos , Proteína do Locus do Complexo MDS1 e EVI1 , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Polimorfismo Conformacional de Fita Simples/genética
19.
Sci Rep ; 6: 38502, 2016 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-27917934

RESUMO

In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC. c-MET expression was significantly greater in OCCCs compared with serous carcinomas and normal ovarian tissues (p < 0.001). In in vitro study, inhibition of c-MET using c-MET inhibitors (SU11274 or crizotinib) significantly decreased the proliferation, and increased the apoptosis of OCCC cells. SU11274 decreased expression of the p-c-MET proteins and blocked the phosphorylation of down-stream proteins Akt and Erk. Furthermore, SU11274 treatment significantly decreased the in vivo tumor weight in xenograft models of RMG1 cell and a PDX model for OCCC compared to control (p = 0.004 and p = 0.009, respectively).


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Crizotinibe , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nanotechnology ; 27(41): 415711, 2016 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-27609354

RESUMO

The local modification of intermolecular interactions in nickel-phthalocyanine molecules (NiPCs) is investigated on an Au(111) substrate using scanning tunneling microscopy. When the molecules are physisorbed on the substrate, they repel each other due to induced charge dipole moments. However, when the NiPC is chemisorbed on the substrate through the dehydrogenation of one of its ligands by a bias pulse, we find that a nearby physisorbed NiPC is attracted to the dehydrogenated ligand and trapped. Using our experimental results in combination with density functional theory calculations, we show that the observed attraction can be ascribed to the local charge redistribution around the dehydrogenated ligand of the chemisorbed NiPC. Furthermore, we demonstrate that desorption of the attracted NiPC from the trapped site can be readily controlled by changing the density of NiPCs around the dehydrogenated ligand.

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