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1.
Cancer Treat Rev ; 82: 101933, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31785412

RESUMO

This systematic review aims to summarize epigenome-wide studies on aberrant DNA methylation and its association with survival in patients with gastrointestinal adenocarcinoma. The 15 studies identified showed a large variety of methodological approaches for the identification of prognostic epigenetic markers from genome-wide methylation analyses. None of the findings were reported by more than one study in this systematic review. Further validation studies, a better reporting of methods and results are needed, as well as a clearer definition of investigated outcomes. At present, no conclusions can be drawn on the clinical relevance of the reported epigenetic markers.


Assuntos
Adenocarcinoma , Metilação de DNA/fisiologia , Neoplasias Gastrointestinais , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais , Epigênese Genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Estudo de Associação Genômica Ampla , Humanos , Prognóstico
2.
Crit Rev Oncol Hematol ; 145: 102854, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31877535

RESUMO

Both environmental and genetic factors are involved in the initiation and development of gastrointestinal cancer. Covalent closed circular RNAs (circRNAs) are produced by a mechanism called "back-splicing" from mRNAs. They are highly stable and show cell and tissue specific expression patterns. Although some functions such as "microRNA sponge" and "RNA binding protein sponge" have been reported for a small number of circRNAs, the function of thousands of other circRNAs is still unknown. Dysregulation of circRNAs has been reported in many GI cancers and are involved in metastasis and invasion. CircRNAs have been reported to be useful as prognostic markers and targets for developing new treatments. We first describe the properties and biogenesis of circRNAs. We then summarize recent reports about circRNA functions, expression status, and their potential to be used as biomarkers in GI cancers including, gastric cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, gallbladder cancer and pancreatic cancer.


Assuntos
Neoplasias Gastrointestinais , MicroRNAs , Processamento de RNA , Biomarcadores , Epigênese Genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , MicroRNAs/genética , Prognóstico
3.
Cancer Metastasis Rev ; 38(3): 525-535, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31773431

RESUMO

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.


Assuntos
Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/terapia , Succinato Desidrogenase/deficiência , Animais , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Humanos , Mutação , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
4.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614517

RESUMO

Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors' ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3-6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 µM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Pirimidinonas/química , Receptor A2A de Adenosina/genética , Receptor A3 de Adenosina/genética , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Piperazina/síntese química , Piperazina/química , Piperazina/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Receptor A2A de Adenosina/química , Relação Estrutura-Atividade
5.
Nat Med ; 25(9): 1415-1421, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501609

RESUMO

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , Neoplasias Gastrointestinais/sangue , Biópsia Líquida , Autopsia , Ácidos Nucleicos Livres/genética , Estudos de Coortes , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sequenciamento Completo do Exoma
6.
J Genet ; 982019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31544800

RESUMO

Long noncoding RNA (lncRNA) H19, a well-known oncogenic lncRNA, is overexpressed in various cancers. Several studies have investigated the association between polymorphisms in lncRNA H19 and the risk of various cancer types; however, the findings were inconsistent. In this study, we performed a meta-analysis to identify the precise association between H19 polymorphisms and cancer risk. Appropriate studies were retrieved from searching Web of Science, PubMed, Scopus, and Google scholar databases, updated 25 November 2018. The pooled odds ratios (ORs with 95% confidence intervals (CIs) were calculated to estimate the strength of the association between H19 polymorphisms and cancer risk. Our findings revealed that the H19-rs217727 C>T polymorphism is significantly associated with an increased risk of overall cancer in homozygous codominant (OR=1.28, 95% CI=1.04-1.57, P =0.020, TT vs CC), dominant (OR=1.20, 95% CI=1.04-1.37, P =0.010, CT+TT vs CC), recessive (OR=1.21, 95% CI=1.00-1.46, P =0.048, TT vs CT+CC), and allele (OR=1.16, 95% CI=1.05-1.28, P =0.003, T vs C) genetic models. No significant correlations were observed between H19: rs2839698 G>A, rs2107425 C>T, rs2735971 C>T, rs3024270 G>C, rs3741219 T>C, rs2839701 C>G, rs2735469 C>T, rs17658052 G>A, and rs3741216 T>A polymorphisms and overall cancer risk. Stratified analysis by cancer type proposed that the rs217727 variant is associated with increased risk of oral squamous cell carcinoma (OSCC) and lung cancer, whereas the rs2839698 variant is associated with increased risk of gastrointestinal cancer. Taken together, these findings support an association between H19 rs217727, and rs2839698 polymorphisms and cancer susceptibility. Larger and well-designed studies are necessary to further confirm these findings in detail.


Assuntos
Neoplasias/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Carcinoma de Células Escamosas/genética , Neoplasias Gastrointestinais/genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Bucais/genética , Fatores de Risco
7.
Cancer Sci ; 110(12): 3821-3833, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31553483

RESUMO

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low- and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.


Assuntos
Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Transdução de Sinais/fisiologia , Progressão da Doença , Genes Supressores de Tumor , Humanos , Perda de Heterozigosidade , Mutação , Oncogenes , Fosfatidilinositol 3-Quinases/fisiologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
8.
Klin Onkol ; 32(Supplementum2): 92-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409084

RESUMO

Gastrointestinal polyposes and Lynch syndrome are a group of heterogenous hereditary tumor syndromes associated with an increased risk of developing colorectal carcinoma and other malignancies. Typical early manifestations of gastrointestinal polyposes include multiple polyps in the gastrointestinal tract. Early recognition of these syndromes enables patients carrying a pathogenic mutation to undergo screening and to instigate precautions to minimize the risk of developing tumors. In some cases, gastrointestinal lesions could be an early indicator of tumor syndrome and histopathologic examination could lead to a recommendation for genetic testing of patients and their families. Supported by Ministry of Health, Czech Republic - Conceptual Development of Research Organization (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products,or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 16. 4. 2019 Accepted: 6. 6. 2019.


Assuntos
Neoplasias Gastrointestinais , Síndromes Neoplásicas Hereditárias , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia
9.
Klin Onkol ; 32(Supplementum2): 97-108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409085

RESUMO

BACKGROUND: It is estimated that 5-10% of colorectal cancers arise due to a known genetic syndrome. Individuals with these cancer syndromes are also at risk of extracolonic cancers. Polyposis and nonpolyposis hereditary syndromes are generally recognized. Inclusion of next-generation sequencing technology, especially multiple-gene panel testing, in routine laboratory practice has made identifying the causes of these diseases significantly easier. PURPOSE: To summarize current knowledge of the causes, clinical manifestations, diagnostic criteria, and recommendations for presymptomatic screening of individuals at risk of hereditary gastrointestinal polyposis and colorectal cancer syndromes. We dicuss currently defined syndromes detected by multiple-gene panel next-generation sequencing; these include constitutional mismatch repair deficiency (biallelic MLH1, MSH2, MSH6, PMS2 gene mutations), gastric adenocarcinoma and proximal polyposis of the stomach (APC gene), NTHL1-associated polyposis, polymerase proofreading-associated polyposis (POLD1, POLE genes), juvenile polyposis (SMAD4, BMPR1A genes), and serrated polyposis syndromes. Another aim is to summarize recent knowledge about well-known syndromes, including hereditary nonpolyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, MUTYH-associated polyposis, and Peutz-Jeghers and Cowden/PTEN hamartoma tumor syndromes. CONCLUSION: Awareness of hereditary polyposis/colon cancer syndromes enables early diagnosis and prevention of cancer in affected individuals and their relatives. Genetic counseling, presymptomatic testing of at-risk individuals, and efficient screening may be beneficial for affected families. Thank to Lenka Foretová, M.D., PhD, (Masaryk Memorial Cancer Institute, Brno) for a critical review of the manuscript and valuable advices. The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 6. 6. 2019.


Assuntos
Neoplasias Gastrointestinais , Síndromes Neoplásicas Hereditárias , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/prevenção & controle , Testes Genéticos , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/prevenção & controle
10.
Oncogene ; 38(38): 6550-6565, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31363162

RESUMO

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Proteínas I-kappa B/metabolismo , Mesilato de Imatinib/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/fisiologia , Fator de Transcrição RelA/metabolismo , Animais , Células COS , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
11.
Nat Commun ; 10(1): 3888, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467274

RESUMO

The biological significance of micro (mi)RNAs has traditionally been evaluated according to their RNA expression levels based on the assumption that miRNAs recognize and regulate their targets in an unvarying fashion. Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition. Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity. These findings provide a basis for diagnostic strategies for early-stage cancer and add a dimension to our understanding of miRNA biology.


Assuntos
Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Epigenômica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metilação , MicroRNAs/sangue , Simulação de Dinâmica Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
Cancer Sci ; 110(10): 3122-3131, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31369178

RESUMO

Delta-like 3 (DLL3) is a member of the Delta/Serrate/Lag2 (DSL) group of Notch receptor ligands. Five DSL ligands are known in mammals, among which DLL3 has a unique structure. In the last few years, DLL3 has attracted attention as a novel molecular targeting gene in neuroendocrine carcinoma of the lung due to its high expression. However, the expression pattern and functions of DLL3 in the gastrointestinal tract and gastrointestinal neuroendocrine carcinoma remain unclear. In this study, we examined the expression and role of DLL3 in the gastrointestinal tract, as well as in gastrointestinal neuroendocrine carcinoma. Immunohistochemical staining of the human normal gastrointestinal tract revealed that DLL3 localized in neuroendocrine cells. DLL3 showed intense staining in chromogranin A-positive gastric cancer specimens. Real-time quantitative RT-PCR and western blotting analyses showed considerable upregulation of DLL3 in gastrointestinal neuroendocrine carcinoma cell lines. Immuno-electron microscopy demonstrated abundant expression of DLL3 in neurosecretory granules in these cells. Furthermore, gene silencing of DLL3 caused significant growth inhibition through the induction of intrinsic apoptosis. Our findings suggest that DLL3 is expressed in neuroendocrine cells of the gastrointestinal tract and that it has a pivotal role in gastrointestinal neuroendocrine carcinoma cells. Based on these findings, further investigations are required to achieve a breakthrough in developing therapeutic strategies for gastrointestinal neuroendocrine carcinoma.


Assuntos
Carcinoma Neuroendócrino/metabolismo , Neoplasias Gastrointestinais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células Neuroendócrinas/metabolismo , Idoso , Apoptose , Carcinoma Neuroendócrino/genética , Linhagem Celular Tumoral , Neoplasias Gastrointestinais/genética , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Regulação para Cima
13.
Int J Oncol ; 55(2): 536-546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268158

RESUMO

Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet­derived growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector of KIT and is therefore a reasonable therapeutic target for this disease. In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the pattern­matching software 'Connectivity Map'. The activity and mechanisms of identified agents were examined using an in vitro model. Four drugs were identified: Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors (HDACIs)] and trifluoperazine and thioridazine (two phenothiazine­class drugs). Western blot analysis demonstrated that all four drugs had ETV1­downregulating effects. As HDACIs have been previously studied in GISTs, we focused on phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead upregulated extracellular­signal­regulated kinase (ERK) activity. A combination of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were activated/upregulated following phenothiazine treatment, and the MEK inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, the findings of this study established phenothiazine as a novel class of therapeutic agents in GIST treatment and demonstrate that a combination of phenothiazine and MEK inhibitor has great potential for use in the treatment of GISTs.


Assuntos
Biomarcadores Tumorais/genética , Conectoma , Proteínas de Ligação a DNA/antagonistas & inibidores , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fenotiazinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Apoptose , Proteínas de Ligação a DNA/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Perfilação da Expressão Gênica , Humanos , Prognóstico , Transdução de Sinais , Fatores de Transcrição/genética
14.
Cells ; 8(7)2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277418

RESUMO

Because traditional treatment strategies for advanced gastrointestinal (GI) cancers often have a limited therapeutic effect, immunotherapy could be a viable approach for the therapy of advanced GI cancers, considering the recent success of immunotherapy in treating various refractory malignancies, including the DNA mismatch repair-deficient GI cancers. However, only a subset of cancer patients currently respond to immunotherapy. Thus, it is important to identify useful biomarkers for predicting cancer immunotherapy response. The tumor suppressor gene ARID1A has a high mutation rate in GI cancers and its deficiency is correlated with the microsatellite instability (MSI) genomic feature of cancer. We investigated the correlation between ARID1A mutations and tumor immunity using three GI cancer genomics datasets by the bioinformatic approach, and found that diverse antitumor immune signatures were more highly enriched in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers. The elevated immune activity in ARID1A-mutated GI cancers was associated with the higher tumor mutation burden and lower tumor aneuploidy level, as well as a higher proportion of MSI cancers in this GI cancer subtype. Moreover, we found that ARID1A-mutated GI cancers more highly expressed PD-L1 than ARID1A-wildtype GI cancers. The elevated antitumor immune signatures and PD-L1 expression could contribute to the more active immunotherapeutic responsiveness and better survival prognosis in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers in the immunotherapy setting, as evidenced in three cancer cohorts receiving immunotherapy. Thus, the ARID1A mutation could be a useful biomarker for identifying GI cancer patients responsive to immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Gastrointestinais/imunologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Estimativa de Kaplan-Meier , Instabilidade de Microssatélites , Seleção de Pacientes , Prognóstico , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
Surg Pathol Clin ; 12(3): 733-743, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352985

RESUMO

The gastrointestinal tract is a common extranodal site of involvement by lymphomas. These may be diagnostically challenging because they can mimic a variety of benign conditions and may be difficult to subclassify when malignant. The classification of gastrointestinal lymphomas is an evolving area with some recent changes. Although some of these entities are rare, they are important to recognize because of the variable clinical presentations, comorbidities, and treatment implications. This article explores new and revised entities in gastrointestinal lymphoproliferative disorders.


Assuntos
Neoplasias Gastrointestinais/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Doença Celíaca/complicações , Doença Crônica , Diagnóstico Diferencial , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Humanos , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/terapia , Prognóstico
16.
Nat Med ; 25(7): 1054-1056, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160815

RESUMO

Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.


Assuntos
Aprendizado Profundo , Neoplasias Gastrointestinais/patologia , Instabilidade de Microssatélites , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Humanos , Imunoterapia
17.
Tumori ; 105(4): 338-352, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31068090

RESUMO

INTRODUCTION: Recent advances in technology and research are rapidly changing the diagnostic approach to hereditary gastrointestinal cancer (HGIC) syndromes. Although the practice of clinical genetics is currently transitioning from targeted criteria-based testing to multigene panels, important challenges remain to be addressed. The aim of this study was to develop and technically validate the performance of a multigene panel for HGIC. METHODS: CGT-colon-G14 is an amplicon-based panel designed to detect single nucleotide variants and small insertions/deletions in 14 well-established or presumed high-penetrance genes involved in HGIC. The assay parameters tested were sensitivity, specificity, accuracy, and inter-run and intra-run reproducibility. Performance and clinical impact were determined using 48 samples of patients with suspected HGIC/polyposis previously tested with the targeted approach. RESULTS: The CGT-colon-G14 panel showed 99.99% accuracy and 100% inter- and intra-run reproducibility. Moreover, panel testing detected 1 actionable pathogenic variant and 16 variants with uncertain clinical impact that were missed by the conventional approach because they were located in genes not previously analyzed. CONCLUSION: Introduction of the CGT-colon-G14 panel into the clinic could provide a higher diagnostic yield than a step-wise approach; however, results may not always be straightforward without the implementation of new genetic counseling models.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Gastrointestinais/genética , Testes Genéticos/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Aconselhamento Genético/métodos , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
18.
Biochim Biophys Acta Rev Cancer ; 1872(1): 1-10, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31059737

RESUMO

Pyroptosis, a type of inflammatory programmed cell death, is mediated by multiple inflammasomes which can recognize danger signals and activate the secretion of pro-inflammatory cytokines like IL-181 and IL-1ß2. It can induce cancer cell death within the gastrointestinal tract. NLRs3, AIM24, GSDM5 family play important roles in pyroptosis signaling pathways in intestinal cancer such as gastric cancer, colitis-associated colorectal cancer and esophageal cancer, etc. Furthermore, several inflammasomes are elucidated to be involved in mucosal innate immune responses and modulate specific enteric pathogens infection. Precise modulation of inflammasome activation and exploration of potential diagnostic markers can contribute to the diagnosis, prevention and treatment of intestinal tumors and inflammatory or infectious disorders in human patients in the near future.


Assuntos
Infecções Bacterianas/genética , Neoplasias Gastrointestinais/genética , Intestinos/microbiologia , Piroptose/genética , Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/microbiologia , Humanos , Imunidade Inata/genética , Inflamassomos/genética , Interleucina-18/genética , Interleucina-1beta/genética , Intestinos/patologia
19.
PLoS One ; 14(5): e0216503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31083682

RESUMO

Photodynamic diagnosis/therapy (PDD/PDT) are novel modalities for the diagnosis and treatment of cancer. The photosensitizer protoporphyrin IX is metabolized from 5-aminolevulinic acid (5-ALA) intracellularly, and PDD/PDT using 5-ALA have been approved in dermatologic malignancies and gliomas. However, the molecular mechanism that defines the efficacy of PDD/PDT is unknown. In this study, we analyzed the functions of ATP-binding cassette (ABC) transporters in PDD using 5-ALA. Most of the human gastrointestinal cancer line cells examined showed a homogenous staining pattern with 5-ALA, except for the pancreatic cancer line PANC-1, which showed heterogeneous staining. To analyze this heterogeneous staining pattern, single cell clones were established from PANC-1 cells and the expression of ABC transporters was assessed. Among the ABC transporter genes examined, ABCG2 showed an inverse correlation with the rate of 5-ALA-positive staining. PANC-1 clone #2 cells showed the highest level of ABCG2 expression and the lowest level of 5-ALA staining, with only a 0.6% positive rate. Knockdown of the ABCG2 gene by small interfering RNAs increased the positive rate of 5-ALA staining in PANC-1 wild-type and clone cells. Interestingly, PANC-1 clone #2 cells showed the high sphere-forming ability and tumor-formation ability, indicating that the cells contained high numbers of cancer stem cells (CSCs). Knockdown or inhibition of ABCG2 increased the rate of 5-ALA staining, but did not decrease sphere-forming ability. These results indicate that gastrointestinal cancer cell lines expressing high levels of ABCG2 are enriched with CSCs and show low rates of 5-ALA staining, but 5-ALA staining rates can be improved by inhibition of ABCG2.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Ácido Aminolevulínico/farmacologia , Neoplasias Gastrointestinais/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Animais , Linhagem Celular Tumoral , Dicetopiperazinas/farmacologia , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/terapia , Regulação Neoplásica da Expressão Gênica , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Camundongos , Transplante de Neoplasias , Protoporfirinas/metabolismo , Análise de Célula Única , Regulação para Cima
20.
Database (Oxford) ; 20192019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31089686

RESUMO

Gastrointestinal (GI) cancer is common, characterized by high mortality, and includes oesophagus, gastric, liver, bile duct, pancreas, rectal and colon cancers. The insufficient specificity and sensitivity of biomarkers is still a key clinical hindrance for GI cancer diagnosis and successful treatment. The emergence of `precision medicine', `basket trial' and `field cancerization' concepts calls for an urgent need and importance for the understanding of how organ system cancers occur at the molecular levels. Knowledge from both the literature and data available in public databases is informative in elucidating the molecular alterations underlying GI cancer. Currently, most available cancer databases have not offered a comprehensive discovery of gene-disease associations, molecular alterations and clinical information by integrated text mining and data mining in GI cancer. We develop GIDB, a panoptic knowledge database that attempts to automate the curation of molecular signatures using natural language processing approaches and multidimensional analyses. GIDB covers information on 8730 genes with both literature and data supporting evidence, 248 miRNAs, 58 lncRNAs, 320 copy number variations, 49 fusion genes and 2381 semantic networks. It presents a comprehensive database, not only in parallelizing supporting evidence and data integration for signatures associated with GI cancer but also in providing the timeline feature of major molecular discoveries. It highlights the most comprehensive overview, research hotspots and the development of historical knowledge of genes in GI cancer. Furthermore, GIDB characterizes genomic abnormalities in multilevel analysis, including simple somatic mutations, gene expression, DNA methylation and prognosis. GIDB offers a user-friendly interface and two customizable online tools (Heatmap and Network) for experimental researchers and clinicians to explore data and help them shorten the learning curve and broaden the scope of knowledge. More importantly, GIDB is an ongoing research project that will continue to be updated and improve the automated method for reducing manual work.


Assuntos
Biomarcadores Tumorais , Curadoria de Dados , Mineração de Dados , Neoplasias Gastrointestinais , Processamento de Linguagem Natural , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Humanos , Medicina de Precisão
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