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1.
Zhonghua Yi Xue Za Zhi ; 100(4): 301-306, 2020 Feb 04.
Artigo em Chinês | MEDLINE | ID: mdl-32075360

RESUMO

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


Assuntos
Neoplasias Colorretais , Genes ras , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Mutação , Estadiamento de Neoplasias
3.
Gene ; 727: 144262, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759987

RESUMO

Neuroblastoma is an extracranial solid tumor that mainly occurs in childhood. Mutations of NRAS gene have been described in several cancers. However, whether NRAS gene polymorphisms can predict the risk of neuroblastoma have not been investigated. We hypothesized that variations of NRAS gene contribute to neuroblastoma predisposition. Therefore, we conducted a multi-center case-control study using 263 cases and 715 controls to examine the association of NRAS gene rs2273267 A>T polymorphism and neuroblastoma risk. We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the strength of the associations. Relative to those with AA genotype, subjects with AT/TT genotype had reduced neuroblastoma risk (adjusted OR = 0.72, 95% CI = 0.54-0.96, P = 0.024). Stratified analysis revealed that rs2273267 AT/TT carriers were less likely to develop neuroblastoma for patients with tumor originating from the adrenal gland (adjusted OR = 0.67, 95% CI = 0.45-0.99, P = 0.047) and clinical stages III + IV (adjusted OR = 0.57, 95% CI = 0.36-0.90, P = 0.015). Our findings underline the likely importance of NRAS gene rs2273267 A>T in the risk of neuroblastoma. Further independent case-control studies with functional analysis are needed to verify the role of NRAS gene rs2273267 A>T polymorphism in the risk of neuroblastoma.


Assuntos
GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Neuroblastoma/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Feminino , GTP Fosfo-Hidrolases/metabolismo , Frequência do Gene/genética , Genes ras/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Lactente , Masculino , Proteínas de Membrana/metabolismo , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
4.
Anticancer Res ; 39(10): 5645-5652, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570462

RESUMO

BACKGROUND/AIM: The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS and treated with targeted agents. PATIENTS AND METHODS: The cohort included 178 patients treated with first-line chemotherapy plus cetuximab, panitumumab or bevacizumab. RESULTS: We observed longer progression-free survival (PFS) and overall survival (OS) in patients with left-sided (L-CRC) compared to right-sided tumours (R-CRC) treated with anti-EGFR mAbs (p=0.0033 and p=0.0037), while there was no difference in patients treated with bevacizumab (p=0.076 and p=0.56). Finally, we observed longer PFS and OS in patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab compared to the reverse combination (p=0.0002 and p=0.011). CONCLUSION: PTS is a predictive factor for anti-EGFR mAbs, not for bevacizumab. Superior survival was observed when anti-EGFR mAbs were used for L-CRC and bevacizumab for R-CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Genes ras/genética , Humanos , Masculino , Panitumumabe/administração & dosagem
6.
Clin Chim Acta ; 498: 47-51, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31430440

RESUMO

Pancreatic cancer is one of the deadliest cancers having an exceptionally high mortality rate. Despite a relatively low incidence (10th among cancers), it is the fourth leading cause of cancer-related deaths in most developed countries. Improving early diagnosis of pancreatic cancer and strengthening the standardised comprehensive treatment remain the main focus of pancreatic cancer research. Tumor markers are usually tumor-associated proteins of clinical relevance in these patients. Although tumor markers carbohydrate antigen (CA 19-9) and carcino-embryonic antigen (CEA) are commonly used, neither demonstrate high diagnostic accuracy. Recently, hematopoietic growth factors (HGFs) and various enzymes have been reported as potential biomarkers for pancreatic cancer. These include macrophage-colony stimulating factor (M-CSF) and granulocyte-colony stimulating factor (G-CSF), interleukin-3 (IL-3), macrophage inhibitory cytokine (MIC-1) and various enzymes (alcohol dehydrogenase, aldehyde dehydrogenase, lysosomal exoglycosidases). With the development of molecular technology, detecting K-ras mutation in serum via polymerase chain reaction (PCR) is becoming more common and efficient. Because K-ras mutation rates are high in many cancers, some regard it as a potential tumor marker. Others have shown the value of serum miRNAs in detection of pancreatic cancer. Unfortunately, there are currently no effective methods of sufficient diagnostic accuracy to detect early-stage surgically resectable pancreatic cancer. In this article we highlight these biomarkers and summarise recent developments in the diagnosis and treatment of pancreatic cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias Pancreáticas/diagnóstico , Patologia Molecular/métodos , Animais , Genes ras/genética , Humanos , Mutação , Neoplasias Pancreáticas/terapia , Patologia Molecular/tendências , Reação em Cadeia da Polimerase
7.
Biochem Soc Trans ; 47(4): 961-972, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31341034

RESUMO

The pancreas is a gland composed mainly by endocrine and exocrine cells, giving rise to three main tumour types. Pancreatic neuroendocrine tumour or PNET arise from the endocrine portion of the pancreas. On the contrary, pancreatic exocrine neoplasms include pancreatic ductal adenocarcinoma (PDAC) and acinar cell carcinoma. PDAC is the most common type of pancreatic cancer and one of the leading causes of cancer-related death. It has been shown that less than 3% of PDAC patients have an overall survival of up to 5 years in the U.K. This mainly arises since the majority of patients diagnosed with PDAC present with advanced unresectable disease, which is highly resistant to all forms of chemotherapy and radiotherapy. Activating mutations of an isoform of the RAS protein, KRAS, are found in almost all PDAC cases and occur during early stages of malignant transformation. KRAS mutations play a critical role as they are involved in both initiating and maintaining PDAC development. The interaction of RAS with GDP/GTP along with its recruitment to the membrane affects transduction of its activating signals to downstream effectors. In this review, we aim to summarise different mutations of RAS and their prevalence in pancreatic cancer along with other RAS-induced tumours. In addition, we briefly discuss the genetically engineered mouse models that have been developed to study KRAS-mutated adenocarcinomas in the pancreas. These provide an opportunity to also address the importance of targeting RAS for better treatment response in PDAC patients along with the challenges incurred herein.


Assuntos
Genes ras , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Mutação , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais
8.
Oncogene ; 38(30): 5890-5904, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31253872

RESUMO

Prior studies demonstrated that the irreversible ERBB1/2/4 inhibitor neratinib caused plasma membrane-associated mutant K-RAS to localize in intracellular vesicles, concomitant with its degradation. Herein, we discovered that neratinib interacted with the chemically distinct irreversible ERBB1/2/4 inhibitor afatinib to reduce expression of ERBB1, ERBB2, K-RAS and N-RAS; this was associated with greater-than-additive cell killing of pancreatic tumor cells. Knock down of Beclin1, ATG16L1, Rubicon or cathepsin B significantly lowered the ability of neratinib to reduce ERBB1 and K-RAS expression, and to cause tumor cell death. Knock down of ATM-AMPK suppressed vesicle formation and knock down of cathepsin B-AIF significantly reduced neratinib lethality. PKG phosphorylates K-RAS and HMG CoA reductase inhibitors reduce K-RAS farnesylation both of which remove K-RAS from the plasma membrane, abolishing its activity. Neratinib interacted with the PKG activator sildenafil and the HMG CoA reductase inhibitor atorvastatin to further reduce K-RAS expression, and to further enhance cell killing. Neratinib is also a Ste20 kinase family inhibitor and in carcinoma cells, and hematopoietic cancer cells lacking ERBB1/2/4, it reduced K-RAS expression and the phosphorylation of MST1/3/4/Ezrin by ~ 30%. Neratinib increased LATS1 phosphorylation as well as that of YAP and TAZ also by ~ 30%, caused the majority of YAP to translocate into the cytosol and reduced YAP/TAZ protein levels. Neratinib lethality was enhanced by knock down of YAP. Neratinib, in a Rubicon-dependent fashion, reduced PAK1 phosphorylation and that of its substrate Merlin. Our data demonstrate that neratinib coordinately suppresses both mutant K-RAS and YAP function to kill pancreatic tumor cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Genes ras , Neoplasias Hematológicas/patologia , Neoplasias Pancreáticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Neoplasias Hematológicas/metabolismo , Humanos , Neoplasias Pancreáticas/metabolismo , Fosforilação , Receptor ErbB-2/metabolismo
9.
Histopathology ; 75(5): 755-766, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31179560

RESUMO

AIMS: Thymic carcinoma is rare and usually has a fatal outcome. Gene mutations in the epidermal growth factor receptor (EGFR) signalling pathway and TP53 have not been well analysed in thymic carcinoma. METHODS AND RESULTS: We examined a large cohort of thymic carcinoma and thymoma type A/B3 and looked for gene mutations in the RAS family, EGFR, PIK3CA, AKT1, BRAF and TP53. Among 54 thymic carcinoma cases, RAS family mutations were detected in 10 cases, EGFR in two, PIK3CA in one, AKT1 in one, BRAF in none and TP53 in five. Among 33 thymoma type A/B3 cases, HRAS gene mutation were found in one, PIK3CA in two and AKT1 in one. All these mutations were those of missense type activating mutations. RAS family mutations were significantly more frequent in thymic carcinoma than in thymoma type A/B3 (P = 0.0461). A prognostic analysis focusing on thymic squamous cell carcinoma cases (n = 44) showed that the overall survival was significantly shorter in patients with EGFR pathway mutations (n = 9) than in those without in a univariate analysis (P = 0.0173). Subsequently, EGFR pathway mutations were selected as an independent factor for a poor overall survival in a multivariate analysis (P = 0.0389). CONCLUSIONS: Mutations in the EGFR pathway and TP53 in thymic carcinoma may be frequent, and the EGFR pathway mutations may be associated with a poor prognosis in thymic squamous cell carcinoma patients. The therapeutic significance of gene mutations in thymic carcinoma should be further clarified.


Assuntos
Genes erbB-1 , Timoma/genética , Neoplasias do Timo/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Classe I de Fosfatidilinositol 3-Quinases/genética , Análise Mutacional de DNA , Receptores ErbB/genética , Feminino , Genes ras/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética
10.
Gastroenterology ; 157(3): 838-850.e6, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31163177

RESUMO

BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.


Assuntos
Anexina A2/metabolismo , Orientação de Axônios , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular , Gânglios Espinais/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Pancreáticas/metabolismo , Semaforinas/metabolismo , Animais , Anexina A2/deficiência , Anexina A2/genética , Orientação de Axônios/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundário , Comunicação Celular , Gânglios Espinais/patologia , Regulação Neoplásica da Expressão Gênica , Genes p53 , Genes ras , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Crescimento Neuronal , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Semaforinas/genética , Transdução de Sinais , Transativadores/genética , Células Tumorais Cultivadas
11.
Int J Cancer ; 145(6): 1625-1634, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31162857

RESUMO

Mutations of KRAS, NRAS, BRAF and DNA mismatch repair (MMR) status have become an important part of the assessment of patients with colorectal cancer (CRC), while respective clinicopathologic features and prognostic significance in specific stages and related detection strategies remain unclear. We retrospectively analyzed clinicopathologic features and prognosis of 1,834 patients with Stage I-IV colorectal adenocarcinoma. Mutations in KRAS, NRAS and BRAF and DNA MMR status were determined. The mutation rates of KRAS, NRAS and BRAF were 46.4, 3.2 and 3.5%, respectively, and the mismatch repair gene deletion (dMMR) rate was 5.6%. In a multivariate analysis, female, advanced age, tumor type histology, mucinous carcinoma and positive tumor deposits were associated with a high KRAS mutation rate. A high BRAF mutation rate was associated with female, poor differentiation, lymphovascular invasion and positive tumor deposits. Factors associated with high dMMR rates included low age, large tumor size, poor differentiation, Stages I-III. Tumor site was independently associated with KRAS mutation, BRAF mutation and dMMR. KRAS and BRAF mutations were independent risk factors for shorter overall survival (OS) in Stage IV tumors but not in Stage I-III tumors. NRAS mutation was an independent risk factor for shorter OS in Stage I-II tumors. dMMR was independently associated with longer OS in Stage III tumors.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Genes ras , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adenocarcinoma/genética , Idoso , China , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
12.
Int J Hematol ; 110(2): 213-227, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129802

RESUMO

A MEK1/2 inhibitor, binimetinib is promising as a therapeutic agent for malignant melanoma with N-RAS mutation. We examined in vitro effects of binimetinib on 10 human myeloid/lymphoid leukemia cell lines, and found that three of five cell lines with N-RAS mutation and one of five without N-RAS mutation were responsive to treatment with binimetinib. Binimetinib inhibited cell growth mainly by inducing G1 arrest and this action mechanism was assisted by gene set enrichment analysis. To identify signaling pathways associated with binimetinib response, we examined the status of MAP kinase/ERK and PI3Kinase/Akt pathways. The basal levels of phosphorylated ERK and Akt varied between the cell lines, and the amounts of phosphorylated ERK and Akt appeared to be reciprocal of each other. Interestingly, most of the binimetinib-resistant cell lines revealed strong Akt phosphorylation compared with binimetinib-sensitive ones. The effect of binimetinib may not be predicted by the presence/absence of N-RAS mutation, but rather by Akt phosphorylation status. Moreover, combination of binimetinib with a PI3K/Akt inhibitor showed additive growth-suppressive effects. These results suggest that binimetinib shows potential anti-leukemic effects and the basal level of phosphorylated Akt might serve as a biomarker predictive of therapeutic effect.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Genes ras , Leucemia/patologia , Proteína Oncogênica p21(ras)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Aminopiridinas/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Fase G1/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Morfolinas/farmacologia , Mutação , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Curr Pharm Des ; 25(10): 1105-1114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057104

RESUMO

RAS (H-ras, K-ras, and N-ras), as the second largest mutated gene driver in various human cancers, has long been a vital research target for cancer. Its function is to transform the extracellular environment into a cascade of intracellular signal transduction. RAS mutant protein regulates tumor cell proliferation, apoptosis, metabolism and angiogenesis through downstream MAPK, PI3K and other signaling pathways. In KRAS or other RAS-driven cancers, current treatments include direct inhibitors and upstream/downstream signaling pathway inhibitors. However, the research on these inhibitors has been largely restricted due to their escape inhibition and off-target toxicity. In this paper, we started with the role of normal and mutant RAS genes in cancer, elucidated the relevant RAS regulating pathways, and highlighted the important research advancements in RAS inhibitor research. We concluded that for the crosstalk between RAS pathways, the effect of single regulation may be limited, and the multi-target drug combined compensation mechanism is becoming a research hotspot.


Assuntos
Mutação , Neoplasias/genética , Proteínas ras/genética , Genes ras , Humanos , Neoplasias/tratamento farmacológico
14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(1): 61-65, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31037906

RESUMO

OBJECTIVE: To analyze the correlation of K-ras gene mutations with the protein expressions of transforming growth factor-ß activating kinase 1 (TAK1) protein and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2) protein in colorectal cancer. METHODS: K-ras gene mutations were detected by DNA sequencing analysis, and the expressions of TAK1 protein and MAP4K2 protein were detected by immunohistochemical method in 76 cases of colorectal cancer tissues. RESULTS: In 76 cases of colorectal cancer tissues, the mutation rate of K-ras gene was 32.89% (25 cases), and K-ras gene mutations were correlated with the degrees of cell differentiation ( P<0.05). The positive rates of TAK1 protein and MAP4K2 protein were 48.68% and 46.05%, respectively. The protein expressions of TAK1 and MAP4K2 were positively correlated with the degrees of cell differentiation and lymph node metastases, respectively ( P<0.05). There was no correlation between K-ras gene mutation and either TAK1 protein or MAP4K2 protein expression ( P>0.05). In 25 cases of colorectal cancer with K-ras mutation, the expression of TAK1 protein was positively correlated with the expression of MAP4K2 protein ( P<0.05). CONCLUSION: K-ras gene mutation, TAK1 and MAP4K2 protein expressions were related to the degree of differentiation of colorectal cancer, but not to the depth of invasion. In colorectal cancer with K-ras gene mutation, the expression of TAK1 protein was positively correlated with the expression of MAP4K2 protein.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Proteínas Proto-Oncogênicas p21(ras)/genética , Genes ras , Humanos , Metástase Linfática , MAP Quinase Quinase Quinases , Mutação , Proteínas Serina-Treonina Quinases
15.
Fish Shellfish Immunol ; 89: 281-289, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953781

RESUMO

H-Ras is a guanosine triphosphatase (GTPase), which acts as a molecular switch and controls multiple important cellular processes including lymphocyte activation and function. However, regulatory mechanism of adaptive immune response by H-Ras remains unclear in non-mammalian animals. In the present study, we investigated the involvement of H-Ras in lymphocyte activation with a teleost model Oreochromis niloticus. H-Ras from O. niloticus (On-H-Ras) is highly conserved with those from other vertebrates. The mRNA of On-H-Ras showed a wide expression pattern in the lymphoid-tissues and with the highest level in liver. After Aeromonas hydrophila infection, transcription of On-H-Ras was significantly induced on day 8 but came back to basal level on day 16, suggesting that On-H-Ras potentially participated in primary response during the adaptive immunity. Furthermore, On-H-Ras mRNA was obviously up-regulated when leukocytes were activated by T lymphocyte mitogen PHA in vitro. Meanwhile, protein level of H-Ras was also augmented once leukocytes were stimulated with lymphocyte receptor signaling agonist PMA and ionomycin. More importantly, once Ras activity was inhibited by specific inhibitor, the up-regulation of lymphocyte activation marker CD122 was obviously impaired during lymphocyte activation process. Therefore, On-H-Ras regulated lymphocyte activation through both mRNA and protein level. Altogether, our results illustrated the involvement of H-Ras in teleost adaptive immunity via controlling lymphocyte activation, and thus provided a novel perspective to understand evolution of the lymphocyte-mediated adaptive immunity.


Assuntos
Imunidade Adaptativa/genética , Ciclídeos/genética , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Genes ras/imunologia , Ativação Linfocitária/genética , Aeromonas hydrophila/fisiologia , Animais , Ciclídeos/imunologia , Proteínas de Peixes/metabolismo , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária
16.
Cancer Cell ; 35(4): 535-537, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991021

RESUMO

In this issue of Cancer Cell, Liao et al. demonstrate that oncogenic KRAS drives an immune suppressive program in colorectal cancer by repressing IRF2 expression, which leads to downregulation of interferon responsive genes, enhanced expression of CXCL3 and recruitment of suppressive myeloid cells, and subsequent resistance to immune checkpoint blockade.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais/genética , Genes ras , Humanos , Fator Regulador 2 de Interferon , Oncogenes , Proteínas Proto-Oncogênicas p21(ras)
17.
Biochem Genet ; 57(6): 767-780, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30997628

RESUMO

Sporadic colorectal cancer (CRC) is a fatal disease, mostly known as the silent killer, due to the fact that this disease is asymptomatic before diagnosis in advanced stage. Screening and the early detection of CRC and colorectal adenoma (CRA) by non-aggressive molecular biomarkers' signature is useful for improvement of survival rate in CRC patients. To achieve such a goal, a better understanding of distinct molecular abnormalities as candidate biomarkers in CRC development is crucial. In this study, seventy-five archived FFPE CRC samples, including colorectal adenocarcinoma, adenomatous polyps (adenoma), and adjacent non-neoplastic mucosa were collected for the investigation by Sanger sequencing at the DNA level and by real-time PCR at the RNA level. The results of the KRAS mutational analysis have shown that the majority of somatic mutations in the KRAS affect only one codon, mainly codon 12(p.G12D) with low frequency in adenomas (13.3%) versus CRCs (36%). The results of dysregulated epigenetic changes of miR-21 clearly showed upregulation of expression in colorectal adenocarcinoma, compared to non-neoplastic mucosa, in colorectal adenoma vs non-neoplastic mucosa: (p < 0.001) and in CRC versus adenoma (p < 0.001); while miR-148a expression were significantly downregulated in CRC, compared to non-neoplastic mucosa, in colorectal adenoma vs non-neoplastic mucosa, and in adenoma vs CRC (p < 0.001). Our findings support the important role of miR-21 in stages I-II of CRC, and the KRAS G12D mutant, and differential miR-148a expression, in advanced stages of CRC.


Assuntos
Adenoma/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Genes ras , MicroRNAs/genética , Mutação , Adenoma/patologia , Carcinoma/patologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA
18.
Anal Chim Acta ; 1065: 98-106, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31005156

RESUMO

The sensitive detection of tumor proto-oncogenes is indispensable because the early diagnosis and accurate treatment of genetic diseases is the key guarantee of patients' health. In this study, we proposed a novel palindromic molecular beacon (PMB) that it bases on the signal amplification strategy for ultrasensitive detection of Kras gene codon 12. PMB is designed to have two palindromic fragments at its two ends, one of which is locked via folding into a hairpin structure and the other promotes the formation of PMB duplex via intermolecular self-hybridization. Target DNA can hybridize to the loop portion of PMB and release the palindromic fragment at the 3' end. Within the PMB duplex, the two palindromic fragments released hybridize with each other and serve as polymerization primer responsible for the strand-displacement amplification (SDA). Namely, hybridized target DNA can be displaced and initiates the next round of reactions, making the polymerization/displacement/hybridization process go forward circularly. As a result, a large number of polymerization products are produced, dramatically enhancing optical signal. Because primer hybridization and polymerization-based displacement occur within PMB duplex, the reaction process is called intramolecular strand-displacement amplification (ISDA). Via utilizing the newly-proposed PMB-based ISDA strategy, the target K-ras gene could be detected down to 10 pM with a wide response range of 1 × 10-11-1.5 × 10-7 M, and point mutations are easily distinguished, realizing the ultrasensitive, highly selective detection of K-ras gene. This impressive sensing paradigm demonstrates a new concept of signal amplification for the detection of disease-related genes only via using a simple way to efficiently amplify optical signal.


Assuntos
Técnicas Biossensoriais , Genes ras/genética , Técnicas de Amplificação de Ácido Nucleico , Humanos , Espectrometria de Fluorescência
19.
Pathol Res Pract ; 215(6): 152405, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981459

RESUMO

To reveal novel lncRNAs and explore how could lncRNA affect the ER/PR positive type breast cancer, 16 different lncRNA transcriptomes (8 breast cancer tissues and 8 normal breast tissues) were successfully sequenced. In total, 8,954 high quality lncRNAs, including 5,516 lncRNAs reported in the previous studies and 3,438 novel lncRNAs, were annotated. The highest expressed lncRNAs were MALAT1, SCARNA10, RP11-206M11.7 and NEAT1, and the highest expressing mRNAs were RPL19, SCGB2A2, FTL and TMSB4 × . Of the 615 differentially expressed lncRNAs, 323 showed up regulated (P < 0.05) expression patterns in breast cancer, and 292 showed down regulated expression patterns. Of the 8,954 genes, 5,516 genes were upregulated in breast cancer, and 3,438 were downregulated. In total, the targets of 238 lncRNAs were confirmed by two lncRNA target prediction programs. Within these genes, Ras responsive element binding protein 1, Ras association domain family member 6, Ras association domain family member 8, Ras protein specific guanine nucleotide releasing factor 1and other 10 different Ras associated different expressed genes were predicted as targets of lncRNAs. These different expressed lncRNAs which could regulate the Ras gene families and ECM pathway may be another mechanism why the expression pattern of Ras genes changed in breast cancer. All these cancer-related genes (Ras genes) were annotated as targets of lncRNAs in the breast cancer transcriptome may provide us with a new way to understand the occurrence and development of breast cancer.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Genes ras/genética , RNA Longo não Codificante/genética , Adulto , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Receptores Estrogênicos/biossíntese , Receptores de Progesterona/biossíntese , Transcriptoma
20.
Genome Med ; 11(1): 21, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30987660

RESUMO

CRISPR/Cas9 has revolutionized cancer mouse models. Although loss-of-function genetics by CRISPR/Cas9 is well-established, generating gain-of-function alleles in somatic cancer models is still challenging because of the low efficiency of gene knock-in. Here we developed CRISPR-based Somatic Oncogene kNock-In for Cancer Modeling (CRISPR-SONIC), a method for rapid in vivo cancer modeling using homology-independent repair to integrate oncogenes at a targeted genomic locus. Using a dual guide RNA strategy, we integrated a plasmid donor in the 3'-UTR of mouse ß-actin, allowing co-expression of reporter genes or oncogenes from the ß-actin promoter. We showed that knock-in of oncogenic Ras and loss of p53 efficiently induced intrahepatic cholangiocarcinoma in mice. Further, our strategy can generate bioluminescent liver cancer to facilitate tumor imaging. This method simplifies in vivo gain-of-function genetics by facilitating targeted integration of oncogenes.


Assuntos
Neoplasias dos Ductos Biliares/genética , Sistemas CRISPR-Cas , Colangiocarcinoma/genética , Técnicas de Introdução de Genes/métodos , Genes ras , Actinas/genética , Animais , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Genes Reporter , Genes p53 , Humanos , Camundongos
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