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1.
BMC Surg ; 20(1): 24, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013941

RESUMO

BACKGROUND: We report a case of an intraabdominal desmoid tumor that occurred at a gastro-pancreatic lesion with spontaneous cystic features, and present the successful laparoscopic resection of the tumor. CASE PRESENTATION: A 20-mm retroperitoneal cystic mass with a solid component was found adjacent to the stomach and pancreatic body in a 52-year-old woman with no history of familial adenomatous polyposis. Laparoscopic spleen-preserving distal pancreatectomy with wedge resection of the stomach was performed, and complete resection was achieved without intraoperative and postoperative complications. Histopathological examination by immunohistochemistry enabled diagnosis of a desmoid tumor that had originated from the stomach and invaded the pancreatic parenchyma with a spontaneous cystic change. We herein report an extremely rare case of an intraabdominal desmoid tumor with a spontaneous cystic change. CONCLUSION: Regardless of its rarity, desmoid tumor should be included in the preoperative differential diagnosis of a cystic intraabdominal mass, and laparoscopic function-preserving surgery may be an optimal treatment option.

2.
Anticancer Res ; 39(11): 6347-6353, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704866

RESUMO

BACKGROUND/AIM: The aim of this study was to determine the significance of immunonutritional and physical index in the assessment of risk associated with pancreaticoduodenectomy (PD) in the elderly. PATIENTS AND METHODS: This study enrolled 92 patients who underwent PD. They were divided into 2 groups: Group A included patients 79 years and younger (n=79) and Group B patients 80 years and older (n=13). Among 37 patients, physical function and body composition were also evaluated. RESULTS: Significantly higher neutrophil-lymphocyte ratio, lower prognostic nutritional index (PNI), and controlling nutritional score were observed in Group B. Muscle strength and walking ability were significantly impaired in Group B, although there was no significant difference in body composition. Age was not correlated with the incidence of postoperative complications, overall survival or recurrence-free survival by univariate and multivariate analysis. CONCLUSION: PD is justified for the elderly, with acceptable morbidity and prognosis. However, immunonutritional status and physical function are significantly impaired; thus, appropriate case selection and active nutritional support are required for the elderly.


Assuntos
Limitação da Mobilidade , Força Muscular , Estado Nutricional , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Neoplasias dos Ductos Biliares/cirurgia , Composição Corporal , Comorbidade , Neoplasias Duodenais/cirurgia , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Avaliação Nutricional , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/mortalidade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Medição de Risco , Albumina Sérica/análise
3.
World J Surg Oncol ; 17(1): 232, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888657

RESUMO

BACKGROUND: The management of infectious complications is important in pancreatoduodenectomy (PD). We sought to determine the significance of preoperative surveillance bile culture in perioperative management of PD. METHODS: This study enrolled 69 patients who underwent PD for malignant tumors at a single institute between 2014 and 2017. Surveillance bile culture was performed before or during surgery. Correlations between the incidence of infectious postoperative complications and clinicopathological parameters, including bile cultures, were evaluated. RESULTS: Preoperative positive bile culture was confirmed in 28 of 51 patients (55%). Bile culture was positive in 27 of 30 cases (90%) with preoperative biliary drainage, and 1 of 21 cases (5%) without drainage (p < 0.01). Preoperative isolated microorganisms in bile were consistent with those detected in surgical sites in 11 of 27 cases (41%). Cases with positive multi-drug-resistant bacteria in preoperative bile culture showed significantly higher incisional SSI after PD (p = 0.01). The risk factors for the incidence of organ/space SSI were soft pancreatic texture (p = 0.01) and smoking history (p = 0.02) by multivariate analysis. Preoperative positive bile culture was neither associated with organ/space SSI nor overall postoperative complications. CONCLUSIONS: Preoperative surveillance bile culture is useful for the management of wound infection, prediction of causative pathogens for infectious complications, and the selection of perioperative antibiotic prophylaxis.

4.
Br J Cancer ; 119(4): 419-423, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30072744

RESUMO

BACKGROUND: We aim to investigate the utility of serial gene mutation tracking for locally advanced CRC in those who underwent curative resection following neoadjuvant chemotherapy. METHODS: We prospectively collected 10 locally advanced CRC cases for which curative resection was performed following preoperative neoadjuvant chemotherapy. Tissues from the primary tumour, distant metastatic tumours, and blood plasma were obtained during serial treatment. Comprehensive mutation analysis of 47 cancer-associated genes was performed using a pre-designed gene panel and next-generation sequencing. RESULTS: All cases showed a partial response to neoadjuvant chemotherapy, and pathological R0 resection was accomplished. In primary tumours, non-synonymous mutations were detected at between 1 and 14 sites before chemotherapy and at between 1 and 2 sites after. Founder mutations were precisely detected in blood plasma and metastatic tumours during longitudinal treatment. CONCLUSIONS: Serial mutational analysis indicated that subclonal selection occurs during chemotherapy and that plasma can substitute for tumourous tissue in mutational analysis for drug selection and treatment decisions.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Quimioterapia Adjuvante , Neoplasias Colorretais/genética , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos da radiação , Humanos , Masculino , Terapia Neoadjuvante , Estudos Prospectivos , Análise de Sequência de DNA , Análise de Sobrevida , Resultado do Tratamento
5.
Oncology ; 95(3): 179-187, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29909415

RESUMO

OBJECTIVE: The involvement of epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. Here, we aimed to identify EMT-related genes associated with TGF-ß in ESCC and to clarify the role of these genes in the progression of ESCC. METHODS: EMT-related genes associated with TGF-ß expression were identified in patients with ESCC using microarray analysis and public datasets. The effects of ubiquitin-like with PHD and ring finger domains 2 (UHRF2) expression were analyzed in ESCC cell lines. Cell proliferation and invasion were measured using MTT and invasion assays, respectively. UHRF2 mRNA expression was also analyzed in 75 ESCC specimens to determine the clinical significance of UHRF2 in ESCC. RESULTS: Treatment of ESCC cell lines with TGF-ß increased UHRF2 expression. UHRF2 overexpression increased CDH1 (E-cadherin) expression and decreased invasive capacity. The 75 ESCC specimens were divided into the UHRF2 high-expression group (n = 61) and the UHRF2 low-expression group (n = 14). Low UHRF2 expression was significantly correlated with vascular invasion (p = 0.034) and was an independent prognostic factor for poor prognosis (p = 0.005). CONCLUSION: UHRF2 may be a negative regulator of EMT and a novel prognostic biomarker for ESCC.


Assuntos
Carcinoma de Células Escamosas/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Ubiquitina-Proteína Ligases/genética , Biomarcadores Tumorais/genética , Caderinas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fator de Crescimento Transformador beta/genética
6.
Biochem Biophys Res Commun ; 501(2): 570-575, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29750959

RESUMO

Members of the BTB-ZF transcription factor family play important roles in lymphocyte development. During T cell development, ZNF131, a BTB-ZF protein, is critical for the double-negative (DN) to double-positive (DP) transition and is also involved in cell proliferation. Here, we report that knockout of Znf131 at the pre-pro-B cell stage in mb1-Cre knock-in mouse resulted in defect of pro-B to pre-B cell transition. ZNF131 was shown to be required for efficient pro-B cell proliferation as well as for immunoglobulin heavy chain gene rearrangement that occurs in the proliferating pro-B cells. We speculate that inefficient gene rearrangement may be due to loss of cell proliferation, since cell cycle progression and immunoglobulin gene rearrangement, which would occur in a mutually exclusive manner, may be interconnected or coupled to avoid occurrence of genomic instability. ZNF131 suppresses expression of Cdk inhibitor, p21cip1, and that of pro-apoptotic factors, Bax and Puma, targets of p53, to facilitate cell cycle progression and suppress unnecessary apoptosis, respectively, of pro-B cells. There results demonstrate the essential roles of ZNF131 in coordinating the B cell differentiation and proliferation.


Assuntos
Linfócitos B/citologia , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linfócitos B/metabolismo , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Proteínas de Ligação a DNA/genética , Deleção de Genes , Expressão Gênica , Camundongos , RNA Mensageiro/genética , Fatores de Transcrição/genética
8.
Oncotarget ; 8(45): 78598-78613, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-29108252

RESUMO

A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis. The mechanism by which tumor cells communicate with host cells to develop premetastatic niches is unclear. We focused on the role of microRNA (miR) signaling in promoting metastasis. Here, we identified miR-203 as a signaling molecule between tumors and monocytes in metastatic colorectal cancer (CRC) patients. Notably, high expression of serum exosomal miR-203, a major form in circulation, was associated with distant metastasis and an independent poor prognostic factor, whereas low expression in tumor tissues was a poor prognostic factor in CRC patients. We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro, suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs). In a xenograft mouse model, miR-203-transfected CRC cells developed more liver metastasis compared to control cells. In conclusion, serum exosomal miR-203 expression is a novel biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Furthermore, we propose the concept of site-dependent functions for miR-203 in tumor progression.

9.
Anticancer Res ; 37(5): 2255-2263, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28476790

RESUMO

BACKGROUND/AIM: SLC9A9 plays an oncogenic role in esophageal squamous carcinoma and glioblastoma. Herein, we showed an oncogenic function of SLC9A9 in colorectal cancer (CRC). MATERIALS AND METHODS: We examined SLC9A9 expression in CRC specimens by immunohistochemistry. In CRC tissues, the relationship between SLC9A9 expression and clinicopathological factors was further elucidated by quantitative real-time polymerase chain reaction (qRT-PCR) and gene set enrichment analysis (GSEA). In vitro, we performed knockdown and overexpression experiments. RESULTS: SLC9A9 was overexpressed in CRC specimens. In clinicopathological analysis of our cohort, high SLC9A9 expression increased liver metastasis and was correlated with worse prognoses in two cohorts. A significantly positive relationship between SLC9A9 and EGFR was revealed. While knockdown of SLC9A9 suppressed proliferation and anchorage-independent growth, up-regulation of SLC9A9 promoted proliferation and anchorage-independent growth in vitro. CONCLUSION: SLC9A9 has an oncogenic function by being related to EGFR signaling, suggesting SLC9A9 may be a novel prognostic indicator and a therapeutic target in CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Receptores ErbB/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Prognóstico , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Trocadores de Sódio-Hidrogênio/genética , Regulação para Cima
10.
Anticancer Res ; 37(5): 2365-2371, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28476802

RESUMO

BACKGROUND/AIM: Amplification of chromosome 7p (Ch.7p) is common in colorectal cancer (CRC). The aim of this study was to identify potential driver genes on Ch.7p that are overexpressed due to DNA copy number amplification and determine their clinical significance in CRC. MATERIALS AND METHODS: We identified phosphoserine phosphatase (PSPH) as a potential driver gene using a CRC dataset from The Cancer Genome Atlas (TCGA) using a bioinformatics approach. The expression of PSPH in 124 primary CRCs was examined by quantitative reverse transcription polymerase chain reaction (PCR) and immunohistochemistry. The biological effect of PSPH expression was explored by Gene Set Enrichment Analysis (GSEA) using the TCGA dataset. RESULTS: PSPH was overexpressed in tumor tissues and PSPH positively correlated with depth of invasion and distant metastasis. On multivariate analysis, high PSPH expression was an independent poor prognostic factor. These results were supported by GSEA. CONCLUSION: PSPH could be a novel prognostic biomarker with malignant potential on Ch.7p in CRC.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 7 , Neoplasias Colorretais/genética , Monoéster Fosfórico Hidrolases/genética , Idoso , Colo/metabolismo , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Prognóstico , RNA Mensageiro/metabolismo
11.
Anticancer Res ; 37(5): 2587-2591, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28476831

RESUMO

BACKGROUND: We previously identified discoidin-domain receptor 2 (DDR2) as a promising driver gene of peritoneal dissemination (PD) in gastric cancer. In the present study we explored the clinical significance of DDR2 expression in colorectal cancer (CRC). MATERIALS AND METHODS: We examined DDR2 expression in CRC specimens by immunohistochemistry. We analyzed the association of DDR2 expression with clinicopathological factors in CRC. We divided 63 CRC cases into two groups according to their level of DDR2 expression and compared several clinicopathological factors and their overall survival. RESULTS: The group with high DDR2 expression had significantly higher frequencies of T4, lymph node metastasis, and PD compared to the group with low DDR2 expression. Furthermore, the prognosis of the group with high DDR2 expression was significantly poorer than the group with low DDR2. CONCLUSION: DDR2 is a powerful biomarker that can predict poor prognosis as well as PD, and might be an effective therapeutic target for CRC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Receptor com Domínio Discoidina 2/metabolismo , Neoplasias Peritoneais/metabolismo , Idoso , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Metástase Neoplásica , Neoplasias Peritoneais/secundário , Prognóstico
13.
Oncology ; 93(1): 67-74, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28448997

RESUMO

OBJECTIVE: MOB1, a core component of the Hippo signaling pathway, suppresses cell proliferation, and MOB1 liver conditional knockout mice develop intrahepatic cholangiocarcinoma (ICC). However, its clinical significance in human ICC has not been established. The aim of this study was to characterize protein levels and the role of Hippo and TGF pathways in ICCs. METHODS: The protein levels of yes-associated protein 1 (YAP1), MOB1, Smad2, and TGFß2 in 88 ICC cases were analyzed. Protein level was graded by a scoring system; then, the clinicopathological factors, including prognosis, were analyzed based on protein level. RESULTS: Nuclear overexpression of YAP1 was seen in 28 cases (31.8%), and it was significantly associated with a poor overall survival rate (p = 0.01). MOB1 expression decreased in 42 cases (47.7%) and was associated with a poor overall survival rate (p = 0.02). SMAD2 nuclear localization was significantly correlated with a high YAP1 level independent of TGFß2. Multivariate analysis revealed that a high YAP1 level, a low MOB1 level, and lymphatic permeation were independent risk factors for overall survival. CONCLUSIONS: These results showed that key components of the Hippo signaling pathway are aberrantly expressed and associated with the malignant potential of human ICC.


Assuntos
Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos Knockout , Pessoa de Meia-Idade
14.
Anticancer Res ; 37(3): 1083-1090, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28314268

RESUMO

BACKGROUND/AIM: Fanconi anemia complementation group D2 (FANCD2) gene is vitally involved in DNA damage responses. We investigated the clinical significance of FANCD2 expression in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: FANCD2 mRNA expression of resected HCC tissues was assessed in two HCC cohorts; Our cases (n=111), and The Cancer Genome Atlas (TCGA; n=371). Gene set enrichment analysis (GSEA) was conducted using the TCGA dataset. Proliferation and invasion assays were performed using siRNAs, and the effect of inhibition of the mechanistic target of rapamycin (mTOR) pathway was evaluated. RESULTS: FANCD2 expression was up-regulated in tumor tissues. Cases with high FANCD2 expression had poorer prognoses in both cohorts, and were associated with larger tumor size and invasive phenotypes. FANCD2 knockdown attenuated proliferation and invasion of HCC cells. FANCD2 expression was suppressed by mTOR inhibition. GSEA supported these findings. CONCLUSION: Elevated FANCD2 expression in HCC could be a novel biomarker for poor prognosis with potential therapeutic relevance.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Perfilação da Expressão Gênica , Neoplasias Hepáticas/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Proliferação de Células , Estudos de Coortes , Dano ao DNA , Progressão da Doença , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Prognóstico , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina-Treonina Quinases TOR/metabolismo
15.
PLoS One ; 12(1): e0169609, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28072855

RESUMO

Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3ß at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-ß-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gß and 4.0% of PI3Kß, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.


Assuntos
Plaquetas/metabolismo , Quimiocina CXCL12/metabolismo , Microdomínios da Membrana/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Agregação Plaquetária , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Humanos , Fosforilação
16.
Dig Surg ; 34(4): 312-318, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27941339

RESUMO

BACKGROUND: Among several candidate genes that promote peritoneal dissemination extracted by comprehensive expression analysis of both in vivo selected metastatic cell lines and patients with gastric cancer, we focused on the chemokine (C-X-C motif) receptor (CXCR7) and explored its clinicopathological significance in gastric cancer. METHODS: CXCR7 expression was evaluated by microarray data in the Singapore cohort (n = 196) and by immunohistochemistry and reverse transcription quantitative real-time polymerase chain reaction in the Japanese cohort (n = 195). The biological function of CXCR7 in gastric cancer was explored using gene set enrichment analysis (GSEA). RESULTS: CXCR7 expression was upregulated in tumor tissues compared to normal tissues. High CXCR7 mRNA expression was associated with peritoneal dissemination and poor prognosis in the Singapore cohort. Consistent with this, the high CXCR7 mRNA expression group showed significantly poorer prognosis and a more aggressive disease course than the low expression group in the Japanese cohort. High CXCR7 mRNA expression and peritoneal dissemination were clinically relevant. GSEA revealed that CXCR7 was significantly enriched in gene expression signatures associated with tumor progression. CONCLUSIONS: CXCR7 may be a prognostic indicator and therapeutic target for gastric cancer with peritoneal dissemination.


Assuntos
Neoplasias Peritoneais/genética , RNA Mensageiro/metabolismo , Receptores CXCR/genética , Neoplasias Gástricas/genética , Idoso , Adesão Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Estudos de Coortes , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neoplasias Peritoneais/secundário , Prognóstico , Receptores CXCR/metabolismo , Singapura , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Regulação para Cima
17.
Oncotarget ; 8(64): 107666-107677, 2017 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29296196

RESUMO

Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets. In conclusion, we identified ivermectin as a potential antitumor agent and found a promising novel therapeutic strategy for inhibition of GC progression by blocking YAP1 expression.

18.
Oncology ; 92(1): 48-54, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27875818

RESUMO

Colon cancer-associated transcription 2 (CCAT2) was recently identified as a novel long noncoding RNA transcript encompassing the single-nucleotide polymorphism rs6983267. CCAT2 is overexpressed in colorectal cancer (CRC) where it promotes tumor growth, metastasis, and chromosomal instability, although the clinical relevance of this enhanced expression is unknown. In this retrospective study, CCAT2 expression was evaluated using real-time polymerase chain reaction in 149 CRC patients, and its associations with clinicopathological characteristics, outcome, rs6983267 genotypes, microsatellite status, DNA ploidy, and BubR1 expression were analyzed. CCAT2 expression in cancer tissue was significantly higher than in noncancer tissue (p < 0.001), particularly in cases of metastatic cancer (p < 0.001). However, relative CCAT2 expression levels and rs6983267 genotypes were not correlated with clinicopathological features or patient prognosis. CRC cases demonstrating high CCAT2 expression were all microsatellite stable (p < 0.005). Together, this indicates that CCAT2 expression was associated with microsatellite-stable CRC.


Assuntos
Neoplasias Colorretais/genética , RNA Longo não Codificante/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Instabilidade Cromossômica , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Estudos Retrospectivos
19.
Dig Surg ; 34(3): 192-196, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27931033

RESUMO

BACKGROUND/AIMS: Despite the development of strategies to minimize blood loss during hepatectomy challenges remain. Our aim was to determine whether low positive airway pressure (PAP) without positive end-expiratory pressure (PEEP) could minimize blood loss during hepatectomy. METHODS: Forty-one living liver donors who underwent extended left lobectomy or right lobectomy between December 2012 and November 2013 were retrospectively analyzed. In the standard PAP group (n = 18), tidal volume was 8-10 ml/kg, respiratory rate was 10-12/min and PEEP was maintained at 5 cm H2O. In the low PAP group (n = 23), tidal volume was reduced to 5 ml/kg, respiratory rate was increased to 15/min and PEEP maintained at 0 cm H2O. Low central venous pressure (CVP) was maintained during surgery in all cases. RESULTS: The low PAP group had significantly less blood loss (p = 0.0075) and shorter operation time (p = 0.0303) than the standard PAP group. In multiple regression analysis, ventilation mode and median CVP were found to be determining factors for blood loss. In no case did the ventilation mode affect perioperative management. CONCLUSIONS: Low PAP without PEEP is a safe mechanical ventilation mode that might help minimize blood loss along with CVP monitoring during hepatectomy.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Pressão Venosa Central , Hepatectomia/efeitos adversos , Respiração com Pressão Positiva/métodos , Adulto , Volume Sanguíneo , Feminino , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Taxa Respiratória , Estudos Retrospectivos , Volume de Ventilação Pulmonar , Adulto Jovem
20.
Ann Surg Oncol ; 24(3): 850-859, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27770342

RESUMO

BACKGROUND: The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC). METHODS: The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro. RESULTS: In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells. CONCLUSIONS: Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Idoso , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Metilação de DNA , Bases de Dados Genéticas , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Seguimentos , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Regiões Promotoras Genéticas , Transdução de Sinais/genética , Taxa de Sobrevida , Proteínas ras/metabolismo
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