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1.
Artigo em Inglês | MEDLINE | ID: mdl-32003276

RESUMO

Background: Endoscopic submucosal tunnel dissection (ESTD) has recently been an effective procedure for resecting large early esophageal neoplasm. However, excessive dissection beyond the distal limit may occur because the prepared distal end often cannot be distinguished through the tunnel. This study aimed to assess the efficacy and safety of a novel crystal violet navigation (CVN) for identifying the distal end.Material and methods: In the observational case series study, all 22 patients who underwent esophageal ESTD using the CVN were included. When setting the distal end, the distal incision line was dyed purple using a crystal violet solution. The rates of purple color identified via the tunnel, successful tunnel penetration without extra dissection, en bloc and curative resection, procedure time for ESTD and CVN, and procedure-associated complications were evaluated.Results: The rates of purple color and successful tunnel penetration were both 100%. En bloc and curative resection were 100%, and 86%, respectively. The mean total procedure time was 103.9 ± 46.2 (mean ± SD) minutes, while the mean time for the CVN was 14.1 ± 3.44 s. No complications were observed.Conclusions: The simple CVN method can be a navigation tool for identifying the distal end during the ESTD procedure.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31905024

RESUMO

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared to nontumor tissue. We thus examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: (1) HBV-related HCC and adjacent nontumor tissue, (2) HCV-related HCC and adjacent nontumor tissue, and (3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes including HBx in the HBV-positive HCC cells. MiR-210-3p might thus be a new biomarker for the risk of HBV-related HCC.

3.
J Gastrointestin Liver Dis ; 28(4): 397-404, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31826062

RESUMO

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) has become a standard treatment for early gastric neoplasia. However, as the upper and middle body of the greater curvature has a rich vasculature and submucosal fibrosis, ESD of neoplasia in these locations requires a specific strategy. We aimed to investigate the efficacy and safety of the J-shaped superficial cutting and splashed submucosal dissection (JSCS) technique for neoplasia of the greater curvature by comparing ESD using JSCS with conventional ESD. METHODS: Twenty-two patients who underwent ESD for gastric neoplasia affecting the upper and middle body of the greater curvature were divided into two groups for retrospective analysis. Nine patients underwent conventional ESD (c-Group), while 13 underwent ESD with JSCS (j-Group). Primary outcome was the en bloc resection rate. Secondary outcomes included complete resection (R0) rate, procedure time, perforation rate, total bleeding time, and the total number of massive bleeding events and of hemostatic forceps times applied during ESD. RESULTS: There were no significant differences between both groups (c-Group vs j-Group) in en bloc resection rate, or R0 resection rate. Compared with the c-Group, the j-Group tended to have a decreased mean procedure time (mean 133 minutes vs 74 minutes, p=0.11) and perforation rate (11% vs 0%, p=0.41). Compared with the c-Group, the j-Group had significantly fewer bleeding incidents (13.4 times vs 6.6 times, p=0.0095), shorter total bleeding time (17.6 min vs 7.4 min, p=0.036), and fewer usages of hemostatic forceps (6.3 times vs 2.4 times, p=0.026) during ESD. CONCLUSION: Endoscopic submucosal dissection with JSCS is superior to conventional ESD, as it reduces intraprocedural bleeding. This technique has the potential to become the standard strategy for neoplasia affecting the upper and middle body of the greater curvature.

4.
Anticancer Drugs ; 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31815765

RESUMO

Gallbladder cancer is the most common biliary tract cancer with poor prognosis and wide variation in incidence rates worldwide, being very high in some countries in Latin America and Asia. Treatment of type 2 diabetes with metformin causes a reduction in the incidence of cancer. Till date, there are no reports on the anti-tumor effects of metformin in gall bladder cancer. Therefore, this study evaluated the effects of metformin on the proliferation of human gallbladder adenocarcinoma cells in vitro and in vivo, as well as explored the microRNAs associated with the anti-tumor effects of metformin. Metformin inhibited the proliferation in gallbladder adenocarcinoma cell lines NOZ, TGBC14TKB, and TGBC24TKB, and blocked the G0 to G1 transition in the cell cycle. This was accompanied by strong reduction in the expression of G1 cyclins, especially cyclin D1 and its catalytic subunits including cyclin-dependent kinase 4, and in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of receptor tyrosine kinases, especially Tie-2, ALK, PYK, EphA4, and EphA10, as well as angiogenesis-related proteins, including RANTES, TGF-ß, and TIMP-1. Moreover, metformin also markedly altered microRNA expression profile leading to an anti-tumor effect. Treatment of athymic nude mice bearing xenograft tumors with metformin inhibited tumor growth. These results suggest that metformin may be used clinically for the treatment of gallbladder adenocarcinoma.

5.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261874

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy. Telmisartan, an angiotensin II type 1 (AT1) receptor blocker (ARB) and a widely used antihypertensive, has been shown to inhibit proliferation of various cancer types. This study evaluated the effects of telmisartan on human ESCC cell proliferation in vitro and in vivo and sought to identify the microRNAs (miRNAs) involved in these antitumor effects. We examined the effects of telmisartan on three human ESCC cell lines (KYSE150, KYSE180, and KYSE850). Telmisartan inhibited proliferation of these three cell lines by inducing S-phase arrest, which was accompanied by decreased expression of cyclin A2, cyclin-dependent kinase 2, and other cell cycle-related proteins. Additionally, telmisartan reduced levels of phosphorylated ErbB3 and thrombospondin-1 in KYSE180 cells. Furthermore, expression of miRNAs was remarkably altered by telmisartan in vitro. Telmisartan also inhibited tumor growth in vivo in a xenograft mouse model. In conclusion, telmisartan inhibited cell proliferation and tumor growth in ESCC cells by inducing cell-cycle arrest.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Fase S/efeitos dos fármacos , Telmisartan/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Linhagem Celular Tumoral , Ciclina A2/genética , Ciclina A2/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Telmisartan/uso terapêutico , Trombospondina 1/genética , Trombospondina 1/metabolismo
6.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146370

RESUMO

Galectin-9 (Gal-9) enhances tumor immunity mediated by T cells, macrophages, and dendritic cells. Its expression level in various cancers correlates with prognosis. Furthermore, Gal-9 directly induces apoptosis in various cancers; however, its mechanism of action and bioactivity has not been clarified. We evaluated Gal-9 antitumor effect against esophageal squamous cell carcinoma (ESCC) to analyze the dynamics of apoptosis-related molecules, elucidate its mechanism of action, and identify relevant changes in miRNA expressions. KYSE-150 and KYSE-180 cells were treated with Gal-9 and their proliferation was evaluated. Gal-9 inhibited cell proliferation in a concentration-dependent manner. The xenograft mouse model established with KYSE-150 cells was administered with Gal-9 and significant suppression in the tumor growth observed. Gal-9 treatment of KYSE-150 cells increased the number of Annexin V-positive cells, activation of caspase-3, and collapse of mitochondrial potential, indicating apoptosis induction. c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) phosphorylation were activated and could be involved in apoptosis. Therefore, Gal-9 induces mitochondria-mediated apoptosis of ESCC and inhibits cell proliferation in vitro and in vivo with JNK and p38 activation.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Galectinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Esofágicas/tratamento farmacológico , Galectinas/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo
7.
Oncol Lett ; 15(1): 407-414, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29387226

RESUMO

Pancreatic cancer is the eighth-leading cause of cancer-associated mortality in males and the ninth-leading cause in females worldwide. Even when diagnosed early enough to be potentially resectable, the prognosis of invasive pancreatic cancer is poor. Galectin-9 (Gal-9) is a tandem-repeat type galectin that has recently been demonstrated to possess an anti-proliferative effect on cancer cells. Therefore, the present study evaluated the effects of Gal-9 on the proliferation of human pancreatic cancer cells and examined the microRNAs that are associated with the antitumor effects of Gal-9. Gal-9 suppressed the proliferation of multiple pancreatic cancer cell lines. In addition, Gal-9 treatment increased the levels of caspase-cleaved keratin 18 and the expression of cytochrome c in pancreatic cancer cell lines. This data suggests that Gal-9 induces intrinsic apoptosis in pancreatic cancer cell lines through the caspase-dependent and caspase-independent pathways. In addition, Gal-9 reduced the expression levels of phosphorylated epidermal growth factor receptor and numerous receptor tyrosine kinases (RTKs). In conclusion, Gal-9 may suppress the growth of human pancreatic cancer cells in vitro. These findings suggest that Gal-9 may be a new therapeutic agent for the treatment of pancreatic cancer.

8.
Oncol Lett ; 15(1): 528-532, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29391887

RESUMO

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Although the clinical success rate for the treatment of early-stage HCC has improved, the prognosis of advanced HCC remains poor owing to the high recurrence rate and the refractory nature of HCC for various anticancer drugs. A better understanding of the pathogenesis of HCC is therefore critically needed in order to treat HCC, including its genetic alterations. Next-generation sequencing (NGS) has provided an unbiased platform to systematically identify gene mutations and reveal the pathogenesis of various cancers. In the present study, a total of 118 samples (59 liver tissues including cancer and adjacent normal tissues) were sequenced using the AmpliSeq Hotspot Cancer Panel (version 2). The most common somatic mutations identified were tumor protein 53 (TP53; 35.6%) and ß-catenin 1 (CTNNB1; 30.5%), and the most frequent variants of those genes were missense variants. In addition, somatic mutations including those in genes encoding colony-stimulating factor 1 receptor (5.1%), epidermal growth factor receptor (6.8%), RET proto-oncogene (3.4%), Erb-B2 receptor tyrosine kinase 4 (ERBB4; 1.7%) and serine/threonine kinase 11 (STK11, also known as liver kinase B1; 6.8%) were also identified at a low frequency in patients with HCC. A frameshift variant in STK11, a splice acceptor variant in TP53, a splice region variant in ERBB4 and a stop-gained variant in TP53 were also specifically determined. The most abundant alteration was a C:G>T:A transition (50%) and other transversions, i.e., C:G>G:C (19.6%), T:A>C:G (19.6%), C:G>A:T (12.5%), T:A>G:C (12.5%) and T:A>A:T (5.4%). This spectrum pattern differs from that in other solid tumors. TP53 mutations in the tumors at advanced stages were significantly more frequent compared with those in early-stage tumors. Additionally, age (<70 vs. ≥70 years) was significantly associated with CTNNB1 mutations. Using NGS, a number of novel gene mutations were identified in HCC, including established mutations and disproved mutations. The results of the present study offer new insight and improved understanding of the etiology and the development of HCC.

9.
Oncol Rep ; 38(5): 2825-2835, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29048654

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third leading cause of cancer-related death. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB) that might inhibit cancer cell proliferation, but the mechanisms through which telmisartan affects various cancers remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human HCC and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on HCC cells using the HLF, HLE, HepG2, HuH-7 and PLC/PRF/5 cell lines. In our experiments, telmisartan inhibited the proliferation of HLF, HLE and HepG2 cells, which represent poorly differentiated types of HCC cells. However, HuH-7 and PLC/PRF/5 cells, which represent well-differentiated types of HCC cells, were not sensitive to telmisartan. Telmisartan induced G0/G1 cell cycle arrest of HLF cells by inhibiting the G0-to-G1 cell cycle transition. This blockade was accompanied by a marked decrease in the levels of cyclin D1, cyclin E and other cell cycle-related proteins. Notably, the activity of the AMP-activated protein kinase (AMPK) pathway was increased, and the mammalian target of rapamycin (mTOR) pathway was inhibited by telmisartan treatment. Additionally, telmisartan increased the level of caspase-cleaved cytokeratin 18 (cCK18), partially contributed to the induction of apoptosis in HLF cells and reduced the phosphorylation of ErbB3 in HLF cells. Furthermore, miRNA expression was markedly altered by telmisartan in vitro. In conclusion, telmisartan inhibits human HCC cell proliferation by inducing cell cycle arrest.


Assuntos
Benzimidazóis/farmacologia , Benzoatos/farmacologia , Carcinoma Hepatocelular/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/tratamento farmacológico , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/genética , Telmisartan
10.
Int J Oncol ; 51(6): 1674-1684, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29075786

RESUMO

Cholangiocarcinoma (CCA) is at an advanced stage at the time of its diagnosis, and developing a more effective treatment of CCA would be desirable. Angiotensin II type 1 (AT1) receptor blocker (ARB), telmisartan may inhibit cancer cell proliferation, but the mechanisms by which telmisartan affects various cancers remain unknown. In this study, we evaluated the effects of telmisartan on human CCA cells and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on CCA cells using two cell lines, HuCCT-1 and TFK-1. In our experiments, telmisartan inhibited the proliferation of HuCCT-1 and TFK-1 cells. Additionally, telmisartan induced G0/G1 cell cycle arrest via blockade of the G0 to G1 cell cycle transition. Notably, telmisartan did not induce apoptosis in HuCCT-1 cells. This blockade was accompanied by a strong decrease in cell cycle-related protein, especially G1 cyclin, cyclin D1, and its catalytic subumits, Cdk4 and Cdk6. Telmisartan reduced the phosphorylation of EGFR (p-EGFR) and TIMP-1 by using p-RTK and angiogenesis array. Furthermore, miRNA expression was markedly altered by telmisartan in HuCCT-1. Telmisartan inhibits tumor growth in CCA xenograft model in vivo. In conclusion, telmisartan was shown to inhibit human CCA cell proliferation by inducing cell cycle arrest.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/irrigação sanguínea , Neoplasias dos Ductos Biliares/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colangiocarcinoma/irrigação sanguínea , Colangiocarcinoma/patologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/biossíntese , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Distribuição Aleatória , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Telmisartan , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Endosc Int Open ; 5(8): E695-E705, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28782002

RESUMO

BACKGROUND AND STUDY AIMS : Endoscopic ultrasound-guided fine needle aspiration (FNA) for gastrointestinal subepithelial lesions (SELs) has limited diagnostic accuracy due to technical problems and small lesion size. We previously reported a novel submucosal tunneling biopsy (STB) technique for sampling SELs. This study aimed to evaluate the diagnostic ability and safety of STB compared to that of FNA for SELs. PATIENTS AND METHODS : The study was a non-randomized, prospective comparative study with crossover design in patients with endoluminal gastric SELs. Forty-three patients, including 29 cases with lesions < 2 cm were enrolled. A crossover design with 2 intervention stages (Group A: FNA followed by STB for 23 SELs, Group B: STB followed by FNA for 20 SELs) was implemented. The primary outcome was the diagnostic yield (DY). Secondary outcomes were technical success rate, procedure time, complication rate, and sample quality. RESULTS : The DY of STB was significantly higher than that of FNA (100 % vs. 34.8 %; P  < 0.0001) in group A, including 100 % in overall STB. The technical success rate of STB was significantly higher than that of FNA (100 % vs. 56.5 %; P  = 0.0006), whereas the median procedure time of STB was significantly longer than that of FNA (37 minutes vs. 18 minutes; P  < 0.0001). The median specimen area of STB samples was markedly larger than that of FNA samples (5.54 mm 2 vs. 0.69 mm 2 ; P  < 0.001). No complications occurred in either method. CONCLUSIONS: STB had significantly superior diagnostic ability and a more adequate sample quality than FNA for endoluminal gastric SELs, indicating the suitability of STB for small SELs. CLINICAL TRIAL REGISTRATION: UMIN 000006754.

12.
Oncol Lett ; 14(1): 355-362, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28693176

RESUMO

Narrow band imaging with magnifying endoscopy (NBI-ME), which is useful for the assessment of micro-vessels, has excellent diagnostic potential for early gastrointestinal epithelial neoplasia. Conventional diagnostic tools for uterine cervical epithelial tumors are still unsatisfactory. An accurate diagnostic tool for uterine cervical epithelial tumors is required to preserve the reproductive ability of young women with uterine cervical tumors. Flexible NBI-ME was performed in patients with cervical squamous cell lesions that required further examinations based on their Pap smear results (cytology ≥ low-grade squamous intraepithelial lesion) at Kagawa University Hospital between April 2014 and April 2015. NBI-ME results concordant with the punch biopsy sites were compared with the histological results. A retrospective review of the NBI-ME images identified abnormal NBI-ME results regarding micro-vascular patterns. All images were categorized as having abnormal features. NBI-ME revealed the following vascular pattern differences of different stage tumors: Dot-like vessels without irregular arrangements and high density in cervical intraepithelial neoplasia (CIN) CIN1-CIN2; dot-like vessels with irregular arrangements and high density in CIN3-carcinoma in situ; crawling vessels in minimum invasive cancer; and willow branch vessels and new tumor vessels in invasive cancer. NBI-ME may be an effective diagnostic tool for uterine cervical epithelial tumors, which may lead to the establishment of a novel classification system.

13.
Int J Oncol ; 51(2): 607-614, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28656219

RESUMO

Liver metastasis from gastrointestinal cancer defines a patient's prognosis. Despite medical developments, pancreatic cancer with liver metastasis confers a very poor prognosis. Galectin-9 (Gal­9) is a tandem-repeat-type galectin that has recently been demonstrated to exert antitumor effects on various types of cancer cells by inducing apoptosis. However, the apoptotic pathway of Gal­9 in solid tumors is unclear. The aim of the present study was to evaluate the effects of Gal­9 on human liver metastasis from pancreatic cancer. Gal­9 suppressed cell proliferation in metastatic liver cancer cell lines derived from pancreatic cancer (KMP2, KMP7, and KMP8) and increased the levels of caspase-cleaved keratin 18 and fluorescein isothiocyanate (FITC)-conjugated Annexin V. Furthermore, expression of apoptosis-related molecules such as caspase-7, cleaved caspase-3, cleaved PARP, cytochrome c, Smac/Diablo and HtrA2/Omi was enhanced. However, Gal­9 did not affect expression of various cell cycle-related proteins. The microRNA (miRNA) expression profile was markedly altered by Gal­9, and various miRNAs might contribute to tumor growth suppression. Our data reveal that Gal­9 suppresses the growth of liver metastasis, possibly by inducing apoptosis through a mechanism involving mitochondria and changes in miRNA expression. Thus, Gal­9 might serve as a therapeutic agent for the treatment of liver metastasis from pancreatic cancer.


Assuntos
Galectinas/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Galectinas/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , MicroRNAs/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Metástase Neoplásica , Neoplasias Pancreáticas/patologia
14.
Oncol Rep ; 38(1): 506-514, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28586026

RESUMO

The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing in western countries. The overall mortality of this disease remains high with a 5-year survival rate of less than 20%, despite remarkable advances in the care of patients with EAC. Galectin-9 (Gal-9) is a tandem-repeat type galectin that exerts anti-proliferative effects on various cancer cell types. The aim of the present study was to evaluate the effects of Gal-9 on human EAC cells and to assess the expression of microRNAs (miRNAs) associated with the antitumor effects of Gal-9 in vitro. Gal-9 suppressed the proliferation of the EAC cell lines OE19, OE33, SK-GT4, and OACM 5.1C. Additionally, Gal-9 treatment induced apoptosis and increased the expression levels of caspase-cleaved cytokeratin 18, activated caspase-3 and activated caspase-9. However, it did not promote cell cycle arrest by reducing cell cycle-related protein levels. Furthermore, Gal-9 increased the level of the angiogenesis-related protein interleukin-8 (IL-8) and markedly altered miRNA expression. Based on these findings, Gal-9 may be of clinical use for the treatment of EAC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Galectinas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/metabolismo , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Autofagia , Caspase 3/metabolismo , Caspase 9/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Galectinas/genética , Galectinas/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Interleucina-8/metabolismo , Queratina-18/metabolismo , MicroRNAs/isolamento & purificação , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
15.
Int J Oncol ; 50(6): 2145-2153, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440424

RESUMO

Small bowel adenocarcinoma (SBAC) accounts for 3% of all gastrointestinal tract tumors and approximately 0.5% of all cancer cases. Recent studies have indicated that the use of metformin, one of the most commonly prescribed antidiabetic drugs, is associated with a better prognosis for certain malignant diseases. However, there have been no reports on the effect of metformin in SBAC. In the present study, we evaluated the effect of metformin on human SBAC cell proliferation in vitro and in vivo and identified the microRNAs (miRNAs) associated with its antitumor effects. Metformin inhibited the proliferation of HuTu80 cells in a time- and dose-dependent manner. Importantly, metformin reduced the expression of cyclin D1, cyclin E, cyclin-dependent kinase 4, and phosphorylated retinoblastoma protein, which resulted in cell cycle arrest at the G0/G1 phase. This arrest was accompanied by activation of AMPKα and inhibition of mammalian target of rapamycin and p70s6k. Additionally, metformin reduced the levels of phosphorylated epidermal growth factor receptor and ROR2 as well as markedly altered miRNA expression in HuTu80 cells. Metformin also inhibited tumor growth in vivo in a xenograft mouse model. Our data suggest that metformin might have therapeutic potential in SBAC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Gastrointestinais/tratamento farmacológico , Metformina/administração & dosagem , Proteínas de Neoplasias/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1 , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Fosforilação , Ensaios Antitumorais Modelo de Xenoenxerto
16.
World J Gastroenterol ; 23(9): 1645-1656, 2017 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-28321166

RESUMO

AIM: To demonstrate the clinical outcomes of a multicenter experience and to suggest guidelines for choosing a suction method. METHODS: This retrospective study at 5 medical centers involved 58 consecutive patients undergoing over-the-scope clips (OTSCs) placement. The overall rates of technical success (TSR), clinical success (CSR), complications, and procedure time were analyzed as major outcomes. Subsequently, 56 patients, excluding two cases that used the Anchor device, were divided into two groups: 14 cases of simple suction (SS-group) and 42 cases using the Twin Grasper (TG-group). Secondary evaluation was performed to clarify the predictors of OTSC success. RESULTS: The TSR, CSR, complication rate, and median procedure time were 89.7%, 84.5%, 1.8%, and 8 (range 1-36) min, respectively, demonstrating good outcomes. However, significant differences were observed between the two groups in terms of the mean procedure time (5.9 min vs 14.1 min). The CSR of the SS- and TG-groups among cases with a maximum defect size ≤ 10 mm and immediate or acute refractory bleeding was 100%, which suggests that SS is a better method than TG in terms of time efficacy. The CSR in the SS-group (78.6%), despite the technical success of the SS method (TSR, 100%), tended to decrease due to delayed leakage compared to that in the TG-group (TSR, CSR; 88.1%), indicating that TG may be desirable for leaks and fistulae with defects of the entire layer. CONCLUSION: OTSC system is a safe and effective therapeutic option for gastrointestinal defects. Individualized selection of the suction method based on particular clinical conditions may contribute to the improvement of OTSC success.


Assuntos
Fístula do Sistema Digestório/cirurgia , Hemorragia Gastrointestinal/cirurgia , Sucção/métodos , Instrumentos Cirúrgicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Endoscopia , Endoscopia Gastrointestinal/métodos , Desenho de Equipamento , Feminino , Hemorragia/cirurgia , Hemostase Endoscópica/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
17.
Oncotarget ; 8(5): 8536-8549, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28052030

RESUMO

Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB). This drug inhibits cancer cell proliferation, but the underlying mechanisms in various cancers, including esophageal cancer, remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human esophageal cancer cell proliferation in vitro and in vivo. We assessed the effects of telmisartan on human esophageal adenocarcinoma (EAC) cells using the cell lines OE19, OE33, and SKGT-4. Telmisartan inhibited the proliferation of these three cell lines via blockade of the G0 to G1 cell cycle transition. This blockade was accompanied by a strong decrease in cyclin D1, cyclin E, and other cell cycle-related proteins. Notably, the AMP-activated protein kinase (AMPK) pathway, a fuel sensor signaling pathway, was enhanced by telmisartan. Compound C, which inhibits the two catalytic subunits of AMPK, enhanced the expression of cyclin E, leading to G0/G1 arrest in human EAC cells. In addition, telmisartan reduced the phosphorylation of epidermal growth factor receptor (p-EGFR) and ERBB2 in vitro. In our in vivo study, intraperitoneal injection of telmisartan led to a 73.2% reduction in tumor growth in mice bearing xenografts derived from OE19 cells. Furthermore, miRNA expression was significantly altered by telmisartan in vitro and in vivo. In conclusion, telmisartan suppressed human EAC cell proliferation and tumor growth by inducing cell cycle arrest via the AMPK/mTOR pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adenocarcinoma/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Fosforilação , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Telmisartan , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
World J Gastroenterol ; 22(13): 3558-63, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27053847

RESUMO

AIM: To apply the laparoscopic and endoscopic cooperative surgery concept, we investigated whether endoscopic cholecystectomy could be performed more safely and rapidly via only 1 port or not. METHODS: Two dogs (11 and 13-mo-old female Beagle) were used in this study. Only 1 blunt port was created, and a flexible endoscope with a tip attachment was inserted between the fundus of gallbladder and liver. After local injection of saline to the gallbladder bed, resection of the gallbladder bed from the liver was performed. After complete resection of the gallbladder bed, the gallbladder was pulled up to resect its neck using the Ring-shaped thread technique. The neck of the gallbladder was cut using scissor forceps. Resected gallbladder was retrieved using endoscopic net forceps via a port. RESULTS: The operation times from general anesthetizing with sevoflurane to finishing the closure of the blunt port site were about 50 min and 60 min respectively. The resection times of gallbladder bed were about 15 min and 13 min respectively without liver injury and bleeding at all. Feed were given just after next day of operation, and they had a good appetite. Two dogs are in good health now and no complications for 1 mo after endoscopic cholecystectomy using only a flexible endoscope via one port. CONCLUSION: We are sure of great feasibility of endoscopic cholecystectomy via single port for human.


Assuntos
Colecistectomia Laparoscópica/instrumentação , Colecistectomia Laparoscópica/métodos , Colecistectomia/instrumentação , Colecistectomia/métodos , Endoscópios , Endoscopia do Sistema Digestório/instrumentação , Animais , Perda Sanguínea Cirúrgica/prevenção & controle , Colecistectomia/efeitos adversos , Colecistectomia Laparoscópica/efeitos adversos , Cães , Endoscopia do Sistema Digestório/efeitos adversos , Desenho de Equipamento , Feminino , Modelos Animais , Duração da Cirurgia , Maleabilidade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Fatores de Tempo
20.
Oncol Rep ; 35(2): 851-60, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26717877

RESUMO

Gastric cancer is the second-leading cause of cancer-related mortality worldwide, and the prognosis of advanced gastric cancer remains poor. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has recently been demonstrated to exert anti-proliferative effects on various types of cancer cells. The aim of our present study was to evaluate the effects of Gal-9 on human gastric cancer cells and the expression levels of microRNAs (miRNAs) associated with the antitumor effects of Gal-9 in vitro. In our initial experiments, Gal-9 suppressed the proliferation of gastric cancer cell lines in vitro. Our data further revealed that Gal-9 increased caspase-cleaved keratin 18 (CCK18) levels in gastric cancer cells. Additionally, Gal-9 reduced the phosphorylation of vascular endothelial growth factor receptor-3 (VEGFR-3) and insulin-like growth factor-1 receptor (IGF-1R). Furthermore, miRNA expression levels were markedly altered with Gal-9 treatment in vitro. In conclusion, Gal-9 suppressed the proliferation of human gastric cancer cells by inducing apoptosis. These findings suggest that Gal-9 could be a potential therapeutic target in the treatment of gastric cancer.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galectinas/farmacologia , Neoplasias Gástricas/patologia , Apoptose/fisiologia , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas In Vitro , Análise de Sequência com Séries de Oligonucleotídeos
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