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BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) for superficial non-ampullary duodenal tumors (SNADETs) is associated with a high rate of en bloc resection. However, the technique for ESD remains challenging. Recent studies have demonstrated the effectiveness of S-O clips in colonic and gastric ESD. We evaluated the efficacy and safety of duodenal ESD using an S-O clip for SNADETs. METHODS: Consecutive patients who underwent ESD for SNADETs between January 2011 and December 2021 were retrospectively enrolled. Propensity score matching analysis was used to compare patients who underwent duodenal ESD with the S-O clip (S-O group) and those who underwent conventional ESD (control group). Intraoperative perforation rate was the primary outcome, while procedure time and R0 resection rate were the secondary outcomes. RESULTS: After propensity score matching, 16 pairs were created: 43 and 17 in the S-O and control groups, respectively. The intraoperative perforation rate in the S-O group was significantly lower than that in the control group (p=0.033). A significant difference was observed in the procedure time between the S-O and control groups (39±9 vs. 82±30 minutes, respectively; p=0.003). CONCLUSION: The S-O clip reduced the intraoperative perforation rate and procedure time, which may be useful and effective in duodenal ESD.
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OBJECTIVE: Ovarian fibromas are benign, sex cord-stromal tumors occurring in both peri- and post-menopausal women. Generally, these tumors are non-functional and do not produce hormones. However, this case report proves the first case of steroid hormone synthesis in an ovarian fibroma by immunohistochemistry. CASE REPORT: A 77-year-old post-menopausal woman presented with a left ovarian tumor, abnormal endometrial thickness, and high levels of estradiol (E2). The tumor was found to be a fibroma, which was positive for alpha-inhibin. We examined estrogen-producing enzymes using immunohistochemistry. The tumor was positive for estrogen receptor, progesterone receptor, 17ß-hydroxysteroid dehydrogenase (HSD)-1, adrenal 4 binding protein/steroidogenic factor 1, 17ß-HSD-5, steroid sulfatase, and P450c17. CONCLUSION: This case study shows that E2 can be locally produced from circulating inactive steroids, by estrogen-producing enzymes. This is the first report of steroid hormone synthesis in an ovarian fibroma.
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Fibroma , Neoplasias Ovarianas , Feminino , Humanos , Idoso , Pós-Menopausa , Neoplasias Ovarianas/patologia , Esteroides , Estrogênios , Estradiol , Esteroide 17-alfa-Hidroxilase/metabolismoRESUMO
A 20-year-old woman was admitted with abdominal pain and a cystic liver tumor. A hemorrhagic cyst was suspected. Contrast-enhanced computed tomography(CT)and magnetic resonance imaging(MRI)revealed a space-occupying solid mass in the right lobule. Positron emission tomography(PET)-CT revealed 18F-fluorodeoxyglucose uptake in the tumor. We performed a right hepatic lobectomy. Histopathological evaluation of the resected tumor revealed an undifferentiated embryonal sarcoma of the liver(UESL). The patient refused adjuvant chemotherapy but showed no recurrence 30 months postoperatively. UESL is a rare malignant mesenchymal tumor that occurs in infants and children. It is extremely rare and is associated with poor prognosis in adults. In this report, we described a case of adult UESL.
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Neoplasias Hepáticas , Neoplasias Embrionárias de Células Germinativas , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Adulto Jovem , Hepatectomia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Sarcoma/diagnóstico por imagem , Sarcoma/cirurgia , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/cirurgiaRESUMO
Esophageal cancer after endoscopic treatment may recur depending on the risk. We present a case of a rare T1b esophageal cancer after endoscopic treatment plus chemoradiotherapy (CRT) that recurred with metastasis of the dorsal muscles. A 70-year-old man was referred for treatment of early-stage esophageal carcinoma. Endoscopic submucosal dissection (ESD) was performed and histopathology showed a poorly differentiated squamous cell carcinoma with invasion to the submucosal layer (sm2) with INFc-type invasion and positive venous invasion. After subsequent CRT, the patient was monitored every 6 months, using computed tomography (CT) and endoscopy. Fifteen months after the treatment, contrast CT revealed a spherical mass with 9 cm ring enhancement within the right erector spinae, that had squamous cell carcinoma confirmed by CT-guided biopsy. Radiation and systemic chemotherapy were initiated for the metastasis of the esophageal carcinoma. However, he died of respiratory failure due to rapid pleural effusion 26 months after ESD. Pathological autopsy showed diffuse squamous cell carcinoma invasion of the cystic wall, forming a lumbar mass, and absence of cancer cell remnants or recurrences in the esophagus. This case report emphasizes the need for systemic observation of superficial esophageal cancer after treatment with a high risk of recurrence.
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Carcinoma de Células Escamosas , Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Masculino , Humanos , Idoso , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Ressecção Endoscópica de Mucosa/métodos , Resultado do Tratamento , Quimiorradioterapia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Recidiva Local de Neoplasia/patologia , Estudos RetrospectivosRESUMO
Background and study aims Although the Japan Esophageal Society's magnifying endoscopic classification for Barrett's epithelium (JES-BE) offers high diagnostic accuracy, some cases are challenging to diagnose as dysplastic or non-dysplastic in daily clinical practice. Therefore, we investigated the diagnostic accuracy of this classification and the clinicopathological features of Barrett's esophagus cases that are difficult to diagnose correctly. Patients and methods Five endoscopists with experience with fewer than 10 cases of magnifying observation for superficial Barrett's esophageal carcinoma reviewed 132 images of Barrett's mucosa or carcinoma (75 dysplastic and 57 non-dysplastic cases) obtained using high-definition magnification endoscopy with narrow-band imaging (ME-NBI). They diagnosed each image as dysplastic or non-dysplastic according to the JES-BE classification, and the diagnostic accuracy was calculated. To identify risk factors for misdiagnosed images, images with a correct rate of less than 40â% were defined as difficult-to-diagnose, and those with 60â% or more were defined as easy-to-diagnose. Logistic regression analysis was performed to identify risk factors for difficult-to-diagnose images. Results The sensitivity, specificity and overall accuracy were 67â%, 80â% and 73â%, respectively. Of the 132 ME-NBI images, 34 (26â%) were difficult-to-diagnose and 99 (74â%) were easy-to-diagnose. Logistic regression analysis showed low-grade dysplasia (LGD) and high-power magnification images were each significant risk factors for difficult-to-diagnose images (OR: 6.80, P â=â0.0017 and OR: 3.31, P â=â0.0125, respectively). Conclusions This image assessment study suggested feasibility of the JES-BE classification for diagnosis of Barrett's esophagus by non-expert endoscopists and risk factors for difficult diagnosis as high-power magnification and LGD histology. For non-experts, high-power magnification images are better evaluated in combination with low-power magnification images.
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It has been reported that various kinds of immune checkpoint inhibitors (iCIs) could induce immune-related liver damage. We should focus on the programmed cell death-receptor-1 (PD-1) antibody and non-small cell lung cancer (NSCLC) to analyze the characteristics of hepatitis related to iCIs and find factors that could be useful biomarkers for the diagnosis. A single-center retrospective study of 252 NSCLC patients who received PD-1 antibody (nivolumab or pembrolizumab). Some of the biochemical markers and immunological markers were analyzed during PD-1-antibody treatment with or without ALT elevation. Histopathological features were reviewed by a single expert of hepatic pathology focusing on the following features: fibrosis, portal inflammation, lobular inflammation, lobular necrosis. The formation of macro- and micro-granulomas was also evaluated. The frequency of liver damage induced by nivolumab including grade 1 to 4 (ALT) was 41.9% (78/186 patients). The positive rate of anti-nuclear antibody in the nivolumab group with iCIs-related hepatitis was significantly higher than that in the nivolumab group without iCIs-related hepatitis (p = 0.00112). Granulomatous changes were significantly increased in patients with iCIs-related hepatitis compared with DILI and AIH patients (p < 0.05). The ratios of inflammatory cells CD4/CD8, and CD138/CD3 in ICIs-related hepatitis were significantly lower than those in AIH or DILI patients (p < 0.05). We demonstrated that the pre-existing ANA and characteristic liver histology including CD8+ cells dominancy and granulomatous hepatitis could be biomarkers for the diagnosis of iCIs-related hepatitis in the NSCLC with anti-PD-1 therapy.
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Carcinoma Pulmonar de Células não Pequenas , Hepatite A , Hepatite , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Granuloma/induzido quimicamente , Hepatite/patologia , Humanos , Inflamação , Neoplasias Pulmonares/patologia , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1 , Estudos RetrospectivosRESUMO
We report the rare and interesting case of cancer of unknown primary (CUP) detected by endoscopic submucosal dissection (ESD). A 67-year-old man with a gastric adenoma was referred to our hospital for endoscopic treatment. Esophagogastroduodenoscopy revealed a 15-mm submucosal tumor (SMT) at the lesser curvature of the lower gastric body, near the gastric adenoma. Both lesions were resected by ESD. Pathological examination showed that the SMT was a poorly differentiated adenocarcinoma with lymphatic tissue. Additional surgical resection was performed, and the lymph nodes were found to have the same pathological findings as the SMT. These lesions were diagnosed as CUP because the obvious primary site was not detected with additional examination. The patient has been followed up for 24 months without recurrence.
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Adenocarcinoma , Ressecção Endoscópica de Mucosa , Neoplasias Primárias Desconhecidas , Neoplasias Gástricas , Adenocarcinoma/cirurgia , Idoso , Mucosa Gástrica/cirurgia , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias Primárias Desconhecidas/cirurgia , Neoplasias Gástricas/cirurgiaRESUMO
Spindle cell carcinoma of the lung consists of only spindle-shaped tumor cells, and accounts for approximately 13.3% of all sarcomatoid carcinomas (SCs), which are a rare subtype of poorly differentiated non-small cell lung cancer (NSCLC). Spindle cell carcinoma of the lung has very poor prognosis owing to resistance to chemotherapy and radiotherapy. This case report describes a 76-year-old man who presented with complaints of dry cough and right-sided neck pain and was later diagnosed with spindle cell carcinoma of the lung. He had a medical history of type 2 diabetes, angina pectoris, atrial fibrillation, hypertension, hyperlipidemia, and hepatitis B and a 20 pack-year history of smoking. A computed tomography (CT) scan revealed a mass with a thick-walled cavity in the right upper lobe of the lung. His neck pain was consistent with PET-CT images, indicating metastases due to invasion of lung cancer cells. The expression of PD-L1 in more than 90% of the tumor cells of the lung biopsy tissue led to the administration of pembrolizumab. The lung and metastatic tumors dramatically decreased in size after 9 weeks, and no tumor regrowth was observed over 11 courses of pembrolizumab administration. To the best of our knowledge, there are no previous reports describing the use of pembrolizumab for spindle cell carcinoma of the lung. This case report suggests that immunotherapy could be a promising treatment option for rare types of lung cancers, including spindle cell carcinoma.
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BACKGROUND: The subcategory "solid component of tumor" is a new criterion of tumor categories in the updated eighth edition of the TNM classification. Nevertheless, the predictors of lymph node metastasis among patients with clinical T1 adenocarcinoma, based on the TNM classification 8th edition, remain unclear. This study aimed to identify the preoperative predictors of lymph node metastasis in clinical T1 adenocarcinoma by comparing clinicopathological characteristics between the groups with and without lymph node metastasis. METHODS: We performed a retrospective observational single-center study at the Sendai Kousei Hospital. From January 2012 to September 2019, we included 515 patients who underwent curative lobectomy or segmentectomy and mediastinal lymph node dissection among those with clinical T1 adenocarcinoma according to the UICC-TNM staging 8th edition. They were divided into two groups: those with lymph node metastasis (positive group) and those without (negative group). The clinicopathological factors were retrospectively analyzed and compared between the groups. RESULTS: In univariate analysis, carcinoembryonic antigen (>5.0 ng/mL) (P=0.0007), maximum standardized uptake (>3.5) (P<0.0001), clinical T factor (T1c) (P<0.0001), and consolidation tumor ratio (>0.85) (P<0.0001) were significant predictors of lymph node metastasis. Multivariate analysis revealed that maximum standardized uptake SUVmax (>3.5) (odds ratio =10.4, P<0.0001) was independently associated with lymph node metastasis. In univariate analysis, carcinoembryonic antigen (>5.0) (P=0.048) was the only predictor of lymph node metastasis among patients of cT1b, while no parameters were identified as significant predictors among patients of cT1c. CONCLUSIONS: SUVmax and CEA are useful preoperative predictors of lymph node metastases in patients with clinical T1 adenocarcinoma, stratified to T1b and T1c, based on the 8th TNM classification.
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BACKGROUND: Secondary aortoenteric fistula is a rare but fatal complication after reconstructive surgery for an aortic aneurysm characterized by abdominal pain, fever, hematochezia, and hematemesis, and the mortality rate is high. It has been suggested that it arises due to either continuous physical stimulation or prosthesis infection during primary surgery. We describe an aortoenteric fistula following reconstructive surgery for an abdominal aortic aneurysm together with postmortem pathological findings. CASE PRESENTATION: A 59-year-old Japanese man who had undergone reconstructive surgery for an abdominal aortic aneurysm 20 months earlier presented with the chief complaint of hematochezia and malaise. Esophagogastroduodenoscopy and total colonoscopy revealed only colon diverticula with no bleeding. Contrast-enhanced computed tomography revealed gas within the aneurysm sac and adhesion between the replaced aortic graft and intestinal tract, suggesting a graft infection. After 18 days of antibiotic treatment, he suddenly went into a state of shock, with massive fresh bloody stool and hematemesis, followed by cardiac arrest. An autopsy revealed communication between the artery and the ileum through an ulcerative fistula at the suture line between the left aortic graft branch and the left common iliac artery. Pathological analysis revealed tight adherence between the arterial and intestinal walls, but no marked sign of infection around the fistula, suggesting that the fistula had arisen due to physical stimuli. CONCLUSIONS: Pathological analysis suggested that the present secondary aortoenteric fistula arose due to physical stimuli. This reaffirms the importance of keeping reconstructed aortas isolated from the intestine after abdominal aortic aneurysm surgery.
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Aneurisma da Aorta Abdominal/cirurgia , Fístula Intestinal/etiologia , Fístula Vascular/etiologia , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Evolução Fatal , Humanos , Fístula Intestinal/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Fístula Vascular/diagnóstico por imagemAssuntos
Mucosa Gástrica/patologia , Hamartoma/diagnóstico , Hamartoma/patologia , Pólipos/diagnóstico , Pólipos/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Endoscopia do Sistema Digestório , Endossonografia , Histocitoquímica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias , Radiografia Abdominal , Tomografia Computadorizada por Raios XRESUMO
Uterine papillary serous carcinoma (UPSC) morphologically resembles ovarian serous carcinoma and is categorized as a type II endometrial cancer. UPSC comprises about 10% of all types of endometrial cancer and has an aggressive clinical course and a poor prognosis. The 14-3-3σ gene was originally discovered as a p53-inducible gene; its expression is induced by DNA damage in a p53-dependent manner, which leads to G2 arrest and repair of damaged DNA. Moreover, it has been reported that expression of 14-3-3σ is frequently lost in various types of human cancer, including ovarian cancer. We therefore examined the association between 14-3-3σ expression determined by immunohistochemistry and clinical outcomes of 51 patients with UPSC. UPSC was considered positive for 14-3-3σ when > 30% of tumor cells were stained with a specific antibody. Of these patients, 29 (58.7%) showed positive immunoreactivity for 14-3-3σ and 22 (41.3%) had decreased 14-3-3σ staining. Decreased immunoreactivity for 14-3-3σ was associated with stage (P = 0.001) and lymphovascular space involvement (P = 0.005). Moreover, decreased 14-3-3σ expression was an independent risk factor for reduced overall survival (P = 0.0416) in multivariate analysis. Direct bisulfite sequencing was performed to evaluate the methylation status of the 27 CpG islands in the promoter region and first exon of the 14-3-3σ gene. These CpG islands were hypermethylated in 30% of 14-3-3σ-positive UPSC and 80% of 14-3-3σ-negative UPSC, although the difference was not statistically significant. These findings suggest that decreased expression of immunoreactive 14-3-3σ may be a predictor of poor prognosis in patients with UPSC.
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Proteínas 14-3-3/metabolismo , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Papilar/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Exorribonucleases/metabolismo , Neoplasias Uterinas/metabolismo , Proteínas 14-3-3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Ilhas de CpG/genética , Cistadenocarcinoma Papilar/genética , Cistadenocarcinoma Papilar/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Metilação de DNA/genética , Intervalo Livre de Doença , Exorribonucleases/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Recidiva , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Útero/metabolismo , Útero/patologiaRESUMO
We analyzed the expression of the steroid and xenobiotic receptor (SXR) in human uterine sarcomas and evaluated its clinical significance. Forty-seven cases with archival specimens were examined for SXR expression using immunohistochemistry. All cases were scored using a semi-quantitative histological scoring (HSCORE) method. Specimens with a HSCORE >40 were regarded as SXR-positive. Various clinicopathological variables, including the expression status of estrogen receptor (ER)-α, progesterone receptor (PR) and Ki67 (MIB-1) were examined. The mean SXR HSCOREs of carcinosarcoma (CS) and leiomyosarcoma (LMS) were 9.13 and 23.6, respectively, and SXR-positive rates were 3 out of 24 (12.5%) and 4 out of 17 (23.5%), respectively. SXR was not detected in endometrial stromal sarcoma (ESS). In CS cases, significant differences were detected between the expression of SXR and age and disease stages. There was no significant correlation between SXR-positive status and either disease-free survival or overall survival. Our results support an association between SXR and malignant behavior. Our results show that overexpression of SXR may represent a useful marker to identify patients with advanced-stage CS. In addition, our results showed that SXR may aid in the diagnosis of uterine sarcomas.
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Aromatase inhibitors (AIs) are considered the gold standard of endocrine therapy for oestrogen receptor-positive postmenopausal breast cancer patients. AI treatment was reported to result in marked alterations of genetic profiles in cancer tissues but its detailed molecular mechanisms have not been elucidated. Therefore, we profiled miRNA expression before and after treatment with letrozole in MCF-7 co-cultured with primary breast cancer stromal cells. Letrozole significantly altered the expression profiles of cancer miRNAs in vitro. Among the elevated miRNAs following letrozole treatment, computational analysis identified let-7f, a tumour-suppressor miRNA which targeted the aromatase gene (CYP19A1) expression. Quantitative real-time PCR assay using MCF-7 and SK-BR-3 cells as well as clinical specimens of a neoadjuvant study demonstrated a significant inverse correlation between aromatase mRNA and let-7f expression. In addition, high let-7f expression was significantly correlated with low aromatase protein levels evaluated by both immunohistochemistry and the western blotting method in breast cancer cases. Results of 3'UTR luciferase assay also demonstrated the actual let-7f binding sites in CYP19A1, indicating that let-7f directly targets the aromatase gene. Subsequent WST-8 and migration assays performed in let-7f-transfected MCF-7 and SK-BR-3 cells revealed a significant decrement of their proliferation and migration. These findings all demonstrated that let-7f, a tumour suppressor miRNA in breast cancer, directly targeted the aromatase gene and was restored by AI treatment. Therefore, AIs may exert tumour-suppressing effects upon breast cancer cells by suppressing aromatase gene expression via restoration of let-7f.
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Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Aromatase/genética , Sítios de Ligação , Western Blotting , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Adjuvante , Técnicas de Cocultura , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Terapia Neoadjuvante , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Fatores de Tempo , Transfecção , Regulação para CimaRESUMO
It is well-known that estrogens immensely contribute to the progression of human breast carcinoma, but their detailed molecular mechanisms remain largely unclear. In this study, we identified nucleobindin 2 (NUCB2) as a gene associated with recurrence based on microarray data of estrogen receptor (ER)-positive breast carcinoma cases (n = 10), and subsequent in vitro study showed that NUCB2 expression was upregulated by estradiol in ER-positive MCF-7 cells. However, NUCB2 has not yet been examined in breast carcinoma, and its significance remains unknown. Therefore, we further examined the biological functions of NUCB2 in breast carcinoma using immunohistochemistry and in vitro studies. NUCB2 immunoreactivity was detected in carcinoma cells in 77 of 161 (48%) breast cancer cases, and positively associated with lymph node metastasis and ER status of the patients. In addition, NUCB2 status was significantly associated with an increased risk of recurrence and adverse clinical outcome of the patients using both univariate and multivariate analyses. Results of siRNA transfection experiments showed that NUCB2 significantly increased cell proliferation, and migration and invasion properties in both MCF-7 and ER-negative SK-BR-3 cells. These results suggest that NUCB2 is upregulated by estrogens and plays an important role, especially in the process of metastasis, in breast carcinomas. NUCB2 status is considered a potent prognostic factor in human breast cancer.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundário , Proteínas de Ligação a DNA/metabolismo , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Proteínas do Tecido Nervoso/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Neoplasias da Mama/mortalidade , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Carcinoma Ductal de Mama/mortalidade , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Estrogênios/farmacologia , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Microdissecção e Captura a Laser , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Nucleobindinas , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Estrogênio/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto JovemRESUMO
Endometrial serous adenocarcinoma (ESC) is aggressive and carries a poor prognosis. p53 is frequently mutated in ESC. microRNAs (miRNAs) are a direct p53 target and have been implicated in cancer cell behavior. In this study, we compared miRNA expression levels in ESC with the levels in endometrial endometrioid adenocarcinoma (EEC) and normal endometria. Six miRNAs were identified as having aberrant down-regulation specific to ESC with miR-34b being most pronounced. miR-34b was found to have promoter hypermethylation, which when reversed, restored miR-34b expression in the cell lines treated with 5-aza-2' deoxycytidine (DAC). Ectopic expression of miR-34b in turn inhibited cell growth, migration and most notably invasion. Our findings suggest a relationship among p53 mutation, miR-34b promoter methylation and tumor cell behavior. These effects are likely mediated by the downstream target of miR-34b, the proto-oncogene mesenchymal-epithelial transition factor (MET), a known prognostic factor in endometrial carcinomas. The expression of MET was reduced following the restoration of miR-34b in cell lines. In summary, our data suggest that miR-34b plays a role in the molecular pathogenesis of endometrial cancer.
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Adenocarcinoma/genética , Neoplasias do Endométrio/genética , Genes Supressores de Tumor , MicroRNAs/fisiologia , Adenocarcinoma/patologia , Apoptose/genética , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Ciclo Celular , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Metilação de DNA , Decitabina , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , MicroRNAs/genética , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Proto-Oncogene Mas , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Mammalian target of rapamycin (mTOR) inhibitors have been clinically used as anticancer agents in several types of human malignancies including neuroendocrine tumor (NET) but the development of clinical resistances or their therapeutic limitations have been also reported. This clinical resistance has been proposed to be partly due to a compensatory activation of an mTOR upstream factor Akt and MEK/ERK pathway in NET cells but its details have not necessarily been reported. Therefore, in this study, we examined the effects of mTOR inhibitors on these activations and of the concomitant treatment of mTOR and MEK inhibitors in two NET cell lines, NCI-H727 and COLO320. We evaluated the effects of RAD001, mTOR inhibitor, and U0126, MEK inhibitor, on cell proliferation and migration of these cells. In addition, an alteration of the factors involved in Akt/mTOR and MEK/ERK pathways was also examined under administration of these agents. RAD001 and U0126 treatment significantly inhibited cell proliferation and their combined treatment synergistically decreased it in both cell lines. Additionally, these treatments above decreased the expression of cell cycle-related factors, suggestive of an involvement of cell cycle arrest in therapeutic effects. The combined treatment also inhibited the cell migration in NCI-H727 via the decrement of MMP2 and 9 in an additive manner. We demonstrated the potential synergistic/combined effects of inhibitors of mTOR and MEK on cell proliferation and migration. These results suggest the potential therapeutic efficacy of the combined therapy of mTOR and MEK inhibitors or a dual inhibitor for the treatment of NET patients.
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Antineoplásicos/farmacologia , Butadienos/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromogranina A/metabolismo , Sinergismo Farmacológico , Everolimo , Expressão Gênica , Humanos , MAP Quinase Quinase Quinases/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Tumores Neuroendócrinos , Fosfopiruvato Hidratase/metabolismo , Sirolimo/farmacologia , Sinaptofisina , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Transporte Vesicular/metabolismoRESUMO
Nudix-type motif 2 (NUDT2) hydrolyzes diadenosine 5',5'''-p1,p4-tetraphosphate (Ap4A) associated with various cellular functions. Previous studies demonstrated its regulation through estrogens, suggesting possible importance of NUDT2 in breast carcinoma. NUDT2, however, has not been examined in malignant tissues. Therefore, we examined its expression and functions in breast carcinoma. Immunohistochemistry for NUDT2 was examined by invasive ductal carcinoma (IDC: n = 145) and pure ductal carcinoma in situ (DCIS: n = 82), and NUDT2 mRNA was examined by real-time PCR in 9 DCIS, 19 IDC and 6 non-neoplastic breast tissues. We also used T47D breast carcinoma cells in in vitro studies. NUDT2 immunoreactivity was detected in 78% of DCIS and 63% of IDC, and NUDT2 mRNA level was significantly higher in DCIS or IDC than non-neoplastic breast. NUDT2 status was significantly correlated with Van Nuys classification, HER2 or Ki-67 in DCIS, and with stage, lymph node metastasis, histological grade or HER2 in IDC. NUDT2 status was significantly associated with adverse clinical outcome of IDC patients and proved an independent prognostic factor. Results of transfection experiments demonstrated that proliferation activity of T47D cells was significantly associated with NUDT2 expression level according to the treatment of estradiol and/or tamoxifen. NUDT2 expression was significantly decreased by estradiol, and it was also significantly decreased in T47D cells transfected with HER2 siRNA. These findings suggest that NUDT2 is an estrogen-repressed gene and is also induced by HER2 pathways in breast carcinoma cells. NUDT2 promotes proliferation of breast carcinoma cells and is a potent prognostic factor in human breast carcinomas.