RESUMO
The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults. Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative/electrophilic stress conditions. Autophagy-deficient mice show aberrant accumulation of p62, a multifunctional scaffold protein, and develop severe liver damage. The p62 accumulation disrupts the Keap1-Nrf2 association and provokes Nrf2 stabilization and accumulation. However, individual contributions of p62 and Nrf2 to the autophagy-deficiency-driven liver pathogenesis have not been clarified. To examine whether Nrf2 caused the liver injury independent of p62, we crossed liver-specific Atg7::Keap1-Alb double-mutant mice into p62- and Nrf2-null backgrounds. Although Atg7::Keap1-Alb::p62(-/-) triple-mutant mice displayed defective autophagy accompanied by the robust accumulation of Nrf2 and severe liver injury, Atg7::Keap1-Alb::Nrf2(-/-) triple-mutant mice did not show any signs of such hepatocellular damage. Importantly, in this study we noticed that Keap1 accumulated in the Atg7- or p62-deficient mouse livers and the Keap1 level did not change by a proteasome inhibitor, indicating that the Keap1 protein is constitutively degraded through the autophagy pathway. This finding is in clear contrast to the Nrf2 degradation through the proteasome pathway. We also found that treatment of cells with tert-butylhydroquinone accelerated the Keap1 degradation. These results thus indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice. The autophagy pathway maintains the integrity of the Keap1-Nrf2 system for the normal liver function by governing the Keap1 turnover.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Citoesqueleto/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Enzimas de Conjugação de Ubiquitina/química , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Autofagia , Proteína 7 Relacionada à Autofagia , Proteínas do Citoesqueleto/química , Células Hep G2 , Homeostase , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteína 1 Associada a ECH Semelhante a Kelch , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Biológicos , Estresse Oxidativo , Complexo de Endopeptidases do Proteassoma/metabolismo , Fator de Transcrição TFIIH , Fatores de Transcrição/metabolismo , Ubiquitina/química , Ubiquitina-Proteína Ligases/metabolismoRESUMO
INTRODUCTION AND IMPORTANCE: Extrahepatically growing hepatocellular carcinoma (HCC) account for only 0.3 %-2.4 % of all hepatocellular carcinoma cases. We present the rare case of a patient in whom endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was used to distinguish an extrahepatically growing HCC from a gastric submucosal tumor. CASE PRESENTATION: The patient was a 44-year-old man who underwent an esophagogastroduodenoscopy (EGD) and was found to have a submucosal tumor (SMT). A gastrointestinal stromal tumor was suspected. Computed tomography (CT) showed an unclear connecting between the tumor and the liver. On immunohistochemical analysis, the tumor cells were positive for CK7, PIVKA-II, and glypican-3, and negative for C-kit. Based on these findings, HCC was suspected, and ethoxybenzyl diethylenetriamine-enhanced magnetic resonance imaging (EOB-MRI) was performed. EOB-MRI revealed the connecting of the tumor and the liver. Thus, the patient was diagnosed as having an extrahepatically protruding HCC, and laparoscopic S2 partial hepatectomy was performed. Pathologically, the tumor was identified as a moderately differentiated HCC. According to the 8th edition of the UICC TNM Classification, the tumor was classified as T1bN0M0 and stage IB. CLINICAL DISCUSSION: Owing to its rarity, the diagnosis of an extrahepatically protruding HCC is often difficult when the differentiation of a gastric SMT and HCC is unclear on CT. As in this case, if an HCC is also differentiated on hematoxylin and eosin staining after EUS-FNA, immunohistochemistry findings can help in the diagnosis. CONCLUSION: The findings show that EUS-FNA could be helpful for diagnosis when an HCC needs to be differentiated from a gastric SMT.
RESUMO
BACKGROUND: Neuroendocrine cell carcinomas (NEC) of the colon and rectum are uncommon, representing ~ 0.1% of all colorectal carcinomas. They are associated with a much worse prognosis compared to adenocarcinoma of the colon and rectum, as death occurs in approximately half of all patients within 1 year. Lynch syndrome (LS) is the most common cause of inherited colorectal cancer, accounting for 2-4% of newly diagnosed colorectal cancer cases. This case is extremely rare which was strongly suspected LS as the background, and NEC as the histological type of colorectal cancer. CASE PRESENTATION: The patient was a 44-year-old man presenting with vomiting as the main complaint. He had undergone ileocecal resection for cecal cancer at age 29. The diagnosis was obstructive descending colorectal cancer, and colonoscopy revealed tumors in the rectum and sigmoid colon in addition. Due to multiple occurrences of colorectal cancer and its prevalence in the patient's family, LS was suspected. The operation which was a subtotal proctocolectomy was performed. Pathological analysis revealed complete curative resection and the descending colon cancer of the obstructed portion was at the most advanced pathological Stage IIIC in UICC TNM classification, and the tissue type was a NEC. The Ki-67 index was 70%. The results of the microsatellite instability (MSI) test showed high-frequency MSI. The BRAF V600E variant was negative. The immunoexpression of MLH1 was positive, MSH2 was negative, PMS2 was positive, and MSH6 was negative. CONCLUSIONS: Extended surgery is recommended for incipient colorectal cancer in LS cases in order to reliably reduce the risk of developing metachronous colorectal cancer. The survival outcome of surgery alone on digestive tract NECs, even locoregional lesions that are completely resection, is extremely poor. It is currently unclear if digestive tract NECs develop more readily in patients with LS. The accumulation of additional cases is necessary.
RESUMO
We report a case of angiosarcoma of the right atrium presenting superior vena cava syndrome. The patient was a 61-year-old man. Echocardiography, CT and MRI revealed a tumor arising in the anterior wall of the right atrium. The tumor was hen-egg sized and unresectable because of the invasion of the pericardium, the right ventricular wall and the superior vena cava. An open biopsy and left brachiocephalic vein-right atrium bypass grafting were performed. The pathological diagnosis was angiosarcoma. The patient agreed to chemotherapy with docetaxel, which is known to be often effective against angiosarcoma of the scalp or face. After 5 courses of docetaxel administration (30 mg/m2 on day 1, 8 and 15 followed by 14 days. rest as one course), echocardiography and CT showed a remarkable tumor reduction, which was evaluated as a partial response. The chemotherapy was suspended for 8 months because of neutropenia and general fatigue as side effects of docetaxel. The administration of docetaxel was resumed and 4 courses were performed. The tumor, however, became resistant to docetaxel and formed metastatic involvements in the liver. Following treatments with paclitaxel, IL-2 and CPT-11 were ineffective for the primary tumor and liver metastases. He died of cardiac tamponade caused by massive hemorrhage into the pericardiac space from the tumor surface. He had long-term survival 31 months after the diagnosis. An effective treatment for cardiac angiosarcoma has not yet been established. Chemotherapy with docetaxel should be considered in the treatment of patients with cardiac angiosarcoma.