Miki Tomoeda

Insulin Receptor Substrate 1/2 (IRS1/2) Regulates Wnt/β-Catenin Signaling through Blocking Autophagic Degradation of Dishevelled2

Background: IRS1/2 is a critical component of insulin signaling, but it remains unclear whether IRS1/2 functions on Wnt signaling. Results: IRS1/2 interacts with and stabilizes Dvl2 by suppressing its autophagic degradation, leading to promotion of Wnt-mediated EMT and cell proliferation. Conclusion: IRS1/2 positively regulates Wnt/β-catenin signaling through Dvl2. Significance: The IRS1/2-Dvl2 node might be implicated in tumorigenesis and metastasis. Wnt signaling plays a pivotal role in cell proliferation, tissue homeostasis, and tumorigenesis. Dishevelled (Dvl) is a central node of Wnt signaling. Insulin receptor substrates (IRSs), as a critical component of insulin signaling, are involved in cell proliferation, metabolism, and cancer development. In this study, we report that IRS1/2 promotes Wnt/β-catenin signaling by stabilizing Dvl2. We found that IRS1/2 interacts with Dvl2. Overexpression of IRS1/2 increased the protein level of Dvl2 and promoted canonical Wnt signaling, as evidenced by the increased T cell-specific factor 4 transcriptional activity and the up-regulation of expression of CYCLIN D1 and c-MYC, two Wnt target genes critical for cell growth, whereas depletion of IRS1/2 reduced the level of Dvl2 and attenuated Wnt/β-catenin signaling. Biochemical analyses revealed that IRS1/2 decreased Lys-63-linked ubiquitination of Dvl2 and stabilized Dvl2 protein via suppressing its autophagy-mediated degradation. We further revealed that IRS1/2 blocks autophagy-induced formation of the Dvl2-p62/SQSTM1 complex, resulting in disabled association of Dvl2 to autophagosomes. We demonstrated that IRS1/2 promoted the induction of epithelial-mesenchymal transition (EMT) and cell proliferation in response to Wnt stimulation, whereas depletion of Dvl2 impaired the IRS1/2-mediated EMT and cell growth. Our findings revealed that IRS1/2 promotes EMT and cell proliferation through stabilizing Dvl2.

Pancreatic fatty degeneration and fibrosis as predisposing factors for the development of pancreatic ductal adenocarcinoma.

Objectives Knowledge of risk factors for development of pancreatic ductal adenocarcinoma (PDAC) is limited. To clarify the background condition of the pancreas for the development of PDAC, we analyzed pancreatic histological changes in noncancerous lesion specimens after pancreatectomy in PDAC patients. Methods Seventy-six patients with PDAC were enrolled in this study. The PDAC was in the pancreatic head in 37 patients, in the body in 31, and in the tail in 8. No patients had a history of clinical chronic pancreatitis. As controls, 98 patients without PDAC were enrolled. The following parameters were examined: fibrosis, fatty degeneration, and inflammatory cell infiltration. More than 5% of fatty degeneration in the specimen, more than 10% of fibrosis, and more than 5% of inflammatory cell infiltration were considered positive changes. Results Pancreatectomy specimens showed a higher ratio of positive change in fibrosis (86% vs 42%), fatty degeneration (72% vs 44%), and inflammatory cell infiltration (14% vs 3%) than control samples. Multivariate analyses demonstrated that each histological change was a significant, independent determinant for PDAC. Conclusions Our study demonstrated that cryptogenic pancreatic inflammation with fatty changes represents an important predisposing factor for PDAC. Screening for subclinical chronic pancreatitis in healthy populations may enable the detection of PDAC at an early stage.

Influential factors in procedure time of endoscopic submucosal dissection for gastric cancer with fibrotic change.

Background:  Factors correlating with the technical difficulty of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) are still unclear. EGC coexisting with fibrosis inside lesions has been a common therapeutic indication for ESD. The aim of this study was to clarify the most important factor related to difficult ESD for EGC.

Malignant mesothelioma of the peritoneum invading the liver and mimicking metastatic carcinoma: a case report.

We present a case of malignant mesothelioma of the peritoneum with massive direct invasion to the liver in a 58-year-old Japanese woman. She had no history of asbestos exposure or other malignancies. Abdominal computed tomography revealed one 8-cm intrahepatic mass adjacent to the abdominal wall with peritoneal thickening, multiple smaller nodules in the peritoneal cavity, and intra-abdominal lymphadenopathy. Liver biopsy showed a small cluster of atypical cells similar to epithelial neoplasm, which formed a tubulopapillary structure. The tumor cells were positive for calretinin with strong nuclear and cytoplasmic expression together with podoplanin (D2-40) and some cytokeratins, but were negative for hepatocyte paraffin 1 and other adenocarcinoma markers. We confirmed a diffuse peritoneal mesothelioma with direct invasion to the liver. Liver masses with other peritoneal nodules are mostly encountered as metastatic diseases. However, the possibility of mesothelioma should be considered, even in women without an apparent history of asbestos exposure.

Malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart: a case report

A rare case is presented of a 61-year-old man with a malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart. The primary tumor originated in the right thigh in 1982. Since then, the patient has had repeated local recurrences in spite of repeated surgical treatment and adjuvant chemotherapy. He has developed previous metastases of the lung and heart. The patient died of cardiac involvement.

Role of Meis1 in mitochondrial gene transcription of pancreatic cancer cells.

Pre-B-cell leukemia transcription factor (PBX)/three-amino-acid loop extension (TALE) class transcription factors [PBX1-4, Meis homeobox (Meis) 1-3, pbx/knotted 1 homeobox (Prep) 1, 2] are involved in tumorigenesis and metastasis. To investigate further the function of PBX/TALE class transcription factors, mRNA expression profile after downregulation of each mRNA expression by siRNA transfection in pancreatic cancer cell line, Panc-1, was examined. Downregulation of Meis1 resulted in downregulation of mitochondrial genes, but those of PBX1 and PBX2 did not. Quantitative reverse transcription polymerase chain reaction confirmed downregulation of mitochondrial genes by Meis1 siRNA transfection. Chromatin immunoprecipitation assay revealed the binding of Meis1 to the mitochondrial promoter region that contained the putative Meis1 binding site. Luciferase reporter assay showed the increase of luciferase activity of a construct containing the Meis1 binding site compared with that with shorter fragment without Meis1 binding region. These findings indicate that Meis1 works as a transcription factor for mitochondrial genes in pancreatic cancer cells.

Prognostic Significance of Phosphorylated FOXO1 Expression in Soft Tissue Sarcoma

BackgroundForkhead box O1 (FOXO1; forkhead in rhabdomyosarcoma, FKHR) is a key transcription factor that regulates the cell cycle and apoptosis, and therefore is considered to be involved in cell transformation and tumorigenesis. Expression of FOXO1 in soft tissue sarcoma (STS) and its correlation with clinicopathological factors and prognostic significance were evaluated.MethodsExpression of phosphorylated FOXO1 (p-FOXO1) in localized STS from 84 adult patients, 50 male and 34 female, aged 15–89 (median 54) years, was evaluated by immunohistochemistry. Staining intensity of p-FOXO1 in the tumors was judged separately for the nucleus and cytoplasm and categorized as follows: level 0, absent or faint staining; level 1, weaker than that of endothelial cells in the same specimen; and level 2, equal to or stronger than that of endothelial cells.ResultsTwenty-three (27.3%), 26 (31.0%), and 35 (41.7%), and 32 (38.1%), 30 (35.7%), and 22 (26.2%) of the tumors showed level 0, 1, and 2 expression of p-FOXO1 for the nucleus and cytoplasm, respectively. Nuclear p-FOXO1 expression correlated with mitotic count, and cytoplasmic p-FOXO1 expression with histological subtype, mitotic count, cellularity, myxoid change, Ki-67 labeling index, histological grade, American Joint Committee on Cancer stage, and patient age. Multivariate analysis revealed nuclear and cytoplasmic p-FOXO1 expression, mitotic count, and tumor size to be independent prognostic indicators for overall survival, and cytoplasmic p-FOXO1 expression for disease-free survival, respectively.ConclusionsThe prognostic significance of p-FOXO1 expression level in STS was demonstrated.

Intraductal polypoid growth variant of pancreatic acinar cell carcinoma metastasizing to the intrahepatic bile duct 6 years after surgery: A case report and literature review

We present the first reported case of intraductal polypoid growth (IPG) variant of pancreatic acinar cell carcinoma (ACC) metastasizing to the intrahepatic bile duct. A 58-year-old Japanese woman had previously presented with obstructive jaundice and a 7.0 cm mass in the pancreatic head. She underwent biliary drainage for 2 months followed by pancreatectomy. Histological examination revealed a carcinoma with acinar pattern, immunohistochemically positive for trypsin, and acinar cell carcinoma was diagnosed. IPGs were prominent in the main pancreatic duct and its tributaries, extending into the intrapancreatic bile duct with tumor casts in the lumen. Imaging examinations 6 years later revealed a growing lesion within the intrahepatic bile duct. Needle biopsy examination suggested metastasis of ACC, and she underwent chemoradiation therapy and partial hepatectomy. Histological examination demonstrated ACC confined to the intrahepatic bile duct. The localization of metastasis and slow growth may indicate indolent biologic behavior of the IPG variant.

Factors Affecting Recurrence of T1 and T2 Tongue Cancer Undergoing Intraoral Resection

1.1. Background: Intraoral resection of early tongue cancer minimally affects the quality of life (QOL) of patients; however, local recurrence of the tumor requires radical resection and negatively affects QOL as well as patient prognosis. The present study was performed to clarify factors affecting recurrence of tongue cancers undergoing intraoral resection. 1.2. Methods: In total, 174 patients (T1: 105 patients and T2: 69 patients) with squamous cell carcinoma of the tongue receiving intraoral resection were enrolled in the study, including 106 male patients and 68 female patients (aged 27-88 years, mean 58 years). Tumor recurrence was observed in 10 of 105 patients with T1 stage cancer (9.5%) and in 6 of 69 patients with T2 stage cancer (8.7%). The clinicopathological factors, including immunohistochemistry for p53, Ki67, and vimentin, were analyzed. 1.3. Results: An infiltration pattern and vimentin expression were associated with tongue cancer recurrence. Specifically, tumors with positive vimentin expression exhibited a higher ratio of endophytic growth, and multivariate analysis revealed that the Ki67 labeling index and vimentin expression were independent factors affecting tumor recurrence. 1.4. Conclusion: The mode of tumor invasion and the epithelial-to-mesenchymal transition, as evidenced by vimentin immunohistochemistry, assisted the identification of high-risk patients with tongue cancer undergoing intraoral resection. Intense follow-up with the aid of multimodal therapies after surgery is necessary in this group of high-risk patients.

Role of antioxidant vitamins administration on the oxidative stress

The health-promoting effects of antioxidant vitamins C and E supplementation are unclear. This study investigated the effects of vitamins C and E on the activities of reactive oxygen species (ROS)-scavenging enzymes and protein and lipid peroxidation statuses under resting and exercise-induced conditions. Thirteen healthy, previously untrained males (age 20–21 years) participated in this study. Seven subjects performed physical exercise using a cycle ergometer, and six performed a 6-min walk test (6MWT) prior to vitamin administration and after 1-week oral administration of vitamin C (1000 mg/day) and vitamin E (300 IU/day). Venous blood samples were collected before and after exercise. Plasma vitamin C concentration, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, and protein carbonyl and thiobarbituric acid-reactive substance (TBARS) contents were measured. Antioxidant supplementation increased vitamin C concentration by 34% (p<0.05), decreased SOD activity by 17% (p<0.05), increased GPx activity by 13% (p<0.05), and increased the GPx/SOD activity ratio by 37% (p<0.05). Protein carbonyl and TBARS contents were unaffected. Antioxidant vitamins effectively increase the plasma GPx/SOD activity ratio, but fail to reduce protein carbonyl levels induced by exercise.