ABSTRACT
Endometrial carcinoma (EMC) is associated with obesity; however, the underlying mechanisms have not yet been elucidated. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that is involved in lipid, glucose, and energy metabolism. PPARα reportedly functions as a tumor suppressor through its effects on lipid metabolism; however, the involvement of PPARα in the development of EMC remains unclear. The present study demonstrated that the immunohistochemical expression of nuclear PPARα was lower in EMC than in normal endometrial tissues, suggesting the tumor suppressive nature of PPARα. A treatment with the PPARα activator, irbesartan, inhibited the EMC cell lines, Ishikawa and HEC1A, by down-regulating sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) and up-regulating the tumor suppressor genes p21 and p27, antioxidant enzymes, and AT-rich interaction domain 1A (ARID1A). These results indicate the potential of the activation of PPARα as a novel therapeutic approach against EMC.
Subject(s)
Endometrial Neoplasms , PPAR alpha , Humans , Female , Sterol Regulatory Element Binding Protein 1/genetics , Irbesartan/pharmacology , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Cell Proliferation , DNA-Binding Proteins , Transcription FactorsABSTRACT
BACKGROUND/AIM: Thrombomodulin™ has cytoprotective and anti-inflammatory function by interacting with G-protein coupled receptor 15 (GPR15). Recombinant TM (rTM), which comprises the extracellular regions of TM, is approved for treatment of disseminated intravascular coagulation. We investigated the anti-tumor effect of rTM for pancreatic ductal adenocarcinoma (PDAC) through GPR15. MATERIALS AND METHODS: We evaluated the expression of GPR15 in human PDAC cell lines and the anti-tumor effect and signals of rTM in vitro and in vivo. To test whether GPR15 would be responsible for the inhibition of cell proliferation by rTM, we evaluated the cell viability of the GPR15 knockdown cells treated with rTM using GPR15-targeting siRNA. RESULTS: We identified PDAC cell lines with GPR15 expression and discovered that rTM inhibited tumor growth and enhanced the effects of gemcitabine (GEM) for the PDAC cell line in a GPR15-dependent manner. Furthermore, we showed that rTM inhibited nuclear factor-kappaB (NF-[Formula: see text]B) and extracellular signal-regulated kinase (ERK) activation through interactions with GPR15. CONCLUSION: We demonstrated that rTM had anti-tumor effect and enhancement of cytotoxic effect of GEM for PDAC cells by inhibiting NF-[Formula: see text]B and ERK activation via GPR15 and suggest that rTM is a potential therapeutic option for PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Anti-Inflammatory Agents/therapeutic use , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Deoxycytidine/analogs & derivatives , Extracellular Signal-Regulated MAP Kinases , Humans , NF-kappa B/metabolism , Pancreatic Neoplasms/pathology , RNA, Small Interfering , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Peptide/therapeutic use , Thrombomodulin/genetics , Thrombomodulin/therapeutic use , Gemcitabine , Pancreatic NeoplasmsABSTRACT
The authors report a case of successful replantation of all fingers in a ten-finger complete amputation. Among the factors responsible for the successful outcome were an adequate number of microsurgically-trained resident surgeons and staff, good organization and supervision by senior staff, emphasis on precision and perseverance in the operative procedures, and postoperative management. Follow-up is 15 months, and the patient now has a pair of functionally and cosmetically good hands.