ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway |
| |
| Affiliation: | 1. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;2. Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;3. Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;1. Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, South Korea;2. Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea;1. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Mayo Clinic, Rochester, MN, USA;2. University of Texas Health Science Center, San Antonio, TX, USA;3. Division of Gastroenterology and Hepatology, University of Illinois Chicago, Chicago, IL, USA;4. Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA;5. Johns Hopkins Medical Institute, Baltimore, MD, USA;6. Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS San Raffaele Scientific Institute, Milan, Italy;7. Division of Gastroenterology, Hospitals of the University of Pennsylvania, Philadelphia, PA, USA;8. University of Iowa, Stead Family Department of Pediatrics, Iowa City, IA, USA;9. Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, USA;10. Fraternal Order of Eagles Diabetes Research Center, USA;1. Division of GI Surgery, GI Oncology, Minimal Access and Bariatric Surgery, Institute of Digestive and Hepatobiliary Sciences, Medanta - the Medicity, Sector 38, Gurugram, Haryana, 122001, India;2. Division of Surgery & Perioperative Medicine, Flinders Medical Center, Bedford Park, Adelaide, South Australia, Australia;1. Anhui University of Science and Technology, Huainan, 232001, China;2. Department of Gastroenterology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China;3. Digestive Endoscopy Center, Shanghai Tenth People''s Hospital, Tongji University School of Medicine, Shanghai, China;1. Division of Gastroenterology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA;2. Pancreatitis Center, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA;3. William H. Welch Medical Library, Johns Hopkins University, Baltimore, MD, USA;4. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;5. Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA;6. Division of Gastroenterology and Hepatology, Indiana University Medical Center, Indiana, USA;7. Centre for Pancreatic Diseases and Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark;8. Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark;1. Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan;2. Natori-Chuo-Clinic, Natori, Japan;3. Department of Surgery, Sendai City Medical Center, Sendai, Japan |
| |
| Abstract: | Background/objectivesPancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation.MethodsWe compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models.ResultsIn analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown.ConclusionsOur findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC. |
| |
| Keywords: | Endoplasmic reticulum stress Stromal remodeling Tunicamycin Tumor-stromal interaction |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
