RRC ID 68976
著者 Guan W, Nakata K, Sagara A, Iwamoto C, Endo S, Matsuda R, Matsumoto S, Ikenaga N, Shindo K, Moriyama T, Onishi H, Ohuchida K, Oda Y, Nakamura M.
タイトル ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway.
ジャーナル Pancreatology
Abstract BACKGROUND/OBJECTIVES:Pancreatic 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.
METHODS:We 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.
RESULTS:In 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.
CONCLUSIONS:Our 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.
巻・号 22(1)
ページ 9-19
公開日 2022-1-1
DOI 10.1016/j.pan.2021.09.012
PII S1424-3903(21)00576-7
PMID 34642112
MeSH Aminopeptidases* / genetics Autophagy* Carcinoma, Pancreatic Ductal* / genetics Carcinoma, Pancreatic Ductal* / pathology Cell Line, Tumor Cell Proliferation Fibrosis Gene Expression Humans Pancreatic Neoplasms* / genetics Pancreatic Neoplasms* / pathology Pancreatic Stellate Cells* / pathology Pancreaticoduodenectomy Signal Transduction
IF 3.241
リソース情報
ヒト・動物細胞 PANC-1(RCB2095)