TY - JOUR
T1 - ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway
AU - Guan, Weiyu
AU - Nakata, Kohei
AU - Sagara, Akiko
AU - Iwamoto, Chika
AU - Endo, Sho
AU - Matsuda, Ryota
AU - Matsumoto, Sokichi
AU - Ikenaga, Naoki
AU - Shindo, Koji
AU - Moriyama, Taiki
AU - Onishi, Hideya
AU - Ohuchida, Kenoki
AU - Oda, Yoshinao
AU - Nakamura, Masafumi
N1 - Funding Information:
This study was partially supported by Takeda Science Foundation , Kobayashi Foundation for Cancer Research , and The Shinnihon Foundation of Advanced Medical Treatment Research . Kohei Nakata was supported in part by Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (B) and (C), and for Young Scientists (grant numbers 18H02880 , 19H03732 , 19K18153 , and 20H03754 ). Weiyu Guan was financially supported by a government scholarship from the China Scholarship Council (grant number 201708050049 ).
Publisher Copyright:
© 2021 IAP and EPC
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.pan.2021.09.012
DO - 10.1016/j.pan.2021.09.012
M3 - Article
C2 - 34642112
AN - SCOPUS:85116672549
VL - 22
SP - 9
EP - 19
JO - Pancreatology
JF - Pancreatology
SN - 1424-3903
IS - 1
ER -