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Language：Japanese   Publisher：(一社)日本乳癌学会  

Language：Japanese   Publisher：(一社)日本乳癌学会  

Language：English   Publisher：Pancreatology  

Figures in this paper contained western blots where the same membrane was probed repeatedly by the indicated antibodies, occasionally resulting in similar band shapes among the individual panels. Moreover, in Figure 5, results from the same membrane were presented in two columns with the panels for the α-SMA and β-actin blots shown twice for easier comparison. We apologize for any misunderstanding this may have caused.

DOI： 10.1016/j.pan.2022.08.013

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PubMed

Language：English   Publisher：Pancreatology  

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.

DOI： 10.1016/j.pan.2021.09.012

Web of Science

Scopus

PubMed

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese