ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway
ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway
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DOI：
10.1016/j.pan.2021.09.012
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发表时间：
2022-01-05
期刊：
影响因子：
3.6
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
--
作者：
Guan, Weiyu;Nakata, Kohei;Nakamura, Masafumi
背景/目的：胰腺导管腺癌（PDAC）的特点是过度的结缔组织增生和自噬依赖性肿瘤生长。胰腺星状细胞（PSCs）作为一种主要的基质细胞类型，在PDAC生物学中起着至关重要的作用。我们以前曾报道过自噬促进PSC激活，然而，其机制仍不清楚。我们研究了自噬在PSC activation.Methods的机制：我们比较了基因表达谱之间的患者来源的PSC从胰腺癌和慢性胰腺炎使用微阵列。分析63例PDAC患者标本中目的基因的间质表达。通过转染小干扰RNA（siRNA）研究目的基因对PSC自噬和活化的影响，并探讨自噬与内质网应激的关系。结果：在基因表达谱芯片分析中，发现肿瘤相关PSC中表达上调的内质网氨肽酶2（ERAP 2）为靶基因。间质ERAP 2高表达与PDAC患者预后不良相关。ERAP 2的敲低抑制未折叠蛋白应答介导的自噬，并导致PSC失活，从而通过抑制IL-6和纤连蛋白的产生来减弱肿瘤-基质相互作用。在体内，PSCs对异种移植肿瘤生长和纤维化的促进作用被ERAP 2敲低所抑制。结论：我们的研究结果证明了一种新的PSCs活化机制，由自噬调节。ERAP 2作为一个有前途的治疗靶点，可能为PDAC的治疗提供一种新的策略。(C)2021年IAP和EPC。Elsevier B. V.出版，保留所有权利。
Background/objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmo-plasia 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. (C) 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.