Suppr超能文献

黑色素瘤抑制活性-2的一种常见基因变异标记了一种内质网应激水平高的胰腺腺癌亚型。

A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels.

作者信息

Kong Bo, Wu Weiwei, Valkovska Nataliya, Jäger Carsten, Hong Xin, Nitsche Ulrich, Friess Helmut, Esposito Irene, Erkan Mert, Kleeff Jörg, Michalski Christoph W

机构信息

Department of Surgery, Technische Universität München, Munich, Germany.

Institute of Pathology, Technische Universität München, Munich, Germany.

出版信息

Sci Rep. 2015 Feb 6;5:8109. doi: 10.1038/srep08109.

Abstract

HNF1 homeobox A (HNF1A)-mediated gene expression constitutes an essential component of the secretory pathway in the exocrine pancreas. Melanoma inhibitory activity 2 (MIA2), a protein facilitating protein secretion, is an HNF1A target. Protein secretion is precisely coordinated by the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) system. Here, we demonstrate that HNFA and MIA2 are expressed in a subset of human PDAC tissues and that HNF1A induced MIA2 in vitro. We identified a common germline variant of MIA2 (c.A617G: p.I141M) associated with a secretory defect of the MIA2 protein in PDAC cells. Patients carrying MIA2(I141M) survived longer after tumor resection but the survival benefit was restricted to those patients who received adjuvant chemotherapy. The MIA2(I141M) variant was associated with high expression of ER stress/UPR genes--in particular those of the ERN1/XBP arm--in human PDAC samples. Accordingly, PDAC cell lines expressing the MIA2(I141M) variant expressed high levels of ERN1 and were more sensitive to gemcitabine. These findings define an interaction between the common MIA2(I141M) variant and the ER stress/UPR system and specify a subgroup of PDAC patients who are more likely to benefit from adjuvant chemotherapy.

摘要

肝细胞核因子1同源框A(HNF1A)介导的基因表达是外分泌胰腺分泌途径的重要组成部分。黑色素瘤抑制活性蛋白2(MIA2)是一种促进蛋白质分泌的蛋白,是HNF1A的靶标。蛋白质分泌由内质网(ER)应激/未折叠蛋白反应(UPR)系统精确协调。在此,我们证明HNF1A和MIA2在一部分人类胰腺导管腺癌(PDAC)组织中表达,并且HNF1A在体外可诱导MIA2表达。我们鉴定出MIA2的一种常见种系变体(c.A617G:p.I141M),其与PDAC细胞中MIA2蛋白的分泌缺陷相关。携带MIA2(I141M)的患者在肿瘤切除后存活时间更长,但生存获益仅限于接受辅助化疗的患者。MIA2(I141M)变体与人类PDAC样本中ER应激/UPR基因的高表达相关,尤其是ERN1/XBP分支的基因。相应地,表达MIA2(I141M)变体的PDAC细胞系表达高水平ERN1,并且对吉西他滨更敏感。这些发现确定了常见的MIA2(I141M)变体与ER应激/UPR系统之间的相互作用,并明确了一组更可能从辅助化疗中获益的PDAC患者亚组。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f20/4319175/7ed6951beacf/srep08109-f1.jpg

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验