XPO1 Expression Is a Poor-Prognosis Marker in Pancreatic Adenocarcinoma
XPO1 Expression Is a Poor-Prognosis Marker in Pancreatic Adenocarcinoma
复制标题
DOI：
10.3390/jcm8050596
复制
发表时间：
2019-05-01
影响因子：
3.9
通讯作者：
Bertucci, Francois
中科院分区：
文献类型：
--
作者：
Birnbaum, David Jeremie;Finetti, Pascal;Bertucci, Francois
胰腺癌（PAC）是最具侵袭性的人类癌症之一，迫切需要新的全身治疗。Exportin-1（XPO 1）是核转运蛋白importin超家族的成员，是许多参与PAC进展的肿瘤抑制蛋白的主要输出蛋白。在PAC中已经报道了使用XPO 1抑制剂的有希望的临床前数据，但是关于临床样品中XPO 1表达的数据非常少。在此之后，我们分析了741个胰腺样本中XPO 1 mRNA的表达，包括95个正常，73个转移性和573个原发性癌症样本，并寻找与临床病理学和分子数据的相关性，包括总生存率。XPO 1的表达在所有样本中是异质的，在转移性样本中的表达高于原发性肿瘤，在原发性肿瘤中的表达高于正常样本。XPO 1高表达的肿瘤与阳性病理淋巴结状态和侵袭性分子亚型相关。在单因素和多因素分析中，它们也与较短的总生存期相关。XPO 1高和XPO 1低肿瘤之间的监督分析鉴定了稳健的268个基因签名，其中本体分析表明XPO 1高肿瘤中的XPO 1活性增加。XPO 1的表达改善了PAC的表达，并且在继发性肿瘤中的表达高于原发性肿瘤，这支持了XPO 1抑制剂在这种致命疾病中的发展。
Pancreatic adenocarcinoma (PAC) is one of the most aggressive human cancers and new systemic therapies are urgently needed. Exportin-1 (XPO1), which is a member of the importin- superfamily of karyopherins, is the major exporter of many tumor suppressor proteins that are involved in the progression of PAC. Promising pre-clinical data using XPO1 inhibitors have been reported in PAC, but very few data are available regarding XPO1 expression in clinical samples. Retrospectively, we analyzed XPO1 mRNA expression in 741 pancreatic samples, including 95 normal, 73 metastatic and 573 primary cancers samples, and searched for correlations with clinicopathological and molecular data, including overall survival. XPO1 expression was heterogeneous across the samples, higher in metastatic samples than in the primary tumors, and higher in primaries than in the normal samples. XPO1-high tumors were associated with positive pathological lymph node status and aggressive molecular subtypes. They were also associated with shorter overall survival in both uni- and multivariate analyses. Supervised analysis between the XPO1-high and XPO1-low tumors identified a robust 268-gene signature, whereby ontology analysis suggested increased XPO1 activity in the XPO1-high tumors. XPO1 expression refines the prognostication in PAC and higher expression exists in secondary versus primary tumors, which supports the development of XPO1 inhibitors in this so-lethal disease.