Altered centriolar cohesion by CEP250 and appendages impact outcome of patients with pancreatic cancer

IF 2.8 2区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pancreatology Pub Date : 2024-09-01 DOI:10.1016/j.pan.2024.06.010
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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cause of cancer death worldwide. PDACs are characterized by centrosome aberrations, but whether centrosome-related genes influence patient outcomes has not been tested.

Methods

Publicly available RNA-sequencing data of patients diagnosed with PDAC were interrogated with unsupervised approaches to identify centrosome protein-encoding genes with prognostic relevance. Candidate genes were validated by immunohistochemistry and multiplex immunofluorescence in a set of clinical PDAC and normal pancreatic tissues.

Results

Results showed that two genes CEP250 and CEP170, involved in centrosome linker and centriolar subdistal appendages, were expressed at high levels in PDAC tissues and were correlated with prognosis of PDAC patients in independent databases.

Large clustered γ-tubulin-labelled centrosomes were linked together by aberrant circular and planar-shaped CEP250 arrangements in CEP250-high expressing PDACs. Furthermore, PDACs displayed prominent centrosome separation and reduced CEP164-centrosomal labelling associated with acetylated-tubulin staining compared to normal pancreatic tissues. Interestingly, in a small validation cohort, CEP250-high expressing patients had shorter disease free- and overall-survival and almost none of those who received gemcitabine plus nab-paclitaxel first-line therapy achieved a clinical response. In contrast, weak CEP250 expression was associated with long-term survivors or responses to medical treatments.

Conclusions

Alteration of the centriolar cohesion and appendages has effect on the survival of patients with PDAC.

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CEP250 和附属物改变的中心粒内聚力会影响胰腺癌患者的预后。
背景:胰腺导管腺癌(PDAC胰腺导管腺癌(PDAC)是全球癌症死亡的主要原因之一。PDAC以中心体畸变为特征,但中心体相关基因是否会影响患者的预后尚未得到检验:方法:采用无监督方法对诊断为PDAC患者的公开RNA测序数据进行分析,以确定与预后相关的中心体蛋白编码基因。候选基因在一组临床 PDAC 和正常胰腺组织中通过免疫组化和多重免疫荧光进行了验证:结果表明,参与中心体连接体和中心体下附属物的两个基因CEP250和CEP170在PDAC组织中高水平表达,并且在独立数据库中与PDAC患者的预后相关。在 CEP250 高表达的 PDACs 中,大簇的γ-管突蛋白标记的中心体通过异常的环形和平面形 CEP250 排列连接在一起。此外,与正常胰腺组织相比,PDAC 表现出明显的中心体分离,与乙酰化微管蛋白染色相关的 CEP164-中心体标记减少。有趣的是,在一个小型验证队列中,CEP250高表达患者的无病生存期和总生存期较短,接受吉西他滨加纳布紫杉醇一线治疗的患者几乎无一获得临床应答。相比之下,CEP250的弱表达与长期存活或对药物治疗的反应有关:结论:中心粒内聚力和附属物的改变对PDAC患者的生存有影响。
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来源期刊
Pancreatology
Pancreatology 医学-胃肠肝病学
CiteScore
7.20
自引率
5.60%
发文量
194
审稿时长
44 days
期刊介绍: Pancreatology is the official journal of the International Association of Pancreatology (IAP), the European Pancreatic Club (EPC) and several national societies and study groups around the world. Dedicated to the understanding and treatment of exocrine as well as endocrine pancreatic disease, this multidisciplinary periodical publishes original basic, translational and clinical pancreatic research from a range of fields including gastroenterology, oncology, surgery, pharmacology, cellular and molecular biology as well as endocrinology, immunology and epidemiology. Readers can expect to gain new insights into pancreatic physiology and into the pathogenesis, diagnosis, therapeutic approaches and prognosis of pancreatic diseases. The journal features original articles, case reports, consensus guidelines and topical, cutting edge reviews, thus representing a source of valuable, novel information for clinical and basic researchers alike.
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