PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2024-02-22 DOI:10.1007/s13402-024-00924-y
Yuming Wang, Yiwei Liu, Hairong Chen, Zhenggang Xu, Wangjie Jiang, Xiao Xu, Jijun Shan, Jiang Chang, Tao Zhou, Jifei Wang, Anlan Chenyan, Shilong Fan, Zifan Tao, Ke Shao, Xiangcheng Li, Xiaofeng Chen, Guwei Ji, Xiaofeng Wu
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引用次数: 0

Abstract

Background

Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood.

Methods

In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.

Results

Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model.

Conclusion

Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.

Graphical Abstract

Abstract Image

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PIN1 通过 RACK1 介导的 ANXA2 磷酸化促进胆管癌细胞转移
背景胆管癌(CCA)是一种原发性肝胆恶性肿瘤,其特点是预后不良且缺乏有效的治疗方法。因此,探索新的治疗方法迫在眉睫。本研究采用组织芯片(TMA)、反转录聚合酶链反应(RT-PCR)和癌症基因组图谱(TCGA)数据库来评估 PIN1 的表达。通过体外和体内功能实验,我们研究了 PIN1 对 CCA 粘附和转移的影响。此外,我们还利用 RNA-seq、Western 印迹、共免疫沉淀、免疫荧光和质谱技术探索了下游分子通路。此外,PIN1 的高表达促进了 CCA 细胞的增殖和迁移。从机理上讲,PIN1 通过调节 ANXA2 磷酸化,从而促进 CCA 的粘附,起到了癌基因的作用。值得注意的是,PIN1 和 ANXA2 之间的相互作用是由 RACK1 促进的。总之,我们的研究强调了 PIN1/RACK1/ANXA2 复合物在 CCA 生长和功能中的关键作用,突出了靶向 PIN1 作为 CCA 治疗策略的潜力。
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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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