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

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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

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Data availability

The datasets collected and/or analyzed during the current study are available from the corresponding author upon reasonable request, and the other part of the study data is detailed in the supplementary material.

Abbreviations

APL:

Acute promyelocytic leukemia

ATRA:

All-trans-retinoic acid

ATO:

Arsenic trioxide

CCA:

Cholangiocarcinoma

CCK-8:

Cell counting kit-8

DMSO:

Dimethyl sulfoxide

GEO:

Gene expression omnibus

PIN1:

Peptidylprolyl cis/trans isomerase, NIMA-interacting 1

PDAC:

Pancreatic ductal adenocarcinoma

PBS:

Phosphate-buffered saline

ICC:

Intrahepatic cholangiocarcinoma

IP:

Immunoprecipitation

IF:

Immunofluorescence

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Acknowledgements

We acknowledge our colleagues for their valuable efforts and comments on this paper.

Funding

We gratefully acknowledge the support of the following grants for this work: National Natural Science Foundation of China (81472306), National Natural Science Foundation of China (82102150), Special Fund for Talents of the Jiangsu Province Hospital (YNRCZN015), and the Natural Science Foundation of Jiangsu Province (BK20210968).

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Author notes

  1. Yuming Wang, Yiwei Liu, Hairong Chen and Zhenggang Xu have contributed equally to this work.

Authors and Affiliations

  1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), 300 Guangzhou Road, Nanjing, China

    Yuming Wang, Yiwei Liu, Zhenggang Xu, Wangjie Jiang, Xiao Xu, Jijun Shan, Jiang Chang, Tao Zhou, Jifei Wang, Anlan Chenyan, Shilong Fan, Zifan Tao, Ke Shao, Xiangcheng Li, Guwei Ji & Xiaofeng Wu

  2. Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China

    Yuming Wang, Yiwei Liu, Zhenggang Xu, Wangjie Jiang, Xiao Xu, Jijun Shan, Jiang Chang, Tao Zhou, Jifei Wang, Anlan Chenyan, Shilong Fan, Zifan Tao, Ke Shao, Xiangcheng Li, Guwei Ji & Xiaofeng Wu

  3. Department of Occupational Medicine and Environmental Health, School of Public Health, Nanjing Medical University, Nanjing, China

    Hairong Chen

  4. Department of Oncology, Jiangsu Province Hospital, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, China

    Xiaofeng Chen

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  1. Yuming Wang
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Contributions

Conception and design: YMW, GWJ, XFW; Development of methodology: YMW, YWL, WJJ, XX, JJS, JC, TZ; Collection and acquisition of data: YMW, ZGX, HRC, JFW, ALCY; Analysis of data: YMW, ZGX, HRC, SLF, ZFT, KS; Writing, review, and/or revision of the manuscript: YMW, YWL, XCL, XFC, GWJ, XFW. All the authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Xiaofeng Chen, Guwei Ji or Xiaofeng Wu.

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This study was approved by the Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University, and informed consent was obtained from each participant. Animal studies were approved by the Nanjing Medical University (NJMU) Institutional Animal Care and Use Committee (Quorum No. IACUC-2203004).

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Wang, Y., Liu, Y., Chen, H. et al. PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2. Cell Oncol. (2024). https://doi.org/10.1007/s13402-024-00924-y

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