Précédent|Prochain

L'aspartoacylase supprime la progression du cancer de la prostate en bloquant l'activation de LYN

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China

Hong Weng1234,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Kang-Ping Xiong1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Wang Wang1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China

Kai-Yu Qian134,  
  • Affiliation：

    Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Shuai Yuan3,  
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Gang Wang13,  
  • Affiliation：

    Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Center for Pathology and Molecular Diagnostics, Wuhan University, Wuhan 430071, China

Fang Yu56,  
  • Affiliation：

    Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Center for Pathology and Molecular Diagnostics, Wuhan University, Wuhan 430071, China

Jun Luo56,  
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Meng-Xin Lu1,  
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Zhong-Hua Yang1,  
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Tao Liu1,  
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Xing Huang1,  
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Hang Zheng1,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

    Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China

    Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China

  • Email：wangxinghuan@whu.edu.cn
  • Introduction：*wangxinghuan@whu.edu.cn
Xing-Huan Wang12347*

résumé

Background:Globally, despite prostate cancer (PCa) representing second most prevalent malignancy in male, the precise molecular mechanisms implicated in its pathogenesis remain unclear. Consequently, elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies, ultimately advancing the management of PCa.Methods:A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University. The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa. The expression of aspartoacylase (ASPA) in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques. To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis, a comprehensive set of in vitro and in vivo assays were conducted, including orthotopic and tumor-bearing mouse models (n=8 for each group). A combination of experimental approaches, such as Western blotting, luciferase assays, immunoprecipitation assays, mass spectrometry, glutathione S-transferase pull-down experiments, and rescue studies, were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa. The Student's t-test was employed to assess the statistical significance between two distinct groups, while one-way analysis of variance was utilized for comparisons involving more than two groups. A two-sided P<0.05 was deemed to indicate statistical significance.Results:ASPA was identified as a novel inhibitor of PCa progression. The expression of ASPA was found to be significantly down-regulated in PCa tissue samples, and its decreased expression was independently associated with patients’ prognosis (HR=0.60, 95%CI 0.40–0.92, P=0.018). Our experiments demonstrated that modulation of ASPA activity, either through gain- or loss-of-function, led to the suppression or enhancement of PCa cell proliferation, migration, and invasion, respectively. The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models. Mechanistically, ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets, JNK1/2 and C-Jun, in both PCa cells and mouse models, in an enzyme-independent manner. Importantly, the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models. Moreover, we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples, suggesting a potential regulatory role of ASPA in modulating LYN signaling.Conclusions:Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy.

mots-clés

prostate cancer;Aspartoacylase;LYN;JNK;AP-1;C-Jun;phosphorylation

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