이전|다음

아스파르토아실레이스는 LYN 활성화를 차단하여 전립선암 진행을 억제합니다

  • 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*

추상적인

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.

키워드

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

References

  1. 1..
    Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
  2. 2..
    GL LY, Albertsen PC, Moore DF, Shih W, Lin Y, DiPaola RS, et al. Outcomes of localized prostate cancer following conservative management. JAMA. 2009;302(11):1202–9.
  3. 3..
    Di Muzio NG, Deantoni CL, Brombin C, Fiorino C, Cozzarini C, Zerbetto F, et al. Ten year results of extensive nodal radiotherapy and moderately hypofractionated simultaneous integrated boost in unfavorable intermediate-, high-, and very high-risk prostate cancer. Cancers (Basel). 2021;13(19):4970.
  4. 4..
    Siegel DA, O’Neil ME, Richards TB, Dowling NF, Weir HK. Prostate cancer incidence and survival, by stage and race/ethnicity—United States, 2001–2017. MMWR Morb Mortal Wkly Rep. 2020;69(41):1473–80.
  5. 5..
    Imber BS, Varghese M, Ehdaie B, Gorovets D. Financial toxicity associated with treatment of localized prostate cancer. Nat Rev Urol. 2020;17(1):28–40.
  6. 6..
    Boevé LMS, Hulshof M, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial. Eur Urol. 2019;75(3):410–8.
  7. 7..
    Perez-Cornago A, Dunneram Y, Watts EL, Key TJ, Travis RC. Adiposity and risk of prostate cancer death: a prospective analysis in UK Biobank and meta-analysis of published studies. BMC Med. 2022;20(1):143.
  8. 8..
    Schaid DJ, Sinnwell JP, Batzler A, McDonnell SK. Polygenic risk for prostate cancer: decreasing relative risk with age but little impact on absolute risk. Am J Hum Genet. 2022;109(5):900–8.
  9. 9..
    Anders MW, Dekant W. Aminoacylases. Adv Pharmacol. 1994;27:431–48.
  10. 10..
    Long PM, Stradecki HM, Minturn JE, Wesley UV, Jaworski DM. Differential aminoacylase expression in neuroblastoma. Int J Cancer. 2011;129(6):1322–30.
  11. 11..
    Cook RM, Burke BJ, Buchhagen DL, Minna JD, Miller YE. Human aminoacylase-1. Cloning, sequence, and expression analysis of a chromosome 3p21 gene inactivated in small cell lung cancer. J Biol Chem. 1993;268(23):17010–7.
  12. 12..
    Zhong Y, Onuki J, Yamasaki T, Ogawa O, Akatsuka S, Toyokuni S. Genomewide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Carcinogenesis. 2009;30(1):158–64.
  13. 13..
    Wei X, Li J, Xie H, Ling Q, Wang J, Lu D, et al. Proteomics-based identification of the tumor suppressor role of aminoacylase 1 in hepatocellular carcinoma. Cancer Lett. 2014;351(1):117–25.
  14. 14..
    Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN Jr. Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Proc Natl Acad Sci U S A. 2007;104(2):456–61.
  15. 15..
    Labbé DP, Zadra G, Yang M, Reyes JM, Lin CY, Cacciatore S, et al. High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program. Nat Commun. 2019;10(1):4358.
  16. 16..
    Penney KL, Sinnott JA, Tyekucheva S, Gerke T, Shui IM, Kraft P, et al. Association of prostate cancer risk variants with gene expression in normal and tumor tissue. Cancer Epidemiol Biomark Prev. 2015;24(1):255–60.
  17. 17..
    Ding Y, Wu H, Warden C, Steele L, Liu X, Iterson MV, et al. Gene expression differences in prostate cancers between young and old men. PLoS Genet. 2016;12(12):e1006477.
  18. 18..
    Ross-Adams H, Lamb AD, Dunning MJ, Halim S, Lindberg J, Massie CM, et al. Integration of copy number and transcriptomics provides risk stratification in prostate cancer: a discovery and validation cohort study. EBioMedicine. 2015;2(9):1133–44.
  19. 19..
    Kuner R, Fälth M, Pressinotti NC, Brase JC, Puig SB, Metzger J, et al. The maternal embryonic leucine zipper kinase (MELK) is up-regulated in high-grade prostate cancer. J Mol Med (Berl). 2013;91(2):237–48.
  20. 20..
    Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L, Assenov Y, et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell. 2018;34(6):996-1011.e8.
  21. 21..
    Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22.
  22. 22..
    Huang ZM, Gao E, Fonseca FV, Hayashi H, Shang X, Hoffman NE, et al. Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury. Sci Signal. 2013;6(299):ra95.
  23. 23..
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.
  24. 24..
    Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately down-regulated in human diabetes. Nat Genet. 2003;34(3):267–73.
  25. 25..
    Jamaspishvili T, Berman DM, Ross AE, Scher HI, de Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15(4):222–34.
  26. 26..
    Wang Z, Song Y, Ye M, Dai X, Zhu X, Wei W. The diverse roles of SPOP in prostate cancer and kidney cancer. Nat Rev Urol. 2020;17(6):339–50.
  27. 27..
    Agarwal N, Sonpavde G, Sternberg CN. Novel molecular targets for the therapy of castration-resistant prostate cancer. Eur Urol. 2012;61(5):950–60.
  28. 28..
    Ciccarese C, Massari F, Iacovelli R, Fiorentino M, Montironi R, di Nunno V, et al. Prostate cancer heterogeneity: discovering novel molecular targets for therapy. Cancer Treat Rev. 2017;54:68–73.
  29. 29..
    Konoshenko MY, Bryzgunova OE, Laktionov PP. miRNAs and androgen deprivation therapy for prostate cancer. Biochim Biophys Acta Rev Cancer. 2021;186(2):188625.
  30. 30..
    Lorente D, de Bono JS. Molecular alterations and emerging targets in castration resistant prostate cancer. Eur J Cancer. 2014;50(4):753–64.
  31. 31..
    Mollica V, Marchetti A, Rosellini M, Nuvola G, Rizzo A, Santoni M, et al. An insight on novel molecular pathways in metastatic prostate cancer: a focus on DDR, MSI and AKT. Int J Mol Sci. 2021;22(24):13519.
  32. 32..
    Stavridi F, Karapanagiotou EM, Syrigos KN. Targeted therapeutic approaches for hormone-refractory prostate cancer. Cancer Treat Rev. 2010;36(2):122–30.
  33. 33..
    Steuber T, O’Brien MF, Lilja H. Serum markers for prostate cancer: a rational approach to the literature. Eur Urol. 2008;54(1):31–40.
  34. 34..
    William WN Jr, Heymach JV, Kim ES, Lippman SM. Molecular targets for cancer chemoprevention. Nat Rev Drug Discov. 2009;8:213–25.
  35. 35..
    Goldenberg-Furmanov M, Stein I, Pikarsky E, Rubin H, Kasem S, Wygoda M, et al. Lyn is a target gene for prostate cancer: sequence-based inhibition induces regression of human tumor xenografts. Cancer Res. 2004;64(3):1058–66.
  36. 36..
    Cai H, Smith DA, Memarzadeh S, Lowell CA, Cooper JA, Witte ON. Differential transformation capacity of Src family kinases during the initiation of prostate cancer. Proc Natl Acad Sci U S A. 2011;108(16):6579–84.
  37. 37..
    Jiang N, Hjorth-Jensen K, Hekmat O, Iglesias-Gato D, Kruse T, Wang C, et al. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth. Oncogene. 2015;34(21):2764–76.
  38. 38..
    Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res. 2005;65(20):9185–9.
  39. 39..
    Park SI, Zhang J, Phillips KA, Araujo JC, Najjar AM, Volgin AY, et al. Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res. 2008;68(9):3323–33.
  40. 40..
    Zardan A, Nip KM, Thaper D, Toren P, Vahid S, Beraldi E, et al. Lyn tyrosine kinase regulates androgen receptor expression and activity in castrate-resistant prostate cancer. Oncogenesis. 2014;3(8):e115.
  41. 41..
    Tatarov O, Mitchell TJ, Seywright M, Leung HY, Brunton VG, Edwards J. SRC family kinase activity is up-regulated in hormone-refractory prostate cancer. Clin Cancer Res. 2009;15(10):3540–9.
  42. 42..
    Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, et al. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013;14(13):1307–16.
  43. 43..
    Brandvold KR, Steffey ME, Fox CC, Soellner MB. Development of a highly selective c-Src kinase inhibitor. ACS Chem Biol. 2012;7(8):1393–8.
  44. 44..
    Li R, Fang L, Pu Q, Lin P, Hoggarth A, Huang H, et al. Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster. Signal Transduct Target Ther. 2016;1:16032.
  45. 45..
    Starling S. White matter disease: targeted aspartoacylase gene therapy reverts Canavan disease. Nat Rev Neurol. 2018;14(1):4.
  46. 46..
    Herga S, Berrin JG, Perrier J, Puigserver A, Giardina T. Identification of the zinc binding ligands and the catalytic residue in human aspartoacylase, an enzyme involved in Canavan disease. FEBS Lett. 2006;580(25):5899–904.

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