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Endo180和基底膜硬度诱导衰老前列腺上皮细胞中的氧化磷酸化和肿瘤转化。

Endo180 and basement membrane stiffness induce OXPHOS and neoplastic transformation in aging prostate epithelia.

作者信息

Pastro Lucia, Martínez Jennyfer, Fontenla Santiago, Chiale Ana C, Faulord Agustina, Frade María P, Díaz Andrea S, Martino-Kunsch Rodrigo, Castro Laura, Schenk Lysann, Quijano Celia, Sturge Justin, Rodríguez-Teja Mercedes

机构信息

Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.

Departamento de Bioquímica, Facultad de Medicina and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.

出版信息

NPJ Aging. 2025 Aug 2;11(1):72. doi: 10.1038/s41514-025-00259-4.

DOI:10.1038/s41514-025-00259-4
PMID:40753084
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12318007/
Abstract

During prostate aging collagen-IV is modified by advanced glycation end-products, inducing crosslinking of the basement membrane surrounding glandular acini. Basement membrane stiffness sensed by Endo180 disrupts its suppressor complex with CD147, triggering epithelial-to-mesenchymal transition and limiting survival in prostate cancer patients. Here we report basement membrane stiffness and Endo180 cooperate in rewiring epithelia for mitochondrial oxidative phosphorylation (OXPHOS) and growth suppressor evasion, cell proliferation promotion, cell death resistance, inflammation, invasion and metastasis without affecting genome instability, highlighting a non-oncogenic biomechanical event in age-related neoplasia. Endo180-CD147 complex coupled to OXPHOS in Gleason 6 and in Gleason ≥7 tumors Endo180 uncoupled from CD147-OXPHOS, identifying a bio-switch for invasive cancer. Endo180 correlated with patient age in normal tissue, Gleason 6 and 7, but not Gleason 8 tumors, suggesting biological age unleashes its suppression of tumorigenesis. Application of Endo180-based diagnostics in age-related glandular cancers could inform treatment decisions, improving quality of life and survival.

摘要

在前列腺衰老过程中，IV型胶原蛋白会被晚期糖基化终产物修饰，从而诱导腺泡周围基底膜的交联。Endo180感知到的基底膜硬度破坏了它与CD147的抑制复合物，触发上皮-间质转化并限制前列腺癌患者的生存期。在此，我们报告基底膜硬度和Endo180协同作用，重新连接上皮细胞以进行线粒体氧化磷酸化（OXPHOS）并逃避生长抑制、促进细胞增殖、抵抗细胞死亡、引发炎症、促进侵袭和转移，而不影响基因组不稳定性，这凸显了与年龄相关的肿瘤形成过程中一种非致癌性的生物力学事件。在Gleason 6级和Gleason≥7级肿瘤中，Endo180-CD147复合物与OXPHOS偶联；在侵袭性癌症中，Endo180与CD147-OXPHOS解偶联，这确定了一种侵袭性癌症的生物开关。在正常组织、Gleason 6级和7级肿瘤中，Endo180与患者年龄相关，但在Gleason 8级肿瘤中并非如此，这表明生物学年龄解除了其对肿瘤发生的抑制作用。将基于Endo180的诊断方法应用于与年龄相关的腺癌，可为治疗决策提供依据，从而改善生活质量和生存期。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/da3bb5e83ec9/41514_2025_259_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/853914bdbfbf/41514_2025_259_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/33d4d0b62939/41514_2025_259_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/bd493788883d/41514_2025_259_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/095c379dc945/41514_2025_259_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/cc903b2e4cba/41514_2025_259_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/da3bb5e83ec9/41514_2025_259_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/853914bdbfbf/41514_2025_259_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/33d4d0b62939/41514_2025_259_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/bd493788883d/41514_2025_259_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/095c379dc945/41514_2025_259_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/cc903b2e4cba/41514_2025_259_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae79/12318007/da3bb5e83ec9/41514_2025_259_Fig6_HTML.jpg

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Radiogenomic analysis of ultrasound phenotypic features coupled to proteomes predicts metastatic risk in primary prostate cancer.基于超声表型特征与蛋白质组学的放射基因组分析预测原发性前列腺癌的转移风险。
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