Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.
Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Anatomical Pathology Service, HURS, Cordoba, Spain.
Cancer Lett. 2024 Mar 1;584:216604. doi: 10.1016/j.canlet.2023.216604. Epub 2024 Jan 19.
Novel biomarkers and therapeutic strategies for prostate-cancer (PCa) are required to overcome its lethal progression. The dysregulation/implication of the RNA-Exosome-complex (REC; cellular machinery controlling the 3'-5'processing/degradation of most RNAs) in different cancer-types, including PCa, is poorly known. Herein, different cellular/molecular/preclinical approaches with human PCa-samples (tissues and/or plasma of 7 independent cohorts), and in-vitro/in-vivo PCa-models were used to comprehensively characterize the REC-profile and explore its role in PCa. Moreover, isoginkgetin (REC-inhibitor) effects were evaluated on PCa-cells. We demonstrated a specific dysregulation of the REC-components in PCa-tissues, identifying the Poly(A)-Binding-Protein-Nuclear 1 (PABPN1) factor as a critical regulator of major cancer hallmarks. PABPN1 is consistently overexpressed in different human PCa-cohorts and associated with poor-progression, invasion and metastasis. PABPN1 silencing decreased relevant cancer hallmarks in multiple PCa-models (proliferation/migration/tumourspheres/colonies, etc.) through the modulation of key cancer-related lncRNAs (PCA3/FALEC/DLEU2) and mRNAs (CDK2/CDK6/CDKN1A). Plasma PABPN1 levels were altered in patients with metastatic and tumour-relapse. Finally, pharmacological inhibition of REC-activity drastically inhibited PCa-cell aggressiveness. Altogether, the REC is drastically dysregulated in PCa, wherein this novel molecular event/mechanism, especially PABPN1 alteration, may be potentially exploited as a novel prognostic and therapeutic tool for PCa.
需要新的生物标志物和治疗策略来克服前列腺癌（PCa）的致命进展。RNA-外泌体复合物（REC；控制大多数 RNA 的 3'-5'加工/降解的细胞机制）在不同癌症类型中的失调/关联，包括 PCa，知之甚少。在此，使用了不同的细胞/分子/临床前方法，结合人类 PCa 样本（7 个独立队列的组织和/或血浆）和体外/体内 PCa 模型，全面描述了 REC 谱，并探讨了其在 PCa 中的作用。此外，还评估了异银杏素（REC 抑制剂）对 PCa 细胞的作用。我们证明了 REC 组件在 PCa 组织中的特异性失调，确定 Poly(A)-Binding-Protein-Nuclear 1（PABPN1）因子是主要癌症特征的关键调节因子。PABPN1 在不同的人类 PCa 队列中一致过表达，并与不良进展、侵袭和转移相关。PABPN1 沉默通过调节关键的癌症相关 lncRNAs（PCA3/FALEC/DLEU2）和 mRNAs（CDK2/CDK6/CDKN1A），降低了多个 PCa 模型中的相关癌症特征。转移性和肿瘤复发患者的血浆 PABPN1 水平发生改变。最后，REC 活性的药理学抑制可显著抑制 PCa 细胞的侵袭性。总之，REC 在 PCa 中严重失调，这种新的分子事件/机制，特别是 PABPN1 的改变，可能作为 PCa 的一种新的预后和治疗工具被开发利用。
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