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先天免疫与NF-κB通路调控前列腺干细胞可塑性、重编程及肿瘤发生

Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation

原文发布日期: 2025-06-23

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摘要翻译：

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先天免疫与NF-κB通路调控前列腺干细胞可塑性、重编程及肿瘤发生

Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation

原文发布日期: 2025-06-23

英文摘要:

Prostate epithelium develops from multipotent stem cells, which are replaced in adult life by different lineage-restricted basal and luminal unipotent stem cells. Deletion of Pten re-induces multipotency in basal cells (BCs); however, the molecular mechanisms regulating BC plasticity and tumor initiation are poorly understood. Here we showed that Pten deletion in BCs led to distinct cell fate reprogramming and tumor initiation in a regionalized manner. Single-cell RNA sequencing, ATAC-seq and in situ characterization revealed that following Pten deletion in anterior and dorsolateral prostates, BCs were highly plastic and reprogrammed into a hillock-like state, progressing into a proximal-like luminal state before giving rise to invasive tumors. This BC reprogramming was associated with the activation of innate immunity. Pharmacological targeting of interleukin-1, JAK–STAT and NF-κB as well as genetic deletion of Nfkb inhibit Pten-induced cell plasticity and reprogramming in a cellular autonomous manner, opening new opportunities for prevention and treatment of prostate cancer.

摘要翻译：

前列腺上皮组织起源于多能干细胞，这些干细胞在成年期被不同谱系限制的基底细胞和管腔单能干细胞所取代。Pten基因缺失会重新诱导基底细胞（BCs）获得多能性，然而调控基底细胞可塑性及肿瘤起始的分子机制尚不明确。本研究发现，基底细胞中Pten缺失会以区域特异性方式引发独特的细胞命运重编程和肿瘤起始。通过单细胞RNA测序、ATAC-seq及原位表征技术揭示：在前列腺前叶和背外侧叶中，Pten缺失后的基底细胞表现出高度可塑性，首先重编程为hillock样状态，继而进展为近端管腔样状态，最终形成侵袭性肿瘤。这种基底细胞重编程过程与先天免疫系统激活密切相关。药理学靶向抑制白细胞介素-1、JAK-STAT和NF-κB通路，以及遗传学敲除Nfkb基因，均能以细胞自主性方式抑制Pten诱导的细胞可塑性与重编程，这为前列腺癌的防治提供了新的干预靶点。