LEADR, a p63 target, dampens interferon signalling in bladder cancer.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-06-03 DOI:10.1038/s41420-025-02546-1

Damiano Barnaba, Mariacristina Franzese Canonico, Manuela Helmer-Citterich, Paolo Gandellini, Gerry Melino, Artem Smirnov, Eleonora Candi

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Abstract

Bladder cancer affects over half a million people worldwide each year. Recent advances in early detection allowed a successful management of non-aggressive cancers, yet the recurrence rate remains high. Aggressive muscle-invasive bladder tumours are life-threatening and challenging to cure. Therefore, understanding of key molecular pathways involved in cancer progression is critical for developing of new personalised targeted therapies. Recently, non-coding RNAs (ncRNAs) have emerged as key regulators orchestrating complex biological processes in cancer, yet their function is not fully understood. Here, we compare non-muscle invasive and muscle invasive cell lines and identify a ncRNA gene MIR205HG and its transcript LEADR among the top ncRNAs downregulated in muscle invasive urothelial tumours. We show that LEADR expression is epigenetically regulated by master transcription factor p63. LEADR is localised in the nuclei of non-muscle invasive bladder cancer cells where it dampens hyperactivation of interferon stimulated genes possibly increasing sensitivity of bladder cancer cells to interferon signalling. These findings uncover an anti-tumoral role of non-coding RNA LEADR in mediating immune response in bladder cancer.

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p63靶点LEADR抑制膀胱癌中的干扰素信号传导。

膀胱癌每年影响全球50多万人。早期发现的最新进展使得非侵袭性癌症的成功管理，但复发率仍然很高。侵袭性肌肉侵袭性膀胱肿瘤危及生命，治疗具有挑战性。因此，了解参与癌症进展的关键分子途径对于开发新的个性化靶向治疗至关重要。近年来，非编码rna （ncRNAs）已成为协调癌症复杂生物过程的关键调节因子，但其功能尚未完全了解。在这里，我们比较了非肌肉侵袭性和肌肉侵袭性细胞系，并在肌肉侵袭性尿路上皮肿瘤中发现了一个ncRNA基因MIR205HG及其转录物LEADR在下调最多的ncRNA中。我们发现LEADR的表达受主转录因子p63的表观遗传调控。LEADR定位于非肌肉浸润性膀胱癌细胞的细胞核中，在那里它抑制干扰素刺激基因的过度激活，可能增加膀胱癌细胞对干扰素信号的敏感性。这些发现揭示了非编码RNA LEADR在膀胱癌免疫应答介导中的抗肿瘤作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.