A mutant p53/Hif1α/miR-30d axis reprograms the secretory pathway promoting the release of a prometastatic secretome.

IF 4.1 Q2 CELL BIOLOGY
Valeria Capaci, Fiamma Mantovani, Giannino Del Sal
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引用次数: 1

Abstract

TP53 missense mutations are frequent driver events during tumorigenesis. The majority of TP53 mutations are missense and occur within the DNA binding domain of p53, leading to expression of mutant p53 (mut-p53) proteins that not only lose the tumor suppressive functions of the wild-type (wt-p53) form, but can also acquire novel oncogenic features fostering tumor growth, metastasis and chemoresistance. Mut-p53 affects fundamental cellular pathways and functions through different mechanisms, a major one being the alteration of gene expression. In our recent work (Capaci et al., 2020, Nat Commun) we found that mut-p53, via miR-30d, modifies structure and function of the Golgi apparatus (GA) and induces increased rate of trafficking. This culminates in the release of a pro-malignant secretome, which is capable of remodeling the tumor microenvironment (TME), to increase stiffness of the extracellular matrix (ECM), favouring metastatic colonization, as shown by cell-based assays and experiments of metastatic niche preconditioning in mouse xenograft models. This study provides new insights into the mechanisms by which mut-p53, through induction of non-coding RNAs, can exert pro-tumorigenic functions in a non-cell-autonomous fashion, and highlights potential non-invasive biomarkers and therapeutic targets to treat tumors harboring mut-p53 (Figure 1).

Abstract Image

Abstract Image

突变的p53/Hif1α/miR-30d轴重编程分泌途径,促进原转移性分泌组的释放。
TP53错义突变是肿瘤发生过程中常见的驱动事件。大多数TP53突变是错义的,发生在p53的DNA结合域内,导致突变型p53 (mutt -p53)蛋白的表达,不仅失去野生型(wt-p53)的肿瘤抑制功能,而且还可以获得新的致癌特征,促进肿瘤生长、转移和化疗耐药。mut53通过不同的机制影响细胞的基本途径和功能,其中最主要的是基因表达的改变。在我们最近的工作(Capaci et al., 2020, Nat comm)中,我们发现mut53通过miR-30d修饰高尔基体(GA)的结构和功能,并诱导运输速率增加。这最终导致了一种促恶性分泌组的释放,这种分泌组能够重塑肿瘤微环境(TME),从而增加细胞外基质(ECM)的硬度,有利于转移性定植,这一点在小鼠异种移植模型中基于细胞的检测和转移性生态位预处理实验中得到了证实。这项研究为mutp53通过诱导非编码rna以非细胞自主方式发挥促肿瘤功能的机制提供了新的见解,并强调了潜在的非侵入性生物标志物和治疗靶点,以治疗含有mutp53的肿瘤(图1)。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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