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TGFβ 对 ΔNp63 和 TAp63 的复杂和可变调节对鳞状上皮细胞向间充质转化的动力学具有重要意义。

Complex and variable regulation of ΔNp63 and TAp63 by TGFβ has implications for the dynamics of squamous cell epithelial to mesenchymal transition.

机构信息

Research Center of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53, Brno, Czech Republic.

State Institute for Drug Control, Šrobárova 48, 100 41, Praha 10, Czech Republic.

出版信息

Sci Rep. 2024 Mar 27;14(1):7304. doi: 10.1038/s41598-024-57895-1.

DOI:10.1038/s41598-024-57895-1
PMID:38538801
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10973453/
Abstract

TGFβ has roles in inflammation, wound healing, epithelial to mesenchymal transition (EMT), and cancer stem cell states, and acts as a tumor suppressor gene for squamous cell carcinoma (SCC). SCCs are also characterized by high levels of ΔNp63, which induces epithelial cell phenotypes and maintains squamous stem cells. Previous studies indicate a complex interplay between ΔNp63 and TGFβ signaling, with contradictory effects reported. We investigated the effects of TGFβ on p63 isoform proteins and mRNAs in non-malignant squamous and SCC cells, and the role of either canonical or non-canonical TGFβ signaling pathways. TGFβ selectively increased ΔNp63 protein levels in non-malignant keratinocytes in association with SMAD3 activation and was prevented by TGFβ receptor inhibition, indicating activation of canonical TGFβ pathway signaling. TP63 isoform mRNAs showed discordance from protein levels, with an initial increase in both TAP63 and ΔNP63 mRNAs followed by a decrease at later times. These data demonstrate complex and heterogeneous effects of TGFβ in squamous cells that depend on the extent of canonical TGFβ pathway aberrations. The interplay between TGFβ and p63 is likely to influence the magnitude of EMT states in SCC, with clinical implications for tumor progression and response to therapy.

摘要

TGFβ 在炎症、伤口愈合、上皮-间充质转化 (EMT) 和癌症干细胞状态中发挥作用，并作为鳞状细胞癌 (SCC) 的肿瘤抑制基因。SCC 还表现出高水平的 ΔNp63，其诱导上皮细胞表型并维持鳞状干细胞。先前的研究表明 ΔNp63 和 TGFβ 信号之间存在复杂的相互作用，报告了相互矛盾的作用。我们研究了 TGFβ 对非恶性鳞状和 SCC 细胞中 p63 同工型蛋白和 mRNAs 的影响，以及经典或非经典 TGFβ 信号通路的作用。TGFβ 选择性地增加非恶性角质形成细胞中 ΔNp63 蛋白水平，与 SMAD3 激活相关，并通过 TGFβ 受体抑制来预防，表明经典 TGFβ 途径信号的激活。TP63 同工型 mRNAs 的蛋白水平不一致，TAP63 和 ΔNP63 mRNAs 最初增加，随后在稍后时间减少。这些数据表明 TGFβ 在鳞状细胞中的作用复杂且具有异质性，这取决于经典 TGFβ 途径异常的程度。TGFβ 和 p63 之间的相互作用可能会影响 SCC 中 EMT 状态的幅度，对肿瘤进展和对治疗的反应具有临床意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/db01a0769c35/41598_2024_57895_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/466ee97fb371/41598_2024_57895_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/6763e77ecc54/41598_2024_57895_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/0f5f65873032/41598_2024_57895_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/4a64948478f4/41598_2024_57895_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/9c8dd1c1e3f0/41598_2024_57895_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/db01a0769c35/41598_2024_57895_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/466ee97fb371/41598_2024_57895_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/6763e77ecc54/41598_2024_57895_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/0f5f65873032/41598_2024_57895_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/4a64948478f4/41598_2024_57895_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/9c8dd1c1e3f0/41598_2024_57895_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/10973453/db01a0769c35/41598_2024_57895_Fig6_HTML.jpg

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本文引用的文献

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The epithelial-mesenchymal plasticity landscape: principles of design and mechanisms of regulation.上皮-间质可塑性全景：设计原则与调控机制
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ΔNp63α 在癌症中的作用：重要性及治疗机会。
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DNA Demethylation Switches Oncogenic ΔNp63 to Tumor Suppressive TAp63 in Squamous Cell Carcinoma.DNA去甲基化在鳞状细胞癌中将致癌性ΔNp63转换为肿瘤抑制性TAp63。
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