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Claudin-3 通过调节淋巴管内皮细胞中的 PI3K 信号通路抑制肿瘤诱导的淋巴管生成。

Claudin-3 inhibits tumor-induced lymphangiogenesis via regulating the PI3K signaling pathway in lymphatic endothelial cells.

机构信息

Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, 450052, Henan, China.

School of Basic Medical Sciences, Zhengzhou University, No. 100 Kexue Road, Zhengzhou, 450001, China.

出版信息

Sci Rep. 2022 Oct 19;12(1):17440. doi: 10.1038/s41598-022-22156-6.

DOI:10.1038/s41598-022-22156-6
PMID:36261482
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9581975/
Abstract

Claudin-3 is a tight junction protein that has often been associated with the progression and metastasis of various tumors. Here, the role of claudin-3 in tumor-induced lymphangiogenesis is investigated. We found an increased lymphangiogenesis in the B16F10 tumor in claudin-3 knockout mice, accompanied by augmented melanoma cell metastasis into sentinel lymph nodes. In vitro, the overexpression of claudin-3 on lymphatic endothelial cells inhibited tube formation by suppressing cell migration, resulting in restricted lymphangiogenesis. Further experiments showed that claudin-3 inhibited lymphatic endothelial cell migration by regulating the PI3K signaling pathway. Interestingly, the expression of claudin-3 in lymphatic endothelial cells is down-regulated by vascular endothelial growth factor C that is often present in the tumor microenvironment. This study indicates that claudin-3 plays an important role as a signaling molecule in lymphatic endothelial cell activity associated with tumor lymphangiogenesis, which may further contribute to melanoma metastasis.

摘要

紧密连接蛋白 Claudin-3 常与多种肿瘤的进展和转移有关。本研究旨在探讨 Claudin-3 在肿瘤诱导的淋巴管生成中的作用。研究发现 Claudin-3 基因敲除的 B16F10 肿瘤中淋巴管生成增加，伴随黑色素瘤细胞向前哨淋巴结转移增加。在体外， Claudin-3 在淋巴管内皮细胞中的过表达通过抑制细胞迁移抑制管形成，导致淋巴管生成受限。进一步的实验表明 Claudin-3 通过调节 PI3K 信号通路抑制淋巴管内皮细胞迁移。有趣的是，血管内皮生长因子 C（通常存在于肿瘤微环境中）下调 Claudin-3 在淋巴管内皮细胞中的表达。本研究表明 Claudin-3 作为一种信号分子在与肿瘤淋巴管生成相关的淋巴管内皮细胞活性中发挥重要作用，这可能进一步促进黑色素瘤转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/19c894b20420/41598_2022_22156_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/7f67c3e7e573/41598_2022_22156_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/ab9ff388ae53/41598_2022_22156_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/8157d2a56ebc/41598_2022_22156_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/86fb855637be/41598_2022_22156_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/540e3dcd3fbb/41598_2022_22156_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/1e8e1ba161e1/41598_2022_22156_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/19c894b20420/41598_2022_22156_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/7f67c3e7e573/41598_2022_22156_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/ab9ff388ae53/41598_2022_22156_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/8157d2a56ebc/41598_2022_22156_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/86fb855637be/41598_2022_22156_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/540e3dcd3fbb/41598_2022_22156_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/1e8e1ba161e1/41598_2022_22156_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b7c/9581975/19c894b20420/41598_2022_22156_Fig7_HTML.jpg

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本文引用的文献

[1]
S100A4-dependent glycolysis promotes lymphatic vessel sprouting in tumor.

Angiogenesis. 2023-2

[2]
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Science. 2020-7-10

[3]
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Nat Commun. 2020-6-8

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Tight junctions in the blood-brain barrier promote edema formation and infarct size in stroke - Ambivalent effects of sealing proteins.

J Cereb Blood Flow Metab. 2021-1

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Mir526b and Mir655 Promote Tumour Associated Angiogenesis and Lymphangiogenesis in Breast Cancer.

Cancers (Basel). 2019-7-4

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Front Physiol. 2019-1-23

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Sci Rep. 2019-1-18

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EMBO J. 2018-10-8

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PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations.

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Curr Opin Immunol. 2018-4-23

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