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EFNB2/EPHB4 轴的适应性激活通过 LDLR 介导的胆固醇摄取促进结直肠癌肝转移的转移后生长。

Adaptive activation of EFNB2/EPHB4 axis promotes post-metastatic growth of colorectal cancer liver metastases by LDLR-mediated cholesterol uptake.

机构信息

Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China.

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, PR China.

出版信息

Oncogene. 2023 Jan;42(2):99-112. doi: 10.1038/s41388-022-02519-z. Epub 2022 Nov 14.

DOI:10.1038/s41388-022-02519-z
PMID:36376513
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9816060/
Abstract

The microenvironment of distant organ plays vital roles in regulating tumor metastases. However, little is known about the crosstalk between metastasized tumor cells and target organs. Herein, we found that EFNB2 expression was upregulated in liver metastases (LM) of colorectal cancer (CRC), but not in pulmonary metastases (PM) or primary CRC tumors. EFNB2 played a tumor-promoting role in CRC LM in vitro and in vivo. Through forward signaling, EFNB2-promoted CRC LM by interacting with the EPHB4 receptor. EFNB2/EPHB4 axis enhances LDLR-mediated cholesterol uptake in CRC LM. Subsequently, EFNB2/EPHB4 axis promotes LDLR transcription by regulating STAT3 phosphorylation. Blocking LDLR reversed the role of the EFNB2/EPHB4 axis in promoting CRC LM. Using clinical data, survival analysis revealed that the survival time of patients with CRC LM was decreased in patients with high EFNB2 expression, compared with low EFNB2 expression. Inhibition of the EFNB2/EPHB4 axis markedly prolonged the survival time of BALB/c nude mice with CRC LM with a high cholesterol diet. These findings revealed a key step in the regulation of cholesterol uptake by EFNB2/EPHB4 axis and its tumor-promoting role in CRC LM.

摘要

远处器官的微环境在调节肿瘤转移中起着至关重要的作用。然而，人们对转移瘤细胞与靶器官之间的串扰知之甚少。在此，我们发现 EFNB2 在结直肠癌（CRC）的肝转移（LM）中上调，但在肺转移（PM）或原发性 CRC 肿瘤中没有上调。EFNB2 在体外和体内均在 CRC LM 中发挥促瘤作用。通过正向信号，EFNB2 通过与 EPHB4 受体相互作用促进 CRC LM。EFNB2/EPHB4 轴增强了 CRC LM 中的 LDLR 介导的胆固醇摄取。随后，EFNB2/EPHB4 轴通过调节 STAT3 磷酸化来促进 LDLR 转录。阻断 LDLR 逆转了 EFNB2/EPHB4 轴在促进 CRC LM 中的作用。利用临床数据进行生存分析显示，CRC LM 患者 EFNB2 高表达者的生存时间较 EFNB2 低表达者缩短。高胆固醇饮食条件下，抑制 EFNB2/EPHB4 轴显著延长了携带 CRC LM 的 BALB/c 裸鼠的生存时间。这些发现揭示了 EFNB2/EPHB4 轴调节胆固醇摄取及其在 CRC LM 中的促瘤作用的关键步骤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/7c4bf1ddf37a/41388_2022_2519_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/c2feed9bb454/41388_2022_2519_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/39206316d4e2/41388_2022_2519_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/a866054b7dcb/41388_2022_2519_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/0e5f7893baa5/41388_2022_2519_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/d0a1c1c716ea/41388_2022_2519_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/e191bc947a12/41388_2022_2519_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/7c4bf1ddf37a/41388_2022_2519_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/c2feed9bb454/41388_2022_2519_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/39206316d4e2/41388_2022_2519_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/a866054b7dcb/41388_2022_2519_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/0e5f7893baa5/41388_2022_2519_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/d0a1c1c716ea/41388_2022_2519_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/e191bc947a12/41388_2022_2519_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e7/9816060/7c4bf1ddf37a/41388_2022_2519_Fig7_HTML.jpg

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[2]
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[3]
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[4]
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[5]
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[6]
Upregulation of Differentiates Intrahepatic Cholangiocarcinoma from Hepatocellular Carcinoma and Both Colorectal and Pancreatic Adenocarcinoma Liver Metastases.

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[7]
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[8]
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Curr Pharm Biotechnol. 2025

[9]
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Cancer Sci. 2024-11

[10]
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本文引用的文献

[1]
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Cancers (Basel). 2021-12-9

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Nat Commun. 2021-8-24

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Nat Rev Cancer. 2021-3

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