Plexin-B3 表达可刺激 MET 信号、乳腺癌干细胞的特化以及肺转移。

Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis.

机构信息

Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.

Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21205, USA.

出版信息

Cell Rep. 2023 Mar 28;42(3):112164. doi: 10.1016/j.celrep.2023.112164. Epub 2023 Feb 28.

DOI:10.1016/j.celrep.2023.112164

PMID:36857181

Abstract

Intratumoral hypoxia is a microenvironmental feature that promotes breast cancer progression and is associated with cancer mortality. Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer, but the underlying mechanisms and consequences have not been thoroughly investigated. Here, we report that PLXNB3 expression is increased in response to hypoxia and that PLXNB3 is a direct target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 expression is correlated with HIF-1α immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) and MET/SRC/STAT3/NANOG signaling as well as hypoxia-induced breast cancer cell migration, invasion, and cancer stem cell specification. PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.

摘要

肿瘤内缺氧是一种促进乳腺癌进展的微环境特征，并与癌症死亡率相关。Plexin B3（PLXNB3）在雌激素受体阴性乳腺癌中高度表达，但潜在的机制和后果尚未得到彻底研究。在这里，我们报告说，PLXNB3 的表达在缺氧时增加，并且 PLXNB3 是人类乳腺癌细胞中缺氧诱导因子 1（HIF-1）的直接靶基因。PLXNB3 的表达与 HIF-1α免疫组化、乳腺癌分级和分期以及患者死亡率相关。在机制上，PLXNB3 是缺氧诱导的 MET/SRC/黏着斑激酶（FAK）和 MET/SRC/STAT3/NANOG 信号以及缺氧诱导的乳腺癌细胞迁移、侵袭和癌症干细胞特化所必需的。PLXNB3 敲低可损害原位乳腺癌小鼠模型中的肿瘤形成和肺转移。