Elevated ER? expression driven by low ASB8-mediated ubiquitination in lung adenocarcinoma promotes lymph node metastasis via tumor-associated neutrophils.

This study investigated the role of estrogen receptor beta (ER?) in the lymph node metastasis of lung adenocarcinoma (LUAD), focusing on its interaction with tumor-associated neutrophils (TANs) and its regulation of lymphangiogenesis. Clinical analysis of LUAD patient samples revealed that high ER? expression was correlated with positive lymph node metastasis ...
and increased lymphatic vessel density. In vitro experiments showed that ER? promotes neutrophil chemotaxis by regulating CCL15 transcription, whereas TANs secrete VEGF-C, enhancing lymphangiogenesis. Using an orthotopic lung cancer model, we confirmed that ER? facilitates LUAD lymph node metastasis through TAN recruitment, and inhibiting neutrophils with anti-Ly6G antibodies or CCR1 antagonists reduced this effect. Additionally, the study found that ASB8, an E3 ubiquitin ligase, degrades ER? through K48-linked polyubiquitination. Low ASB8 expression results in increased ER? stability and promotes LUAD metastasis. These findings suggest that ER?, by recruiting TANs through the CCL15-CCR1 axis, plays a key role in LUAD lymph node metastasis, with ASB8 acting as a crucial regulator of ER? stability. Targeting ER? and ASB8 could offer new therapeutic strategies for LUAD metastasis, warranting further investigation of their clinical applications.
Mesh Terms:
Adenocarcinoma of Lung, Animals, Cell Line, Tumor, Estrogen Receptor beta, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Lymphangiogenesis, Lymphatic Metastasis, Male, Mice, Mice, Nude, Neutrophils, Receptors, CCR1, Ubiquitination
Cell Death Dis
Date: Jul. 30, 2025
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