Sun Eun-Gene, Vijayan Veena, Park Mi-Ra, Yoo Kyung Hyun, Cho Sang-Hee, Bae Woo-Kyun, Shim Hyun-Jeong, Hwang Jun-Eul, Park In-Kyu, Chung Ik-Joo
Department of Hematology and Oncology, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea.
Immunotherapy Innovation Center, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea.
Cell Death Discov. 2023 Apr 11;9(1):122. doi: 10.1038/s41420-023-01419-9.
Transforming growth factor-β-activated kinase 1 (TAK1), which is highly expressed and aberrantly activated in triple-negative breast cancer (TNBC), plays a pivotal role in metastasis and progression. This makes it a potential therapeutic target for TNBC. Previously, we reported lectin galactoside-binding soluble 3 binding protein (LGALS3BP) as a negative regulator of TAK1 signaling in the inflammatory response and inflammation-associated cancer progression. However, the role of LGALS3BP and its molecular interaction with TAK1 in TNBC remain unclear. This study aimed to investigate the function and underlying mechanism of action of LGALS3BP in TNBC progression and determine the therapeutic potential of nanoparticle-mediated delivery of LGALS3BP in TNBC. We found that LGALS3BP overexpression suppressed the overall aggressive phenotype of TNBC cells in vitro and in vivo. LGALS3BP inhibited TNF-α-mediated gene expression of matrix metalloproteinase 9 (MMP9), which encodes a protein crucial for lung metastasis in TNBC patients. Mechanistically, LGALS3BP suppressed TNF-α-mediated activation of TAK1, a key kinase linking TNF-α stimulation and MMP9 expression in TNBC. Nanoparticle-mediated delivery enabled tumor-specific targeting and inhibited TAK1 phosphorylation and MMP9 expression in tumor tissues, suppressing primary tumor growth and lung metastasis in vivo. Our findings reveal a novel role of LGALS3BP in TNBC progression and demonstrate the therapeutic potential of nanoparticle-mediated delivery of LGALS3BP in TNBC.
转化生长因子-β激活激酶1（TAK1）在三阴性乳腺癌（TNBC）中高表达且异常激活，在转移和进展中起关键作用。这使其成为TNBC的潜在治疗靶点。此前，我们报道了凝集素半乳糖苷结合可溶性3结合蛋白（LGALS3BP）在炎症反应和炎症相关癌症进展中作为TAK1信号的负调节因子。然而，LGALS3BP在TNBC中的作用及其与TAK1的分子相互作用仍不清楚。本研究旨在探讨LGALS3BP在TNBC进展中的功能和潜在作用机制，并确定纳米颗粒介导的LGALS3BP递送在TNBC中的治疗潜力。我们发现LGALS3BP过表达在体外和体内均抑制了TNBC细胞的整体侵袭性表型。LGALS3BP抑制了肿瘤坏死因子-α（TNF-α）介导的基质金属蛋白酶9（MMP9）的基因表达，MMP9编码一种对TNBC患者肺转移至关重要的蛋白质。机制上，LGALS3BP抑制了TNF-α介导的TAK1激活，TAK1是连接TNF-α刺激和TNBC中MMP9表达的关键激酶。纳米颗粒介导的递送实现了肿瘤特异性靶向，并抑制了肿瘤组织中TAK1的磷酸化和MMP9的表达，在体内抑制了原发性肿瘤生长和肺转移。我们的研究结果揭示了LGALS3BP在TNBC进展中的新作用，并证明了纳米颗粒介导的LGALS3BP递送在TNBC中的治疗潜力。
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