Targeting LAYN inhibits colorectal cancer metastasis and tumor- associated macrophage infiltration induced by hyaluronan oligosaccharides
Targeting LAYN inhibits colorectal cancer metastasis and tumor- associated macrophage infiltration induced by hyaluronan oligosaccharides
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DOI：
10.1016/j.matbio.2023.02.005
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发表时间：
2023-02-24
期刊：
影响因子：
6.9
通讯作者：
Pan, Jinghua
中科院分区：
文献类型：
--
作者：
Yang, Yabing;Chen, Zuyang;Pan, Jinghua
透明质酸低聚糖(OHA)在结直肠癌中的蓄积与肿瘤转移密切相关，但其机制尚不清楚。在这项研究中，我们首先描述了一种新的HA受体LAYN在结直肠癌组织中上调。LAYN的异常表达与结直肠癌转移和预后不良有关，与肿瘤相关巨噬细胞()的侵袭和M2巨噬细胞极化呈正相关。体外和体内研究表明，LAYN被OHA激活，继而诱导结直肠癌转移和巨噬细胞浸润。机制研究表明，OHA通过与细胞外段的第60-68位氨基酸结合来激活LAYN。OHA诱导的LAYN激活通过核因子-kB途径促进肿瘤细胞的转移和CCL20分泌。此外，使用封闭抗体靶向LAYN可以阻止OHA介导的肿瘤转移、侵袭和M2极化。这项研究揭示了LAYN的激活机制，并确定了用于治疗OHA水平高的CRC肿瘤的潜在靶点。(C)2023 Elsevier B.V.保留所有权利。
The accumulation of hyaluronan oligosaccharides (oHA) in colorectal cancer (CRC) is closely related to tumor metastasis, but the underlying mechanism remains unclear. In this study, we first described that LAYN, a novel HA receptor, was upregulated in CRC tissue. Aberrant LAYN expression correlated with CRC metasta-sis and poor prognosis and positively correlated with tumor-associated macrophage (TAM) infiltration and M2 macrophage polarization in the tumor environment. Both in vitro and in vivo studies demonstrated that LAYN is activated by oHA and subsequently induces CRC metastasis and macrophage infiltration. Mechanistic studies demonstrated that oHA activates LAYN by binding to the 60-68th amino acid region of the extracellu-lar segment. oHA-induced LAYN activation promoted metastasis and CCL20 secretion through the NF-kB pathway in CRC cells. Furthermore, targeting LAYN using a blocking antibody prevented oHA-mediated tumor metastasis, TAM infiltration and M2 polarization. This study revealed the LAYN activation mechanism and identified a potential target for the treatment of CRC tumor exhibiting high oHA levels.(c) 2023 Elsevier B.V. All rights reserved.