小细胞肺癌 (SCLC) 是一种高度转移和难治的恶性肿瘤。转移是导致 SCLC 患者死亡的主要原因，但其机制仍不清楚。由于低分子量 HA 的积累，细胞外基质中透明质酸降解失衡加速了实体肿瘤的恶性进展。我们之前发现，一种新型透明质酸酶 CEMIP 可能作为 SCLC 的转移触发器。在本研究中，我们发现患者标本的 SCLC 组织和癌旁组织以及体内正位移植模型中，CEMIP 和 HA 水平都高于对照组织。另外，高表达的 CEMIP 与 SCLC 患者淋巴转移有关，并且体外结果显示，SCLC 细胞中 CEMIP 的表达相对于人支气管上皮细胞升高。从机理上讲，CEMIP 促进了 HA 的降解和 LMW-HA 的积累。LMW-HA 激活其受体 TLR2，随后招募 c-Src 激活 ERK1/2 信号通路，从而促进 SCLC 细胞的 F-actin 重排、迁移和侵袭。此外，体内结果验证了 CEMIP 缺乏减轻了 SCLC 移植物中 HA 水平以及 TLR2、c-Src、ERK1/2 磷酸化表达，以及肝脏和脑转移。此外，肌动蛋白丝抑制剂拉曲霉素 A 的应用显著抑制了 SCLC 的肝脏和脑转移。总的来说，我们的研究揭示了 CEMIP 介导的 HA 降解在 SCLC 转移中的关键作用，并建议其作为一种引人注目的靶点和 SCLC 治疗的新策略的翻译潜力。 版权所有 ©2023 Elsevier B.V. 发表。

Small-cell lung cancer (SCLC) is a highly metastatic and recalcitrant malignancy. Metastasis is the major cause of death in patients with SCLC but its mechanism remains poorly understood. An imbalance of hyaluronan catabolism in the extracellular matrix accelerates malignant progression in solid cancers due to the accumulation of low-molecular-weight HA. We previously found that CEMIP, a novel hyaluronidase, may act as a metastatic trigger in SCLC. In the present study, we found that both CEMIP and HA levels were higher in SCLC tissues than in paracancerous tissues from patient specimens and in vivo orthotopic models. Additionally, high expression of CEMIP was associated with lymphatic metastasis in patients with SCLC, and in vitro results showed that CEMIP expression was elevated in SCLC cells relative to human bronchial epithelial cells. Mechanistically, CEMIP facilitates the breakdown of HA and accumulation of LMW-HA. LMW-HA activates its receptor TLR2, and subsequently recruits c-Src to activate ERK1/2 signalling, thereby promoting F-actin rearrangement as well as migration and invasion of SCLC cells. In addition, the in vivo results verified that depletion of CEMIP attenuated HA levels and the expressions of TLR2, c-Src, and phosphorylation of ERK1/2, as well as liver and brain metastasis in SCLC xenografts. Furthermore, the application of the actin filament inhibitor latrunculin A significantly inhibited the liver and brain metastasis of SCLC in vivo. Collectively, our findings reveal the critical role of CEMIP-mediated HA degradation in SCLC metastasis and suggest its translational potential as an attractive target and a novel strategy for SCLC therapy.Copyright © 2023. Published by Elsevier B.V.