CEMIP-mediated hyaluronan metabolism facilitates SCLC metastasis by activating TLR2/c-Src/ERK1/2 axis

转移 癌症研究 体内 细胞外基质 细胞迁移 肌动蛋白 生物 原癌基因酪氨酸蛋白激酶Src 病理 癌症 医学 化学 细胞 细胞生物学 磷酸化 内科学 生物化学 生物技术
作者
Li Li,Xiaoju Shen,Xiaoxiang Mo,Zhiquan Chen,Fei Yu,Xiaocheng Mo,Jinjing Song,Guolin Huang,Kai Liang,Zhuo Luo,Naiquan Mao,Jie Yang
出处
期刊:Biochimica et biophysica acta. Molecular cell research [Elsevier]
卷期号:1870 (5): 119451-119451 被引量:4
标识
DOI:10.1016/j.bbamcr.2023.119451
摘要

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.
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