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Proangiogenic factor midkine is increased in melanoma patients with sleep apnea and induces tumor cell proliferation
The FASEB Journal ( IF 4.8 ) Pub Date : 2020-10-15 , DOI: 10.1096/fj.202001247rr
Carolina Cubillos‐Zapata 1, 2 , Miguel Ángel Martínez‐García 3 , Elena Díaz‐García 1, 2 , Victor Toledano 2, 4, 5 , Francisco Campos‐Rodríguez 2, 6 , Manuel Sánchez‐de‐la‐Torre 2, 7 , Eduardo Nagore 8 , Antonio Martorell‐Calatayud 9 , Luis Hernández Blasco 10, 11 , Esther Pastor 12 , Jorge Abad‐Capa 2, 13 , Josep María Montserrat 2, 14 , Valentín Cabriada‐Nuño 15 , Irene Cano‐Pumarega 16 , Jaime Corral‐Peñafiel 2, 17 , Eva Arias 18 , Olga Mediano 2, 19 , María Somoza‐González 20 , Joan Dalmau‐Arias 21 , Isaac Almendros 2, 22, 23 , Ramón Farré 2, 22, 23 , Eduardo López‐Collazo 2, 4, 5 , David Gozal 24 , Francisco García‐Río 1, 2, 25 ,
Affiliation  

Midkine (MDK) might mediate the proangiogenic effect of intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) and cutaneous melanoma (CM). We compare circulating MDK in CM patients with and without OSA, and their relationship with tumor aggressiveness, while exploring in vitro effects of soluble MDK on human lymphatic endothelial (HLEC) and melanoma cell proliferation. In 360 CM patients, sleep studies and MDK serum level measurements were performed. The effect of MDK on cell proliferation was assessed using HLEC and melanoma cell lines with patient sera under both normoxia and IH. MDK levels were higher in severe OSA compared to mild OSA or non‐OSA patients, whereas no differences in VEGF levels emerged. In OSA patients, MDK levels correlated with nocturnal hypoxemia and CM mitotic rate. In vitro, MDK promotes HLEC proliferation under IH conditions. Moreover, cultures of the human melanoma cell line C81‐61 with sera from patients with the highest MDK levels promoted tumor cell proliferation, which was attenuated after the addition of MDK antibody. These responses were enhanced by IH exposures. In conclusion, in CM patients, OSA severity is associated with higher MDK levels, which, appear to enhance both the lymphangiogenesis as the intrinsic aggressiveness of CM tumor cells.

中文翻译:

睡眠呼吸暂停黑色素瘤患者促血管生成因子中期因子增加并诱导肿瘤细胞增殖

Midkine (MDK) 可能介导间歇性缺氧 (IH) 对阻塞性睡眠呼吸暂停 (OSA) 和皮肤黑色素瘤 (CM) 患者的促血管生成作用。我们比较了有和没有 OSA 的 CM 患者的循环 MDK 及其与肿瘤侵袭性的关系,同时探索可溶性 MDK 对人淋巴管内皮 (HLEC) 和黑色素瘤细胞增殖的体外影响。在 360 名 CM 患者中,进行了睡眠研究和 MDK 血清水平测量。在常氧和 IH 下,使用 HLEC 和黑色素瘤细胞系以及患者血清评估 MDK 对细胞增殖的影响。与轻度 OSA 或非 OSA 患者相比,重度 OSA 患者的 MDK 水平更高,而 VEGF 水平没有出现差异。在 OSA 患者中,MDK 水平与夜间低氧血症和 CM 有丝分裂率相关。体外,MDK 在 IH 条件下促进 HLEC 增殖。此外,人黑色素瘤细胞系 C81-61 与来自具有最高 MDK 水平的患者的血清的培养促进了肿瘤细胞增殖,在添加 MDK 抗体后其减弱。IH 暴露增强了这些反应。总之,在 CM 患者中,OSA 的严重程度与更高的 MDK 水平相关,这似乎增强了淋巴管生成和 CM 肿瘤细胞的内在侵袭性。
更新日期:2020-10-15
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