s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide.
s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide.
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s-HBEGF/SIRT1 电路控制的血管内皮细胞和角质形成细胞之间的串扰介导索拉非尼诱导的手足皮肤反应，该反应可被烟酰胺逆转
DOI：
10.1038/s41422-020-0309-6
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发表时间：
2020-09
期刊：
影响因子：
44.1
通讯作者：
He Q
中科院分区：
文献类型：
--
作者：
Luo P;Yan H;Chen X;Zhang Y;Zhao Z;Cao J;Zhu Y;Du J;Xu Z;Zhang X;Zeng S;Yang B;Ma S;He Q
手足皮肤反应（HFSR）是索拉非尼最显著的不良反应之一，限制了这种一线药物治疗各种恶性肿瘤的临床获益。这种毒性的机制仍然知之甚少，因此缺乏有效的干预策略。在本研究中，我们发现血管内皮细胞是索拉非尼诱导的HFSR的主要细胞靶点，其中可溶性肝素结合表皮生长因子（s-HBEGF）介导血管内皮细胞和角质形成细胞之间的串扰。从机制上讲，从血管内皮细胞释放的s-HBEGF激活角质形成细胞上的表皮生长因子受体（EGFR）并促进c-Jun N-末端激酶2（JNK 2）的磷酸化，JNK 2稳定了sirtuin 1（SIRT 1），这是一种必需的角质化诱导剂，并最终产生HFSR。在体内施用s-HBEGF可以在没有索拉非尼治疗的情况下充分诱导过度角化。此外，我们报告了HBEGF中和抗体、Sirt 1敲低和经典的SIRT 1抑制剂烟酰胺都可以显著降低小鼠模型中索拉非尼诱导的HFSR。值得注意的是，在初步临床研究中，烟酰胺的前药烟酸可以在10名患者中实质上逆转索拉非尼诱导的HFSR。总的来说，我们的研究结果揭示了血管内皮细胞促进角质形成细胞角质化的机制，并为索拉非尼诱导的HFSR的治疗提供了一个潜在的有前途的治疗策略。
Hand–foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR.
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影响因子：
168.9
作者：
Brose, Marcia S.;Nutting, Christopher M.;Jarzab, Barbara;Elisei, Rossella;Siena, Salvatore;Bastholt, Lars;de la Fouchardiere, Christelle;Pacini, Furio;Paschke, Ralf;Shong, Young Kee;Sherman, Steven I.;Smit, Johannes W. A.;Chung, John;Kappeler, Christian;Pena, Carol;Molnar, Istvan;Schlumberger, Martin J.
通讯作者：
Schlumberger, Martin J.
影响因子：
6.5
作者：
Blander, Gil;Bhimavarapu, Anupama;Loureiro, Joseph Jorge
通讯作者：
Loureiro, Joseph Jorge
影响因子：
4.8
作者：
Gaviglio, Angela L.;Knelson, Erik H.;Blobe, Gerard C.
通讯作者：
Blobe, Gerard C.
影响因子：
4.3
作者：
Ford, Jack;Ahmed, Shafiq;Milner, Jo
通讯作者：
Milner, Jo
角质形成细胞在卡培他滨刺激的手足综合征中的作用
影响因子：
4.3
作者：
Chen, Min;Chen, Jian;He, Qiaojun
通讯作者：
He, Qiaojun