血管内皮细胞与表皮细胞间通讯致索拉非尼手足皮肤反应的作用及机制研究

Sorafinib is a kind of first-line drug used for liver cancer and other solid tumors. Every year more than ten thousands patients benefit from it. However, the use of sorafenib could cause hand-foot skin reaction (HFSR), which characterized as excessive skin keratinization. The occurrence of HFSR is about 30%. The mechanism of sorafenib-induced HFSR is not clear at present. Through previous study we find that hand-foot skin reaction is accompanied by vascular injury, the up-regulation of epidermic growth factor HBEGF, which remind us HBEGF propably is the key factor in the mechanism of hand-foot skin reaction through activating SIRT1. Based on the content of above, we will research on the role of vascular injury caused by sorafinib in excessive skin keratinization, to confirm HBEGF as medium between the vascular injury and keratinization, and illuminate the molecular mechanism of HBEGF-SIRT1 pathway regulating the connection of vascular endothelial cell and epidermal cell. In a word, our research will clarify the mechanism of hand-foot skin reaction induced by VEGFR2-targeted drugs, and explore effective clinical intervention strategy for hand-foot skin reaction.

索拉非尼是治疗肝癌等多种实体瘤的一线药物，每年超过十万患者从中获益，但发生率高达30%以上、以表皮过度角质化为特征的手足皮肤反应限制了其长期使用。目前因发生机制不明，临床缺乏切实有效的保护手段。我们前期发现索拉非尼造成肢端血管内皮细胞损伤是手足皮肤反应发生的重要原因。血管内皮细胞损伤后释放的HBEGF，在表皮细胞过度角质化中发挥关键作用，并极可能通过调控SIRT1的表达导致表皮角质化。基于此，本课题将明确索拉非尼造成的血管内皮细胞损伤在表皮细胞过度角质化中的作用，确证HBEGF在两者之间发挥的媒介角色，阐明HBEGF-SIRT1信号轴调控血管内皮细胞与表皮细胞通讯致索拉非尼手足皮肤反应的分子过程，并探索SIRT1抑制剂治疗索拉非尼手足皮肤反应的可行性。本课题不仅阐明索拉非尼手足皮肤反应全新分子机制，发现HBEGF的新生物学功能，还为索拉非尼临床长期安全使用提供新策略。

本课题以索拉非尼引起角质形成细胞过度角质化为切入点，明确索拉非尼可引起血管内皮细胞释放HB-EGF，导致角质形成细胞发生过度角质化；揭示HB-EGF/SIRT1信号轴调控血管内皮细胞与角质形成细胞通讯所致索拉非尼手足皮肤反应的分子过程，在这一分子过程中，HB-EGF通过激活JNK2的磷酸化以提高SIRT1的蛋白水平从而发挥其促进角质化的生物学功能；此外发现SIRT1抑制剂尼克酰胺对索拉非尼的手足皮肤反应具有干预作用，为临床上索拉非尼手足皮肤反应的治疗提供理论依据和策略。