Midkine mediates dysfunction of liver sinusoidal endothelial cells through integrin α4 and α6

Midkine (MK)² is an important regulatory molecule that promotes pathological angiogenesis of hepatocellular carcinoma (HCC). Although some studies have shown that its expression is increased in chronic liver disease, its effect on sinusoidal vasculopathy are still unclear. In this study, we demonstrated that MK was mainly secreted by liver sinus endothelial cells (LSECs) during the stage of precancerous lesions. Increased expression of its receptor integrin was an important mechanism by which MK participated in sinusoidal vasculopathy through autocrine and positive feedback effects. LSECs with high expression of integrin α6 (Itgα6⁺) and integrin α4 (Itgα4⁺) were used to study the mechanism of MK, and it was found that the effect of MK on LSECs was closely related to the integrin subtypes. The activation of MK /integrin α6/Src/Shc signaling pathway promoted the expression of ET-1, TXA2 and reduced the production of NO, and then induced the capillary vascularization of liver sinusoids, while the activation of MK/integrin α4/NF-κB pathway mainly induced angiogenesis by promoting the production of VEGF and Ang2. In the three-dimensional co-culture system of hepatocytes (BRL-3A) and LSECs, MK significantly increased the production of reactive oxygen species (ROS) in the co-culture system of highly expressed integrin LSECs and decreased the expression of tumor suppressor gene P53 in hepatocytes. These results suggested that MK /integrin signaling pathway, especially MK /integrin α6, was an important mechanism leaded to persistent sinusoidal hepatic vasculopathy in chronic liver disease and induced HCC，while MK/integrin α 4 activation was more involved in pathological angiogenesis.