脾酪氨酸激酶SYK通过驱动肌动蛋白骨架聚合促进胆管癌转移OA

AIM:To elucidate the mechanism by which spleen tyrosine kinase(SYK)drives cholangiocarci-noma(CCA)metastasis and to develop a targeted intervention strategy.METHODS:A spontaneous mouse CCA model was established by diethylnitrosamine(DEN)induction combined with left median bile duct ligation(LMBDL).The mice were randomly divided into control and model groups(n=5 per group).H&E and immunohistochemical(IHC)staining were used to analyse SYK expression during CCA progression.A clinical cohort comprising 182 CCA tissue samples and 44 adjacent normal tissue samples was included to correlate SYK expression levels with clinicopathological features of pa-tients.Tandem mass tag(TMT)-based quantitative phosphoproteomics was used to elucidate the SYK-regulated phosphor-ylation network in the context of CCA metastasis.Phalloidin staining was performed to examine the effect of SYK expres-sion on the actin cytoskeleton of CCA cells,and Western blotting was used to verify the effects of SYK on the phosphoryla-tion of LIM domain kinase 1(LIMK1)and cofilin 1.In an orthotopic xenograft mouse model of human CCA,mice were randomly assigned to control and treatment groups(n=7 per group),and the biodistribution and antimetastatic efficacy of cholesterol-conjugated SYK heteroduplex oligonucleotides(SYK-HDOs)were evaluated.RESULTS:SYK expression was significantly elevated in hyperplastic bile duct and CCA tissues from mice.In human CCA tissues,SYK expression was significantly higher than that in adjacent normal tissues(P<0.01).High SYK expression was significantly correlated with intrahepatic metastasis(P<0.05),lymph node metastasis(P<0.01),distant metastasis(P<0.01),postoperative re-currence(P<0.05),and shortened overall survival(P<0.01)in patients with CCA.SYK promoted F-actin cytoskeleton remodelling via the LIMK1-cofilin 1 axis to drive CCA metastasis.Cholesterol-conjugated SYK-HDOs were enriched in the liver and significantly inhibited intrahepatic metastasis of human CCA in mice(P<0.01).CONCLUSION:SYK drives CCA metastasis by promoting F-actin cytoskeleton polymerization via the LIMK1-cofilin 1 axis.Cholesterol-conju-gated SYK-HDOs demonstrate favourable hepatic targeting properties and antimetastatic efficacy against CCA.