Metastasis is the leading cause of cancer-related death.The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastas...Metastasis is the leading cause of cancer-related death.The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis.Surgery is a common intervention for most primary solid tumors.However,surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells(ECs).Currently,there are no effective interventions to prevent distant metastasis.Here,we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models.HECTD3 depletion downregulates expression of adhesion molecules,such as VCAM-1,ICAM-1 and E-selectin,in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo.We demonstrate that HECTD3 promotes stabilization,nuclear localization and kinase activity of IKKa by ubiquitinating IKKa with K27-and K63-linked polyubiquitin chains at K296,increasing phosphorylation of histone H3 to promote NF-kB target gene transcription.Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization,while conditional knockin promotes that.IKKa kinase inhibitors prevented LPS-induced pulmonary metastasis.These findings reveal the promotional role of the HECTD3-IKKa axis in tumor hematogenous metastasis and providea potential strategy for tumormetastasis prevention.展开更多
基金This work was supported by grants from the National Key Research and Development Program of China(2020YFA0112300 and 2018YFC2000400 to C.C.)the National Postdoctoral Program for Innovative Talents(BX20190088 to F.L.)+2 种基金the National Natural Science Foundation of China(82000817 to F.L.,81773149 to Y.K.,U2102203 and 81830087 to C.C.,82173014 and 81872414 to D.J.,81772847 to R.L.)the China Postdoctoral Science Foundation(2019M662869 to F.L.,182703 and 230794 to Y.K.,CAS Light of West China program(Young Scholar 2021000006 to D.J.)the Yunnan Applied Basic Research Projects(202101AS070050 to C.C.,202001AU070095 to H.L.,2018FB134 to Y.K.,2019FB112 and 202001AW070018 to D.J.).
文摘Metastasis is the leading cause of cancer-related death.The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis.Surgery is a common intervention for most primary solid tumors.However,surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells(ECs).Currently,there are no effective interventions to prevent distant metastasis.Here,we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models.HECTD3 depletion downregulates expression of adhesion molecules,such as VCAM-1,ICAM-1 and E-selectin,in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo.We demonstrate that HECTD3 promotes stabilization,nuclear localization and kinase activity of IKKa by ubiquitinating IKKa with K27-and K63-linked polyubiquitin chains at K296,increasing phosphorylation of histone H3 to promote NF-kB target gene transcription.Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization,while conditional knockin promotes that.IKKa kinase inhibitors prevented LPS-induced pulmonary metastasis.These findings reveal the promotional role of the HECTD3-IKKa axis in tumor hematogenous metastasis and providea potential strategy for tumormetastasis prevention.
