Autophagy-dependent expression of osteopontin and its downstream Stat3 signaling contributes to lymphatic malformation progression to lymphangiosarcoma.
Autophagy-dependent expression of osteopontin and its downstream Stat3 signaling contributes to lymphatic malformation progression to lymphangiosarcoma.
复制标题
骨桥蛋白及其下游 Stat3 信号的自噬依赖性表达有助于淋巴管畸形进展为淋巴管肉瘤。
DOI：
10.1080/15548627.2023.2213527
复制
发表时间：
2024
期刊：
影响因子：
13.3
通讯作者：
Guan,Jun-Lin
中科院分区：
文献类型：
--
作者：
Yang,Fuchun;Guan,Jun-Lin
淋巴管畸形（LM）是一种淋巴管内皮细胞（EC）的血管异常，部分患者可发展为致命的恶性淋巴管肉瘤（LAS）。使用遗传工具删除一个重要的自噬基因Rb 1cc 1/FIP 200或其突变特异性阻断其自噬功能，我们证明了自噬抑制废除LM进展为LAS，虽然不影响LM形成在我们最近开发的小鼠模型LAS。对体内小鼠模型和体外血管肿瘤细胞的分析表明，自噬抑制降低了体外血管肿瘤细胞增殖和体内致瘤性，而不直接影响作为致癌驱动因子的mTORC 1信号传导。自噬缺陷肿瘤细胞的转录谱分析和进一步的机制研究揭示了骨桥蛋白（OPN）及其下游Jak/Stat 3信号转导在介导自噬调节血管肿瘤细胞中的作用。总之，这些结果支持潜在的新的预防策略，以靶向自噬和/或其下游OPN表达，以防止良性LM发展为恶性和致命的LAS.Abbreviations：LM：淋巴管畸形; EC：内皮细胞; LAS：淋巴管肉瘤; OPN：骨桥蛋白; RB 1CC 1：RB 1诱导卷曲螺旋1; FIP 200：FAK家族相互作用蛋白200 kDa。
Lymphatic malformation (LM) is a vascular anomaly from lymphatic endothelial cells (ECs), and a fraction of the patients could progress to the deadly malignant lymphangiosarcoma (LAS). Using genetic tools to delete an essential autophagy gene Rb1cc1/FIP200 or its mutation specifically blocking its autophagy function, we demonstrated that autophagy inhibition abrogated LM progression to LAS although not affecting LM formation in our recently developed mouse model of LAS. Analysis of the mouse models in vivo and vascular tumor cells in vitro showed that autophagy inhibition reduced vascular tumor cell proliferation in vitro and tumorigenicity in vivo without affecting mTORC1 signaling as an oncogenic driver directly. Transcriptional profiling of autophagy-deficient tumor cells and further mechanistic studies revealed a role for osteopontin (OPN) and its downstream Jak/Stat3 signaling in mediating regulation of vascular tumor cells by autophagy. Together, these results support potential new prophylactic strategies to targeting autophagy and/or its downstream OPN expression to prevent progression of the benign LM to the malignant and deadly LAS.Abbreviations:LM: lymphatic malformation; EC: endothelial cell; LAS: lymphangiosarcoma; OPN: osteopontin; RB1CC1: RB1 Inducible Coiled-Coil 1; FIP200: FAK family-interacting protein of 200 kDa.