RNF219/α-Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications.
RNF219/α-Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications.
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RNF219/-Catenin/LGALS3 轴促进肝细胞癌骨转移及相关骨骼并发症
DOI：
10.1002/advs.202001961
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Zhang S;Xu Y;Xie C;Ren L;Wu G;Yang M;Wu X;Tang M;Hu Y;Li Z;Yu R;Liao X;Mo S;Wu J;Li M;Song E;Qi Y;Song L;Li J
由于肝细胞癌（HCC）患者总体生存期的延长，在过去的十年中，HCC骨转移的发生率显著增加。然而，HCC骨转移的潜在机制在很大程度上仍然未知。在目前的研究中，发现HCC分泌的凝集素半乳糖苷结合可溶性3（LGALS 3）显著上调，并与HCC患者较短的无骨转移生存期相关。LGALS 3的过表达增强了HCC细胞向骨的转移能力，并通过促进破骨细胞融合和足体形成骨转移前小生境来诱导骨骼相关事件。机械上，泛素连接酶RNF 219介导的α-连环蛋白降解促进LGALS 3启动子的YAP 1/β-连环蛋白复合物依赖性表观遗传修饰，导致LGALS 3上调和转移性骨疾病。重要的是，用用于黄斑变性的临床药物维替泊芬治疗，降低LGALS 3表达并有效抑制HCC的骨骼并发症。这些发现揭示了HCC分泌的LGALS 3在转移前小生境中的合理作用，并可以为HCC骨转移的临床干预提供有希望的策略。肝细胞癌（HCC）分泌的LGALS 3通过促进破骨细胞融合和podosome形成诱导溶骨性骨转移（BM）。从机制上讲，RNF 219介导的α-catenin降解导致LGALS 3启动子上的YAP 1/β-catenin依赖性表观遗传修饰，引发HCC中LGALS 3上调。通过维替泊芬阻断LGALS 3启动子上YAP 1/β-catenin复合物的形成可降低LGALS 3表达并有效抑制HCC骨转移（HCC-BM），这代表了HCC-BM临床治疗的潜在策略。
The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone‐metastasis remain largely unknown. In the current study, HCC‐secreted lectin galactoside‐binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone‐metastasis‐free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal‐related events by forming a bone pre‐metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219‐meidated α‐catenin degradation prompts YAP1/β‐catenin complex‐dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC‐secreted LGALS3 in pre‐metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone‐metastasis. Hepatocellular carcinoma (HCC)‐secreted LGALS3 induces osteolytic bone metastasis (BM) via promoting osteoclast fusion and podosome formation. Mechanistically, RNF219‐mediated α‐catenin degradation results in YAP1/β‐catenin‐dependent epigenetic modifications on LGALS3 promoter, eliciting in LGALS3 upregulation in HCC. Blocking YAP1/β‐catenin complex formation on LGALS3 promoter via verteporfin reduces LGALS3 expression and effectively inhibits HCC bone‐metastasis (HCC‐BM), which represents a potential strategy for HCC‐BM clinical treatment.
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影响因子：
11.2
作者：
Nakajima K;Kho DH;Yanagawa T;Harazono Y;Hogan V;Chen W;Ali-Fehmi R;Mehra R;Raz A
通讯作者：
Raz A
通过生物素化 dCas9 原位捕获染色质相互作用
影响因子：
64.5
作者：
Liu X;Zhang Y;Chen Y;Li M;Zhou F;Li K;Cao H;Ni M;Liu Y;Gu Z;Dickerson KE;Xie S;Hon GC;Xuan Z;Zhang MQ;Shao Z;Xu J
通讯作者：
Xu J
DOI：
10.1007/bf02547227
发表时间：
1973-01-01
期刊：
CALCIFIED TISSUE RESEARCH
影响因子：
--
作者：
JUNG, A;BISAZ, S;FLEISCH, H
通讯作者：
FLEISCH, H
影响因子：
4.1
作者：
Gibault, Floriane;Corvaisier, Matthieu;Cotelle, Philippe
通讯作者：
Cotelle, Philippe
DOI：
10.6004/jnccn.2017.7024
发表时间：
2018-01-01
影响因子：
13.4
作者：
Harding, James J.;Abu-Zeinah, Ghaith;Abou-Alfa, Ghassan K.
通讯作者：
Abou-Alfa, Ghassan K.