Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma.
Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma.
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缺氧通过调节人肝细胞癌中 BCL9 的表达激活 Wnt/β-catenin 信号传导
DOI：
10.1038/srep40446
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发表时间：
2017-01-11
影响因子：
4.6
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Xu W;Zhou W;Cheng M;Wang J;Liu Z;He S;Luo X;Huang W;Chen T;Yan W;Xiao J
Wnt/β-catenin信号在肝细胞癌（HCC）的发生发展过程中异常激活。BCL 9是Wnt/β-catenin信号传导中的必需共激活剂。重要的是，BCL 9在源自正常细胞对应物的肿瘤中不存在，并在包括肝癌在内的许多癌症中过表达。但BCL 9过表达的机制仍不清楚。大量证据表明缺氧诱导因子（HIF）在肝癌的发生发展中起作用。我们的研究发现，BCL 9在原发性肝癌和骨转移标本中均过表达; BCL 9的缺失抑制了肝癌的增殖、迁移和血管生成;缺氧机械诱导了BCL 9的表达。低氧条件下BCL 9的诱导主要由HIF-1α介导，而不是HIF 2 α。来自异种移植模型的体外证据表明，BCL 9启动子/基因敲除抑制HCC肿瘤生长和血管生成。值得注意的是，我们发现BCL 9和HIF-1α在人HCC标本中协同调节。提示缺氧可促进BCL 9的表达，与肝癌的发生发展有关。HIF-1α对BCL 9表达的特异性调控可能是Wnt/β-catenin信号通路和缺氧信号通路之间的潜在串扰。
The Wnt/β-catenin signaling is abnormally activated in the progression of hepatocellular carcinoma (HCC). BCL9 is an essential co-activator in the Wnt/β-catenin signaling. Importantly, BCL9 is absent from tumors originating from normal cellular counterparts and overexpressed in many cancers including HCC. But the mechanism for BCL9 overexpression remains unknown. Ample evidence indicates that hypoxia inducible factors (HIFs) play a role in the development of HCC. It was found in our study that BCL9 was overexpressed in both primary HCC and bone metastasis specimens; loss of BCL9 inhibited the proliferation, migration and angiogenesis of HCC; and that that hypoxia mechanically induced the expression of BCL9. BCL9 induction under the hypoxic condition was predominantly mediated by HIF-1α but not HIF2α. In vitro evidence from xenograft models indicated that BCL9 promoter/gene knockout inhibited HCC tumor growth and angiogenesis. Notably, we found that BCL9 and HIF-1α were coordinately regulated in human HCC specimen. The above findings suggest that hypoxia may promote the expression of BCL9 and associate with the development of HCC. Specific regulation of BCL9 expression by HIF-1α may prove to be an underlying crosstalk between Wnt/β-catenin signaling and hypoxia signaling pathways.