HIPK2 suppresses tumor growth and progression of hepatocellular carcinoma through promoting the degradation of HIF-1α
HIPK2 suppresses tumor growth and progression of hepatocellular carcinoma through promoting the degradation of HIF-1α
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HIPK2通过促进HIF-1α的降解抑制肿瘤生长和肝细胞癌的进展
DOI：
10.1038/s41388-020-1190-y
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发表时间：
2020-02-07
期刊：
影响因子：
8
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Chen, Peizhan;Duan, Xiaohua;Wang, Hui
肝细胞癌（HCC）的异常血管生成导致肿瘤生长和局部或远处转移。揭示肝癌新生血管形成的机制，可以为临床提供新的潜在治疗靶点。在此，我们报道了丝氨酸/苏氨酸同源域相互作用蛋白激酶2（HIPK 2）在肝癌组织中的表达较癌旁正常组织频繁下调，且HIPK 2蛋白表达较低的患者总体生存率较低。在体外和体内，HIPK 2抑制HCC细胞的迁移，以及异种移植和原位同基因HCC小鼠模型中的肿瘤生长和转移。此外，HIPK 2抑制HCC肿瘤中的血管生成。在低氧条件下，HIPK 2基因敲低可促进肿瘤血管生成，并促进HIF-1α信号通路的关键调节因子的表达;而HIPK 2基因过表达可抑制肿瘤血管生成，并抑制HIF-1α信号通路的表达。在肝癌细胞中，HIPK 2可直接与HIF-1α结合，并刺激HIF-1α泛素化，使其降解为蛋白酶体。HIF-1α基因敲除部分挽救了HIPK 2缺失对血管生成和肿瘤生长的促进作用。结论：下调HIPK 2表达可通过诱导HIF-1α通路促进肝癌血管生成，进而促进肿瘤的生长和转移，为肝癌的治疗提供新的思路。
Aberrant angiogenesis of hepatocellular carcinoma (HCC) leads to tumor growth and local or distant metastasis. Uncovering the underlying mechanisms for the neoangiogenesis of HCC can provide novel potential therapeutic targets in the clinic. Here, we reported that serine/threonine homeodomain-interacting protein kinase 2 (HIPK2) was frequently downregulated in HCC tissues compared with the adjacent normal tissues, and patients with lower HIPK2 protein expression were associated with worse overall survival. Both in vitro and in vivo, HIPK2 inhibited the migration of HCC cells, as well as tumor growth and metastasis in xenograft and orthotopic syngeneic HCC mouse models. Furthermore, HIPK2 inhibited the angiogenesis in HCC tumors. Under the hypoxic condition, HIPK2 knockdown enhanced the angiogenesis and the key regulator, HIF-1α signaling pathway; however, HIPK2 overexpression downregulated the tumoral angiogenesis and HIF-1α signaling. In HCC cells, HIPK2 could directly bind to HIF-1α and stimulate the ubiquitination of HIF-1α for proteasomal degradation. HIF-1α knockout partially rescued the promoting effect of HIPK2 depletion on angiogenesis and tumor growth. In conclusion, the downregulation of HIPK2 could enhance the angiogenesis in HCC through inducing the HIF-1α pathway, and further contribute to tumor growth and metastasis, which may provide a novel therapeutic strategy for HCC.