State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, PR China.
CAS Key Laboratory of Nutrition, Metabolism and Food safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, PR China.
Oncogene. 2020 Apr;39(14):2863-2876. doi: 10.1038/s41388-020-1190-y. Epub 2020 Feb 7.
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.
肝癌（HCC）的异常血管生成导致肿瘤生长和局部或远处转移。揭示 HCC 新生血管形成的潜在机制可以为临床提供新的潜在治疗靶点。在这里，我们报道与相邻正常组织相比，丝氨酸/苏氨酸同源结构域相互作用蛋白激酶 2（HIPK2）在 HCC 组织中经常下调，并且 HIPK2 蛋白表达较低的患者总生存期较差。在体外和体内，HIPK2 均抑制 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，HIPK2 抑制 HCC 肿瘤中的血管生成。在缺氧条件下，HIPK2 敲低增强了血管生成和关键调节因子 HIF-1α 信号通路；然而，HIPK2 过表达下调了肿瘤血管生成和 HIF-1α 信号通路。在 HCC 细胞中，HIPK2 可以直接与 HIF-1α 结合，并刺激 HIF-1α 的泛素化，从而进行蛋白酶体降解。HIF-1α 敲除部分挽救了 HIPK2 耗竭对血管生成和肿瘤生长的促进作用。总之，HIPK2 的下调通过诱导 HIF-1α 通路可增强 HCC 中的血管生成，并进一步促进肿瘤生长和转移，这可能为 HCC 提供一种新的治疗策略。
