Heat-Shock protein A12A is a novel PCNA-binding protein and promotes hepatocellular carcinoma growth
Heat-Shock protein A12A is a novel PCNA-binding protein and promotes hepatocellular carcinoma growth
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热休克蛋白 12A 是一种新型 PCNA 结合蛋白，可促进肝细胞癌生长
DOI：
10.1111/febs.15276
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发表时间：
2020-03-25
期刊：
影响因子：
5.4
通讯作者：
Ding, Zhengnian
中科院分区：
文献类型：
--
作者：
Cheng, Hao;Cao, Xiaofei;Ding, Zhengnian
肝细胞癌（HCC）是癌症相关死亡的主要原因。增殖细胞核抗原（PCNA）在肿瘤的发生、发展中起着重要作用。然而，肝癌的长期预后令人沮丧，需要更多的研究来确定肝癌发病机制中的新调节因子。热休克蛋白A12 A（Heat-shock protein A12 A，HSPA 12 A）是HSP 70家族的一个新成员。在这里，我们报告，肝癌细胞表现出增加HSPA 12 A的表达，和HSPA 12 A的过表达促进肝癌生长和血管生成的小鼠。获得和丧失功能的研究表明，HCC HepG 2细胞的增殖，以及β-连环蛋白的表达和核转位，促进了HSPA 12 A过表达，但反过来抑制HSPA 12 A敲低。HSPA 12 A并不影响PCNA的表达，然而，质谱和免疫共沉淀免疫印迹分析显示，HSPA 12 A直接结合到PCNA，并促进其三聚体，这是一个重要的功能性构象的PCNA的致癌作用。重要的是，PCNA抑制PCNA-I1逆转了HSPA 12 A介导的HepG 2细胞分化。这些发现表明，HSPA 12 A是一种新的肝癌细胞增殖和肿瘤生长的调节剂，通过结合PCNA的三聚体。HSPA 12 A抑制可能是治疗人类HCC的可行策略。
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Proliferating cell nuclear antigen (PCNA) plays a pivotal role in cancer development and progression. However, the long-term dismal prognosis of HCC mandates more investigation to identify novel regulators in HCC pathogenesis. Heat-shock protein A12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that HCC cells showed increased HSPA12A expression, and overexpression of HSPA12A promoted HCC growth and angiogenesis in mice. Gain- and loss-of-functional studies demonstrated that the proliferation of HCC HepG2 cells, as well as beta-catenin expression and nuclear translocation, was promoted by HSPA12A overexpression, but in turn suppressed by HSPA12A knockdown. HSPA12A did not impact PCNA expression; however, mass spectrometry and co-immunoprecipitation immunoblotting analysis revealed that HSPA12A directly binds to PCNA and promotes its trimerization, which is an essential functional conformation of PCNA for carcinogenesis. Importantly, PCNA inhibition by PCNA-I1 reversed the HSPA12A-mediated HepG2 cell differentiation. These findings indicate that HSPA12A is a novel regulator of HCC cell proliferation and tumor growth through binding to PCNA for its trimerization. HSPA12A inhibition might represent a viable strategy for the management of HCC in humans.