Liu Jingmei, Han Ping, Li Mengke, Yan Wei, Liu Jin, Liu Jiqiao, He Jiayi, Tu Wei, Xia Yujia, Zhou Zhenzhen, Gong Jin, Liu Mei, Ding Qiang, Tian Dean
Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Department of Medical Ultrasound, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Oncotarget. 2015 Mar 30;6(9):6811-24. doi: 10.18632/oncotarget.3049.
The histidine-rich calcium binding protein (HRC) is a regulator of Ca2+-homeostasis. Herein, we found that HRC was frequently upregulated in human hepatocellular carcinoma (HCC) tissues, and its expression was correlated with tumor size and metastasis. Moreover, HRC expression was positively related to the metastatic potential of HCC cell lines. Knockdown of HRC suppressed cell invasion and migration in vitro, whereas ectopic expression of HRC resulted in increased cell invasion and migration in vitro and intrahepatic and lung metastasis in vivo. Interestingly, the pro-invasion and pro-migration effects of HRC were associated with focal adhesion turnover, which was a consequence of FAK phosphorylation. Further experiments showed that HRC induced phospho-FAK, focal adhesion turnover and cell migration through Ca2+/CaM singaling. We found that HRC increased [Ca2+]i by inhibiting the expression of SERCA2. In addition, upregulation of HRC in HCC was attributed to SATB1, which is known to promote HCC metastasis. Ectopic expression of SATB1 enhanced HRC gene transcription by activating AP-1 in mainly a JNK-dependent manner. Our findings highlight HRC as a potential therapeutic target for HCC treatment.
富含组氨酸的钙结合蛋白（HRC）是一种钙稳态调节因子。在此，我们发现HRC在人肝细胞癌（HCC）组织中经常上调，其表达与肿瘤大小和转移相关。此外，HRC表达与HCC细胞系的转移潜能呈正相关。敲低HRC可抑制体外细胞侵袭和迁移，而异位表达HRC则导致体外细胞侵袭和迁移增加以及体内肝内和肺转移增加。有趣的是，HRC的促侵袭和促迁移作用与粘着斑周转有关，这是FAK磷酸化的结果。进一步的实验表明，HRC通过Ca2+/CaM信号传导诱导磷酸化FAK、粘着斑周转和细胞迁移。我们发现HRC通过抑制SERCA2的表达增加细胞内钙离子浓度（[Ca2+]i）。此外，HCC中HRC的上调归因于SATB1，已知SATB1可促进HCC转移。SATB1的异位表达主要通过JNK依赖的方式激活AP-1来增强HRC基因转录。我们的研究结果突出了HRC作为HCC治疗潜在靶点的作用。
