Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang 330006, China; Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang 330006, China.
Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang 330006, China; Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang 330006, China.
Exp Cell Res. 2018 Apr 1;365(1):1-11. doi: 10.1016/j.yexcr.2018.02.007. Epub 2018 Feb 16.
Glucose-regulated protein 78(GRP78) and the ubiquitin-like protein FAT10 each promote proliferation in hepatocellular carcinoma(HCC). However, the relationship of GRP78 and FAT10 in HCC proliferation are still not known. In this study, we found that GRP78 and FAT10 were significantly overexpressed in HCC tissues compare with adjacent non-cancerous tissues, and a positive correlation was found between their expression and associated proliferation characteristics. High expression of GRP78 and FAT10 were positively correlated with tumor proliferation and poor prognosis in HCC. Moreover, GRP78 knockdown reduced FAT10 expression and suppressed HCC proliferation in vitro and in vivo. The effects of GRP78 knockdown were rescued by FAT10 up-regulation, whereas FAT10 knockdown reduced HCC proliferation enhanced by GRP78 up-regulation. Furthermore, GRP78 modulated FAT10 expression by regulating the NF-κB pathway, direct activation of the NF-κB pathway increased the expression of FAT10, a gene counteracting the tumor suppressor p53. Taken together, these results suggest that this newly identified GRP78-NF-κB-FAT10 axis will provide novel insight into the understanding of the regulatory mechanisms of proliferation in human HCC.
葡萄糖调节蛋白 78(GRP78)和泛素样蛋白 FAT10 均可促进肝细胞癌(HCC)的增殖。然而，GRP78 和 FAT10 在 HCC 增殖中的关系尚不清楚。在本研究中，我们发现 GRP78 和 FAT10 在 HCC 组织中的表达明显高于相邻的非癌组织，并且它们的表达与相关的增殖特征呈正相关。GRP78 和 FAT10 的高表达与 HCC 的肿瘤增殖和预后不良呈正相关。此外，GRP78 敲低可降低 FAT10 的表达，并抑制 HCC 在体外和体内的增殖。FAT10 的上调可挽救 GRP78 敲低的作用，而 FAT10 的下调可增强 GRP78 上调对 HCC 增殖的促进作用。此外，GRP78 通过调节 NF-κB 通路来调节 FAT10 的表达，NF-κB 通路的直接激活增加了 FAT10 的表达，FAT10 是一种与肿瘤抑制因子 p53 相拮抗的基因。总之，这些结果表明，这个新确定的 GRP78-NF-κB-FAT10 轴将为理解人类 HCC 增殖的调控机制提供新的见解。
