c-Myc transactivates GP73 and promotes metastasis of hepatocellular carcinoma cells through GP73-mediated MMP-7 trafficking in a mildly hypoxic microenvironment
c-Myc transactivates GP73 and promotes metastasis of hepatocellular carcinoma cells through GP73-mediated MMP-7 trafficking in a mildly hypoxic microenvironment
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DOI：
10.1038/s41389-019-0166-7
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发表时间：
2019-10-07
期刊：
影响因子：
6.2
通讯作者：
Zhou, Linfu
中科院分区：
文献类型：
--
作者：
Liu, Yiming;Zhou, Sining;Zhou, Linfu
由GOLM1编码的高尔基磷酸化蛋白73 （GP73）是肝细胞癌（HCC）细胞中的高表达因子，多年来一直被认为是HCC诊断的重要血清生物标志物。近年来，研究发现上调GP73可促进肿瘤转移，但其机制复杂，甚至不清楚该基因在HCC细胞中的反激活机制。本研究发现c-Myc在轻度缺氧微环境下可反激活GP73， c-Myc的激活可上调基质金属蛋白酶-7 （matrix metalloproteinase-7, MMP-7）的表达。此外，研究表明GP73在细胞质区域与细胞内MMP-7相互作用，促进MMP-7的转运和分泌，导致细胞转移。本研究表明，GP73可被c-Myc反激活，并作为转运体参与HCC细胞内MMP-7的转运。这些发现表明GP73是对抗转移性HCC的潜在靶点。
Golgi phosphoprotein 73 (GP73), encoded by GOLM1, is a highly expressed factor in hepatocellular carcinoma (HCC) cells and has been regarded for several years as a remarkable serum biomarker for the diagnosis of HCC. Recently, it was found that upregulation of GP73 promotes cancer metastasis, but the mechanism is complex, and it is even unclear how the gene is transactivated in HCC cells. In this study, it was discovered that c-Myc transactivated GP73 in a mildly hypoxic microenvironment and that the activation of c-Myc upregulated the expression of matrix metalloproteinase-7 (MMP-7). Moreover, it is shown that GP73 interacted with intracellular MMP-7 in the region of the cytoplasmic domain and facilitated the trafficking and secretion of MMP-7, resulting in cell metastasis. This study indicates that GP73 is transactivated by c-Myc and serves as a transporter in the trafficking of intracellular MMP-7 in HCC cells. These findings suggest that GP73 is a potential target for combating metastatic HCC.