Huang Da, Du Xiaohong, Yuan Rongfa, Chen Leifeng, Liu Tiande, Wen Chongyu, Huang Mingwen, Li Ming, Hao Liang, Shao Jianghua
Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China; Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China.
Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.
Biochem Biophys Res Commun. 2014 Oct 10;453(1):49-56. doi: 10.1016/j.bbrc.2014.09.061. Epub 2014 Sep 22.
Rho-associated coiled-coil-containing protein kinase 2 (Rock2) is a downstream effector of Rho that plays an important role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). Matrix metalloproteinase 2 (MMP2) is a master regulator of tumor metastasis. In this study, we investigated the collections of Rock2 and MMP2 in HCCs and determined the potential role and molecular mechanism of Rock2 in MMP2-mediated invasiveness and metastasis. We found that Rock2 and MMP2 were markedly overexpressed in HCCs compared with the corresponding adjacent tissues, where a positive correlation in their expression was found. The knockdown of Rock2 significantly decreased MMP2 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo. Additionally, the upregulation of MMP2 rescued the decreased migration and invasion induced by the knockdown of Rock2, whereas the knockdown of MMP2 decreased Rock2-enhanced HCC migration and invasion. Mechanistically, Rock2 stabilized MMP2 by preventing its ubiquitination and degradation. Together, our results link two drivers of invasion and metastasis in HCC and identify a novel pathway for MMP2 control.
Rho相关卷曲螺旋蛋白激酶2（Rock2）是Rho的下游效应器，在肝细胞癌（HCC）的肿瘤发生和进展中起重要作用。基质金属蛋白酶2（MMP2）是肿瘤转移的主要调节因子。在本研究中，我们调查了HCC中Rock2和MMP2的表达情况，并确定了Rock2在MMP2介导的侵袭和转移中的潜在作用及分子机制。我们发现，与相应的癌旁组织相比，Rock2和MMP2在HCC中明显过表达，且它们的表达呈正相关。敲低Rock2可显著降低MMP2的表达，并在体外和体内抑制HCC的侵袭和转移。此外，MMP2的上调挽救了因敲低Rock2而导致的迁移和侵袭能力下降，而敲低MMP2则降低了Rock2增强的HCC迁移和侵袭能力。机制上，Rock2通过防止MMP2的泛素化和降解来使其稳定。总之，我们的结果将HCC侵袭和转移的两个驱动因素联系起来，并确定了一种控制MMP2的新途径。
