Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
Gastroenterology. 2012 Oct;143(4):1084-94.e7. doi: 10.1053/j.gastro.2012.06.038. Epub 2012 Jun 26.
BACKGROUND & AIMS: Chronic oxidative stress from reactive oxygen species (ROS) produced by the mitochondria promotes hepatocarcinogenesis and tumor progression. However, the exact mechanism by which mitochondrial ROS contributes to tumor cell invasion is not known. We investigated the role of ROS modulator 1 (Romo1) in hepatocellular carcinoma (HCC) development and tumor cell invasiveness.
We performed real-time, semi-quantitative, reverse transcriptase polymerase chain reaction; invasion and luciferase assays; and immunofluorescence and immunohistochemical analyses. The formation of pulmonary metastatic nodules after tumor cell injection was tested in severe combined immunodeficient mice. We analyzed Romo1 expression in HCC cell lines and tissues (n = 95).
Expression of Romo1 was increased in HCC cells, compared with normal human lung fibroblast cells. Exogenous expression of Romo1 in HCC cells increased their invasive activity, compared with control cells. Knockdown of Romo1 in Hep3B and Huh-7 HCC cells reduced their invasive activity in response to stimulation with 12-O-tetradecanoylphorbol-13-acetate. Levels of Romo1 were increased compared with normal liver tissues in 63 of 95 HCC samples from patients. In HCC samples from patients, there was an inverse correlation between Romo1 overexpression and patient survival times. Increased levels of Romo1 also correlated with vascular invasion by the tumors, reduced differentiation, and larger tumor size.
Romo1 is a biomarker of HCC progression that might be used in diagnosis. Reagents that inhibit activity of Romo1 and suppress mitochondrial ROS production, rather than eliminate up-regulated intracellular ROS, might be developed as cancer therapies.
线粒体产生的活性氧（ROS）引起的慢性氧化应激促进肝癌发生和肿瘤进展。然而，线粒体 ROS 促进肿瘤细胞侵袭的确切机制尚不清楚。我们研究了 ROS 调节剂 1（Romo1）在肝细胞癌（HCC）发展和肿瘤细胞侵袭性中的作用。
我们进行了实时、半定量、逆转录聚合酶链反应；侵袭和荧光素酶测定；免疫荧光和免疫组织化学分析。在严重联合免疫缺陷小鼠中测试肿瘤细胞注射后肺转移结节的形成。我们分析了 Romo1 在 HCC 细胞系和组织中的表达（n = 95）。
与正常的人肺成纤维细胞相比，Romo1 在 HCC 细胞中的表达增加。与对照细胞相比，外源性表达 Romo1 增加了 HCC 细胞的侵袭活性。在 Hep3B 和 Huh-7 HCC 细胞中敲低 Romo1 可降低其对 12-O-十四烷酰佛波醇-13-乙酸刺激的侵袭活性。与正常肝组织相比，在 95 例 HCC 患者的样本中，有 63 例 Romo1 水平升高。在 HCC 患者样本中，Romo1 过表达与患者生存时间呈负相关。Romo1 水平升高也与肿瘤的血管侵犯、分化减少和肿瘤体积增大有关。
Romo1 是 HCC 进展的生物标志物，可用于诊断。抑制 Romo1 活性和抑制线粒体 ROS 产生的试剂，而不是消除上调的细胞内 ROS，可能被开发为癌症治疗方法。
