Overexpression of Romo1 promotes production of reactive oxygen species and invasiveness of hepatic tumor cells

Jin Sil Chung, Sunhoo Park, Seon Ho Park, Eun Ran Park, Pu Hyeon Cha, Bu Yeo Kim, Young Min Chung, Seon Rang Woo, Chul Ju Han, Sang Bum Kim, Kyung Suk Suh, Ja June Jang, Kyoungbun Lee, Dong Wook Choi, Sora Lee, Gi Young Lee, Ki Baik Hahm, Jung Ar Shin, Byung Soo Kim, Kyung Hee NohTae Woo Kim, Kee Ho Lee, Young Do Yoo

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Abstract

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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish
JournalGastroenterology
Volume143
Issue number4
DOIs
Publication statusPublished - 2012 Oct 1

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Keywords

  • Chemotherapy Resistance
  • Liver Cancer
  • Metastasis
  • Prognostic Factor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Chung, J. S., Park, S., Park, S. H., Park, E. R., Cha, P. H., Kim, B. Y., Chung, Y. M., Woo, S. R., Han, C. J., Kim, S. B., Suh, K. S., Jang, J. J., Lee, K., Choi, D. W., Lee, S., Lee, G. Y., Hahm, K. B., Shin, J. A., Kim, B. S., ... Yoo, Y. D. (2012). Overexpression of Romo1 promotes production of reactive oxygen species and invasiveness of hepatic tumor cells. Gastroenterology, 143(4). https://doi.org/10.1053/j.gastro.2012.06.038