Seo Young Park1, Jiyou Han2, Jong Bin Kim3, Man-Gil Yang4, Yoon Jun Kim3, Hee-Joung Lim2, Su Yeon An2, Jong-Hoon Kim5. 1. Laboratory of Stem Cell Biology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 133-713, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. 2. Laboratory of Stem Cell Biology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 133-713, Republic of Korea. 3. Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. 4. Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. 5. Laboratory of Stem Cell Biology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 133-713, Republic of Korea. Electronic address: jhkim@korea.ac.kr.
Abstract
AIM: Interleukin-8 (IL-8) has been suggested as a prognostic biomarker for human hepatocellular carcinoma (HCC), but its roles in HCC progression and drug resistance have not been studied. This study investigates the role and underlying mechanism of IL-8 in the chemoresistance and progressive growth of HCC. METHODS: The change of chemosensitivity and proportion of side population in hepatoma cells was examined by cell growth and flow cytometric analyses after anti-cancer treatments or knockdown of IL-8. Expression of IL-8 and ATP-binding cassette (ABC) transporters in hepatoma cells, xenograft and clinical HCC tissues was determined by Western blot and immunohistochemical analyses. Tumourigenicity of hepatoma cells was evaluated in vivo after silencing IL-8 gene. RESULTS: Treatment of hepatoma cells with anti-cancer drugs increased the production of IL-8 and its receptor, as well as the proportion of side population (SP). Exogenous IL-8 increased the SP fraction and expression of multidrug resistance-1, decreasing the drug sensitivity. Silencing of IL-8 gene decreased the ratio of SP cells and drug resistance properties. Both IL-8 and ABC transporters were highly expressed in xenograft and clinical HCC tissues, and knockdown of IL-8 significantly reduced tumour size in vivo. CONCLUSION: Anti-cancer drug-induced IL-8 secretion increased the expression of ABC transporters and SP cells, promoting the growth of HCC in vitro. Thus IL-8 may be a potential therapeutic target in the treatment of HCC.
AIM: Interleukin-8 (IL-8) has been suggested as a prognostic biomarker for humanhepatocellular carcinoma (HCC), but its roles in HCC progression and drug resistance have not been studied. This study investigates the role and underlying mechanism of IL-8 in the chemoresistance and progressive growth of HCC. METHODS: The change of chemosensitivity and proportion of side population in hepatoma cells was examined by cell growth and flow cytometric analyses after anti-cancer treatments or knockdown of IL-8. Expression of IL-8 and ATP-binding cassette (ABC) transporters in hepatoma cells, xenograft and clinical HCC tissues was determined by Western blot and immunohistochemical analyses. Tumourigenicity of hepatoma cells was evaluated in vivo after silencing IL-8 gene. RESULTS: Treatment of hepatoma cells with anti-cancer drugs increased the production of IL-8 and its receptor, as well as the proportion of side population (SP). Exogenous IL-8 increased the SP fraction and expression of multidrug resistance-1, decreasing the drug sensitivity. Silencing of IL-8 gene decreased the ratio of SP cells and drug resistance properties. Both IL-8 and ABC transporters were highly expressed in xenograft and clinical HCC tissues, and knockdown of IL-8 significantly reduced tumour size in vivo. CONCLUSION: Anti-cancer drug-induced IL-8 secretion increased the expression of ABC transporters and SP cells, promoting the growth of HCC in vitro. Thus IL-8 may be a potential therapeutic target in the treatment of HCC.