title: Involvement of SULF2 in y-irradiation-induced invasion and resistance of cancer cells by inducing IL-6 expression.
abstract: Cancer cells that survive radiotherapy often display enhanced invasiveness and resistance to death stimuli. Previous findings have suggested that ionizing radiation (IR) induces such undesirable effects by stimulating the STAT3/Bcl-XL pathway. To identify novel cellular components that mediate these actions of IR, we irradiated lung cancer cells with sublethal doses of y-rays and screened for the induction of IR-responsive genes by microarray analysis. The genes encoding 2 extracellular proteins, SULF2 and IL-6, were found to be upregulated, and these results were confirmed by polymerase chain reactions and western blot analyses. Because the IR-mediated induction of SULF2 was a novel finding, we also confirmed the phenomenon in vivo using xenograft tumors in mice. Analyses of signaling processes revealed that IR induced SULF2 expression via p53, which then promoted IL-6 expression by stabilizing β-catenin, followed by stimulation of the STAT3/Bcl-XL pathway. Consistently, both SULF2 and IL-6 mediated IR-induced invasion and resistance to death stimuli. To investigate whether SULF2 contributes to IR-induced tumor metastasis, we irradiated tumors in mice with sublethal doses of IR. This treatment promoted the entry of tumor cells into the blood stream (intravasation), which was abolished by downregulating SULF2 expression in tumor cells. These results demonstrated that SULF2 can mediate the detrimental effects of IR in vivo. Therefore, SULF2 may be potentially used as a therapeutic and diagnostic target to predict and overcome the malignant effects of IR, particularly in tumors expressing p53 wild-type.
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
authors.forename: Chan-Hun
authors.initials: CH
authors.lastname: Jung
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.|Present address: Biomedical Research Institute, Department of Urology, Seoul National University Bundang Hospital, Seongnam 463-707, Korea.
authors.forename: Jin-Nyoung
authors.initials: JN
authors.lastname: Ho
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005720:Gamma Rays; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D011836:Radiation Tolerance / Q000502:physiology*; D013429:Sulfatases; D015238:Sulfotransferases / Q000378:metabolism* / Q000528:radiation effects
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases
keywords: IL-6; SULF2; cancer invasion; radiotherapy; resistance