title: CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages.
abstract: BACKGROUND
  Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients.
  
  
  METHODS
  We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages.
  
  
  RESULTS
  CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis.
  
  
  CONCLUSIONS
  Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Kee
authors.forename: Aya
authors.initials: A
authors.lastname: Ito
authors.forename: Shozo
authors.initials: S
authors.lastname: Hojo
authors.forename: Isaya
authors.initials: I
authors.lastname: Hashimoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukada
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Irimura
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Shibahara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takasaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Inujima
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshie
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.affiliation: Division of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kkoizumi@inm.u-toyama.ac.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004351:Drug Resistance / Q000235:genetics; D015870:Gene Expression; D020868:Gene Silencing; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D034622:RNA Interference; D051116:Receptors, Scavenger / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D000099185:Interferon Regulatory Factor-8
chemical_list: D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D050835:Interferon Regulatory Factors; D051116:Receptors, Scavenger; D014409:Tumor Necrosis Factor-alpha; D000099185:Interferon Regulatory Factor-8; C423727:CXCL16 protein, human