title: Duffy antigen receptor for chemokines (DARC) expressing in cancer cells inhibits tumor progression by suppressing CXCR2 signaling in human pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Chemokines play important roles in the progression of many malignancies; however, the role of chemokine receptor expression in clinical cases of PDAC is unclear. Moreover, little is known about DARC, a decoy receptor of CXC chemokines, in the regulation of tumor progression.
  
  
  
  Functions of chemokine receptors were evaluated using surgical specimens collected from PDAC patients, and PDAC cell lines.
  
  
  
  CXCR2 expression had no impacts on predicting prognosis, but low DARC expression in cancer cells was an independent risk factor for poor prognosis. In PDAC with low DARC expression, tumor sizes were larger and vascular invasion was increased. High CXCR2 expression was a significant predictor for poor prognosis, only in PDAC patients with low DARC expression. CXCR2 signaling induced STAT3 activation in PDAC, resulting in promoting cell cycle progression, inhibiting apoptosis, inducing angiogenesis, and enhancing invasiveness. DARC inhibited STAT3 activation by down-regulating CXCR2 signaling. These effects were confirmed by EMSA in vitro. DARC knockdown significantly increased cell proliferation in CFPAC-1 cells with high DARC expression, by activating STAT3. In contrast, CXCR2 knockdown inhibited the proliferative effects of IL-8 in MIA PaCa-2 cells with low DARC expression. Moreover, the inhibitory effect of CXCR2 antagonist on PDAC cell proliferation was more powerful in MIA PaCa-2 cells than CFPAC-1 cells.
  
  
  
  DARC expressing in cancer cells inhibits PDAC progression by suppressing STAT3 activation through the inhibition of CXCR2 signaling. Therefore, DARC is a novel prognostic predictor and a potential therapeutic target for PDAC.
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan. Electronic address: satoshi.kuboki@faculty.chiba-u.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuboki
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohtsuka
mesh_terms: D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004375:Duffy Blood-Group System / Q000378:metabolism*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C473745:ACKR1 protein, human; D004375:Duffy Blood-Group System; D016209:Interleukin-8; D011956:Receptors, Cell Surface; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: CXC chemokine; CXC chemokine receptor-2; Duffy antigen receptor for chemokines; Pancreatic cancer; Prognostic factor; Signal transducer and activator of transcription-3