title: Chemokine (C-X-C motif) ligand 12 is associated with gallbladder carcinoma progression and is a novel independent poor prognostic factor.
abstract: OBJECTIVE
  Although recent studies have suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) is important in the progression of various malignancies, its role in gallbladder carcinoma (GBC) remains unknown. We investigated CXCL12 expression in GBC and its biologic and prognostic role in GBC tumorigenesis.
  
  
  METHODS
  We examined CXCL12 expression in tumor specimens from 72 patients with GBC by immunohistochemistry and analyzed the correlation between CXCL12 expression and clinicopathologic factors or survival. The functional significance of CXCL12 expression was investigated by CXCL12 treatment and suppression of CXCR4, a major receptor of CXCL12, as well as by CXCL12 overexpression in in vitro and in vivo studies.
  
  
  RESULTS
  CXCL12 was differentially expressed in GBC tissues. CXCL12 expression was significantly associated with a high histologic grade (P = 0.042) and nodal metastasis (P = 0.015). Multivariate analyses showed that CXCL12 expression (HR, 8.675; P = 0.014) was an independent risk factor for patient survival. CXCL12 significantly increased anchorage-dependent and -independent growth, migration, invasion, adhesiveness, and survival of GBC cells in vitro, and these effects were dependent on CXCR4. Consistent with these results, overexpression of CXCL12 significantly promoted GBC tumorigenicity in a xenograft model.
  
  
  CONCLUSIONS
  Our results indicate that GBC cells express both CXCL12 and its receptor CXCR4, and CXCL12 may have a role in GBC progression through an autocrine mechanism. In addition, CXCL12 is a novel independent poor prognostic factor in patients with GBCs. Thus, targeting CXCL12 and CXCR4 may provide a novel therapeutic strategy for GBC treatment.
authors.affiliation: Department of Pathology, Cancer Research Institute, and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Lee
authors.forename: Dong Gwang
authors.initials: DG
authors.lastname: Lee
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Bae
authors.forename: Jang-Seong
authors.initials: JS
authors.lastname: Kim
authors.forename: Zhe Long
authors.initials: ZL
authors.lastname: Liang
authors.forename: Song Mei
authors.initials: SM
authors.lastname: Huang
authors.forename: Yoon
authors.initials: Y
authors.lastname: Suk Oh
authors.forename: Ha Yon
authors.initials: HY
authors.lastname: Kim
authors.forename: Deog Yeon
authors.initials: DY
authors.lastname: Jo
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D005706:Gallbladder Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4