title: WNT5A modulates cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells.
abstract: BACKGROUND
  Although there are many studies on the mechanism of chemoresistance in cancers, studies on the relations between WNT5A and chemoresistance in pancreatic cancer are rare. The present study was to examine the role of WNT5A in the regulation of cell cycle progression and in chemo-resistance in pancreatic cancer tissues and cell lines.
  
  
  METHODS
  Fresh pancreatic cancer and paracarcinoma tissues were obtained from 32 patients. The expressions of WNT5A, AKT/p-AKT and Cyclin D1 were detected by immunohistochemistry, and the correlation between WNT5A expression and clinicopathological characteristics was analyzed. The relationship between WNT5A expression and gemcitabine resistance was studied in PANC-1 and MIAPaCa2 cell lines. The effect of WNT5A on the regulation of cell cycle and gemcitabine cytotoxicity were investigated. The associations among the expressions of p-AKT, Cyclin D1 and WNT5A were also analyzed in cell lines and the effect of WNT5A on restriction-point (R-point) progression was evaluated.
  
  
  RESULTS
  WNT5A, p-AKT and Cyclin D1 were highly expressed in pancreatic cancer tissues, and the WNT5A expression was correlated with the TNM stages. In vitro, WNT5A expression was associated with gemcitabine chemoresistance. The percentage of cells was increased in G0/G1 phase and decreased in S phase after knockdown of WNT5A in PANC-1. WNT5A promoted Cyclin D1 expression through phosphorylation of AKT which consequently enhanced G1-S transition and gemcitabine resistance. Furthermore, WNT5A enhanced the cell cycle progression toward R-point through regulation of retinoblastoma protein (pRb) and pRb-E2F complex formation.
  
  
  CONCLUSIONS
  WNT5A induced chemoresistance by regulation of G1-S transition in pancreatic cancer cells. WNT5A might serve as a predictor of gemcitabine response and as a potential target for tumor chemotherapy.
authors.affiliation: Department of Pathophysiology, School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. shenxiaohong@nankai.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Sun
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Hong-Yue
authors.initials: HY
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Shen
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056741:Cyclin D / Q000032:analysis / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010179:Pancreas / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D051153:Wnt Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D056741:Cyclin D; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D003841:Deoxycytidine; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine