title: WNT5A Promoter Methylation Is Associated with Better Responses and Longer Progression-Free Survival in Colorectal Cancer Patients Treated with 5-Fluorouracil-Based Chemotherapy.
abstract: BACKGROUND
  Aberrant activation of the canonical WNT or WNT/β-catenin signaling pathway plays a pivotal role in multiple types of cancers. WNT5A, a nontransforming WNT protein suppressing the Wnt/β-catenin signaling pathway, is frequently detected to be hypermethylated in colorectal cancer (CRC). In this study, we investigated the prognostic value of WNT5A methylation in human patients and its potential underlying molecular mechanisms in cultured human CRC cells.
  
  
  METHODS
  We measured WNT5A mRNA level using qRT-PCR and DNA methylation using methylation-specific PCR (MSP) in HCT116, HT29, SW620, HCT8, LoVo, SW480, and Rko CRC cells. 5-FU-mediated tumor suppression was determined by measuring cell viability using MTT assay in cultured CRC cells. We also determined whether WNT5A methylation was associated with drug response and progression-free survival in CRC patients (n = 126) treated with 5-FU-based chemotherapy as first-line treatment.
  
  
  RESULTS
  WNT5A expression inversely correlated with methylation status of CRC cells. Moreover, WNT5A expression was restored upon demethylation in hypermethylated cells. 5-FU-induced tumor suppression (reduced cell viability) was reduced by WNT5A overexpression in hypermethylated HCT116 and SW620 cells and enhanced by WNT5A downregulation in unmethylated LoVo and SW480 cells. In 5-FU-treated CRC patients, WNT5A methylation status is associated with better drug response and longer progression-free survival, suggesting that 5-FU is more effective in CRC with WNT5A hypermethylation.
  
  
  CONCLUSIONS
  WNT5A methylation status is prognostic and is useful as a potential drug selection biomarker in CRC.
authors.affiliation: 1 Department of Pathology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, China .|2 School of Basic Medicine, Zhengzhou University , Zhengzhou, China .
authors.forename: Guozhong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: 1 Department of Pathology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, China .
authors.forename: Jiangxin
authors.initials: J
authors.lastname: Lin
authors.affiliation: 1 Department of Pathology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, China .|2 School of Basic Medicine, Zhengzhou University , Zhengzhou, China .
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 3 Department of Pathology, Henan Tumor Hospital , Zhengzhou, China .
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Sun
authors.affiliation: 1 Department of Pathology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, China .|2 School of Basic Medicine, Zhengzhou University , Zhengzhou, China .
authors.forename: Kuisheng
authors.initials: K
authors.lastname: Chen
authors.affiliation: 4 Department of Oncology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, China .
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019175:DNA Methylation; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D016896:Treatment Outcome; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein / Q000096:biosynthesis / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; D051176:beta Catenin; D005472:Fluorouracil
keywords: 5-FU chemotherapy; WNT5A; colorectal cancer; methylation; progression-free survival