title: WNT10A plays an oncogenic role in renal cell carcinoma by activating WNT/β-catenin pathway.
abstract: Renal cell carcinoma (RCC) is a malignancy with poor prognosis. WNT/β-catenin signaling dysregulation, especially β-catenin overactivation and WNT antagonist silencing, is associated with RCC carcinogenesis and progression. However, the role of WNT ligands in RCC has not yet been determined. We screened 19 WNT ligands from normal kidney and RCC cell lines and tissues and found that WNT10A was significantly increased in RCC cell lines and tissues as compared to that in normal controls. The clinical significance of increase in WNT10A was evaluated by performing an immunohistochemical association study in a 19-year follow-up cohort comprising 284 RCC and 267 benign renal disease (BRD) patients. The results of this study showed that WNT10A was dramatically upregulated in RCC tissues as compared to that in BRD tissues. This result suggests that WNT10A, nuclear β-catenin, and nuclear cyclin D1 act as independent risk factors for RCC carcinogenesis and progression, with accumulative risk effects. Molecular validation of cell line models with gain- or loss-of-function designs showed that forced WNT10A expression induced RCC cell proliferation and aggressiveness, including higher chemoresistance, cell migration, invasiveness, and cell transformation, due to the activation of β-catenin-dependent signaling. Conversely, WNT10A siRNA knockdown decreased cell proliferation and aggressiveness of RCC cells. In conclusion, we showed that WNT10A acts as an autocrine oncogene both in RCC carcinogenesis and progression by activating WNT/β-catenin signaling.
authors.affiliation: Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ren-Jun
authors.initials: RJ
authors.lastname: Hsu
authors.forename: Jar-Yi
authors.initials: JY
authors.lastname: Ho
authors.forename: Tai-Lung
authors.initials: TL
authors.lastname: Cha
authors.forename: Dah-Shyong
authors.initials: DS
authors.lastname: Yu
authors.forename: Chieh-Lin
authors.initials: CL
authors.lastname: Wu
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Huang
authors.forename: Pauling
authors.initials: P
authors.lastname: Chu
authors.forename: Ying-Hsin
authors.initials: YH
authors.lastname: Chen
authors.forename: Jiann-Torng
authors.initials: JT
authors.lastname: Chen
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Yu
mesh_terms: D000328:Adult; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D051437:Renal Insufficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C484142:WNT10A protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1