title: SPOP promotes tumor progression via activation of β-catenin/TCF4 complex in clear cell renal cell carcinoma.
abstract: Renal cell carcinoma (RCC) is the most common type of kidney cancer, about one third of the cases are diagnosed at advanced stages with metastases and effective treatments for metastatic RCC are lacking. The molecular events supporting RCC progression remain poorly understood. SPOP, an E3 ubiquitin ligase component, was recently showed to sufficiently promote RCC tumorigenesis, however, other potential functions of SPOP in RCC have not been studied. In the present investigation, by assessing the immunohistochemical staining of SPOP in urological tumors, we found the protein was highly expressed in RCC, in particular, it was specifically expressed in clear cell RCC. cDNA microarray data showed that SPOP mRNA level was significantly increased in clear cell RCC compared to normal kidney tissues, which might be the result of the abnormal DNA copy number of this gene. More interestingly, SPOP was positive in tumors with local invasion or metastasis, and it was associated with tumor recurrence-free survival of clear cell RCC patients. Further in vitro assays demonstrated that SPOP drove RCC epithelial-mesenchymal transition (EMT) and promoted cell invasion. Mechanistically, SPOP enhanced β-catenin protein expression as well as its nuclear translocation, and elevated TCF4 expression. Both β-catenin and TCF4 upregulated the critical EMT-inducing transcription factor ZEB1, which functioned as an effector of β-catenin/TCF4 signaling in RCC invasion. These data identified SPOP as a new marker and prognostic factor for clear cell RCC, and its functions provide new insight into the molecular mechanisms of RCC progression, in which SPOP appears to be an EMT activator.
authors: Department of Urology, Shaanxi Provincal People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors: Wencai
authors: W
authors: Zhao
authors: Department of Urology, Shaanxi Provincal People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors: Jiancheng
authors: J
authors: Zhou
authors: Department of Gynecology, Shaanxi Provincal People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors: Zhuo
authors: Z
authors: Deng
authors: Department of Urology, Shaanxi Provincal People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors: Yang
authors: Y
authors: Gao
authors: Department of Urology, Shaanxi Provincal People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors: Yongyi
authors: Y
authors: Cheng
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin