title: Cyr61/CCN1 is regulated by Wnt/β-catenin signaling and plays an important role in the progression of hepatocellular carcinoma.
abstract: Abnormal activation of the canonical Wnt signaling pathway has been implicated in carcinogenesis. Transcription of Wnt target genes is regulated by nuclear β-catenin, whose over-expression is observed in Hepatocellular Carcinoma (HCC) tissue. Cyr61, a member of the CCN complex family of multifunctional proteins, is also found over-expressed in many types of tumor and plays dramatically different roles in tumorigenesis. In this study, we investigated the relationship between Cyr61 and β-catenin in HCC. We found that while Cyr61 protein was not expressed at a detectable level in the liver tissue of healthy individuals, its expression level was elevated in the HCC and HCC adjacent tissues and was markedly increased in cancer-adjacent hepatic cirrhosis tissue. Over-expression of Cyr61 was positively correlated with increased levels of β-catenin in human HCC samples. Activation of β-catenin signaling elevated the mRNA level of Cyr61 in HepG2 cells, while inhibition of β-catenin signaling reduced both mRNA and protein levels of Cyr61. We identified two TCF4-binding elements in the promoter region of human Cyr61 gene and demonstrated that β-catenin/TCF4 complex specifically bound to the Cyr61 promoter in vivo and directly regulated its promoter activity. Furthermore, we found that over-expression of Cyr61 in HepG2 cells promoted the progression of HCC xenografts in SCID mice. These findings indicate that Cyr61 is a direct target of β-catenin signaling in HCC and may play an important role in the progression of HCC.
authors.affiliation: Department of Clinical Hematology, Third Military Medical University, Chongqing, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Shi-Jun
authors.initials: SJ
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Wei-Ru
authors.initials: WR
authors.lastname: Wu
authors.forename: Wei-Ke
authors.initials: WK
authors.lastname: Si
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011401:Promoter Regions, Genetic; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D055515:Cysteine-Rich Protein 61; D051153:Wnt Proteins; D051176:beta Catenin