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.

Multilayer‐omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome

“…Somatic mutation of MACF1 (Table 1) may also participate in the Wnt/β-catenin-related carcinogenetic pathway in clear cell RCCs. With respect to 29 RCCs for which transcriptome analysis was performed, mRNA expression levels of the targets genes of the Wnt/β-catenin signaling, such as MYC ,37 MYCN ,37 IGF2 ,38 POU5F1 ,39 SOX9 ,40 CYR61 ,41 ENPP2 42 and MITF ,43 tended to be higher in the 8 RCCs with mutations of any of the GCN1L1, MED12, CCNC and MACF1 genes than in 21 RCCs without them (Supporting Information Table S10), indicating that such mutations may result in activation of Wnt/β-catenin signaling.…”

Genetic alterations in hepatocellular carcinoma: An update

“…A recent study found that the up-regulated genes v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G ( MAFG ) and synovial sarcoma, X breakpoint 1 ( SSX1 ) significantly synergized with the transcriptional activity of β-catenin, and the overexpression of the downregulated genes one cut homeobox 1 ( Onecut1 ) and forkhead box protein A3 ( FOXA3 ) potently inhibited the growth of a CTNNB1 -mutation-positive (HepG2) cell line and negative (Huh-7 and Hep3B) cell lines[260]. In another study, the over-expression of cysteine-rich protein 61 (Cyr61/CCN1) was positively correlated with increased levels of β-catenin in human HCC samples, indicating that Cyr61 is a direct target of β-catenin signaling in HCC[261]. Therefore, the findings of these studies indicate that β-catenin mutations can interact with other oncogenic alterations or pathways to result in hepatocarcinogenesis more often than previously recognized.…”

Overexpression of NDRG2 Can Inhibit Neuroblastoma Cell Proliferation through Negative Regulation by CYR61

“…However, the role of CYR61 in cancer development is complex. Several studies have shown that CYR61 can promote tumorigenesis, progression and invasion in breast cancer (Tsai et al, 2002), gliomas , and hepatocellular carcinoma (Li et al, 2012). It was also found that CYR61 played important roles in inducing apoptosis, inhibiting tumor growth in non-small-cell lung cancer (Tong et al, 2001).…”

“…CYR61, a member of the CCN family of tissue growth factors (CYR61/CTGF/NOV), is highly expressed in various cancer tissues (Li et al, 2012;Sabile et al, 2012). CYR61 regulates multiple cellular activities such as cell proliferation, adhesion, migration, survival and apoptosis (Chien et al, 2004;Yu et al, 2008;Jandova et al, 2012;Lee et al, 2012).…”