Given the importance of Wnt/β-catenin pathway in normal embryonic and adult liver development, it is not surprising to see that its activity is perturbed in HCC. About 50%–70% of HCC are found to have an increased level of β-catenin in the cytoplasm or nucleus, which is believed to provide growth advantage for tumor cells. Many of the target genes of Wnt/β-catenin signaling pathway are involved in promoting cell proliferation.
In the present study, we showed that Cyr61 is over-expressed in HCC, and that it is one of the target genes for Wnt/β-catenin pathway. We also demonstrated that increased expression of Cyr61 promoted the growth of HepG2 cell xenografts in SCID mice.
The roles of the Cyr61 in cancer development are complex. A higher level of Cyr61 is found in breast cancer and it is shown to induce estrogen-independence and to promote invasiveness of breast cancer 
. Cyr61 is shown to have elevated mRNA and protein levels in pancreatic cancer 
. However, in endometrial tumor, Cyr61 level is decreased compared to normal endometrium 
. It is also reported that a high Cyr61 level is associated with a lower risk of recurrence of prostate cancer after surgery 
. The involvement of Cyr61 in tumorigenesis has been mentioned in other investigations. Its exact role is not conclusive. Cyr61 is critical for pancreatic carcinogenesis through inducing EMT and stemness 
. Cyr61 promotes colony formation and cell growth in esophageal squamous cell carcinoma 
. However, it has also been reported that Cyr61 suppresses the growth of non-small-cell lung cancer cells 
In our study, it is worth noticing that Cyr61 is expressed markedly higher in cancer-adjacent hepatic cirrhosis tissue, which was recognized as precancerous lesions, than in the tumor tissue itself. These results suggest that the abnormal expression of Cyr61 may be closely related to the development of HCC and hepatic cirrhosis, and Cyr61 may be involved in the progression of hepatic cirrhosis to HCC. It is also noted that the expression of Cyr61 is reduced in poorly differentiated HCC. Similar findings are seen in colorectal cancer 
and gastric cancer 
, in which Cyr61 is over-expressed, while its expression is reduced in more advanced cancer. This data suggested that Cyr61 might be a helpful early diagnosis marker for HCC and one of the indicators for the transformation of liver cirrhosis to HCC.
The exact role of Cyr61 in human cancers remains largely undefined. Both inhibitory and promoting effects of Cyr61 on cancers have been reported. We demonstrated in this study that Cyr61 protein expression was increased in HCC, which is consistent with our previous work and that of the others 
. However, some other studies found that Cyr61 was down-regulated in HCC tumor tissues by quantitative real-time PCR 
or cDNA array 
analysis. There were also studies showing that no significant expression of Cyr61 was detected in HCC compared to the normal tissue 
. The reasons for the discrepancy can be many folds. Difference in recognition of the boundaries between tumor tissue and tumor-adjacent normal liver tissue may produce different results among the laboratories. Regardless that we demonstrated in our studies that HCC of hepatic cirrhosis or non-cirrhosis origin and the stages of cancer influence Cyr61 expression. These variations, however, are not considered in the other reported studies. Experimentally, we studied both the mRNA and protein levels of Cyr61 in HCC, HCC adjacent tissue and normal liver tissue.
Feng et al showed that Cyr61 suppressed proliferation of HCC cell line, and negatively regulated cell motility and invasiveness. The author concluded that Cyr61 acts as a tumor suppressor in HCC 
. Our previously published data had shown that over-expression of exogenous Cyr61 promoted the proliferation and migration of HepG2 cells 
. In the present study, we have repeated our experiments for the effect of Cyr61 on the growth of HepG2 cells xenografts in SCID mice. Our results indicate that Cyr61 can promote the proliferation of HepG2 cells not only in vitro
but also in vivo
. Animal experiments are in general considered as a better assessment for tumor development than the in vitro
experiments. Overall, we believe that our conclusion is supported by our in vitro
and in vivo
Cyr61 is known to interact with various integrins, including αγ
, which leads to a variety of biological activities, including cell adhesion, migration, and invasion 
. Furthermore, several studies showed that Cyr61 can be activated under hypoxia or trauma and is involved in angiogenesis 
and cancer cell invasion 
. The complex function of Cyr61 makes it difficult to simply define it as an oncogene or a tumor suppressor gene in the development of hepatocellular carcinoma. It likely has a variety of functions in the development of HCC at different stages and may work with a variety of factors.
In summary, our study indicates that Cyr61 is a target gene of β-catenin signaling in HCC. Over-expression of Cyr61 is induced by abnormal expression of β-catenin and promotes the growth and migration of HCC cell line in vitro and the progression of HCC xenografts in SCID mice. Based on our results, it is reasonable to hypothesize that early interference with Cyr61 signaling pathway may prevent the transition from hepatic dysplasia to HCC. Future studies about the complex role and mechanism of Cyr61 in tumorigenesis and progression of HCC are needed.