Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response.
Cyr61/CCN1 is a secreted extracellular matrix associated protein involved in diverse biological functions and plays multiple roles in tumorigenesis. Cyr61 was down-regulated in HCC tumor tissues as observed in our previous cDNA microarray study, but its potential role in hepatocarcinogenesis is still unclear. To explore the biological significance of Cyr61 in HCC development, over-expression of this gene was established in HCC cell lines and its effects on cell proliferation, adhesion, migration and invasion were analyzed in this study. Cyr61 expression was down-regulated in HCC tumors as measured by quantitative real-time PCR and its protein level was decreased in most HCC cell lines as detected by Western blot. Over-expression of Cyr61 in HCC cell lines suppressed cell proliferation in monolayer and anchorage-independent growth in soft agar, whereas down-regulation of Cyr61 by siRNA increased cell proliferation rate. Over-expression of Cyr61 also significantly enhanced adhesion activities of HepG2 cells to various ECM proteins. Moreover, stably transfected HepG2-Cyr61 cells showed inhibited cell mobility (40-45%) and reduced invasiveness (30-40%) compared to HepG2-Neo controls. Furthermore, upon exposure to 5-Fluorouracil and UV irradiation, Cyr61 was rapidly induced in both p53(+/+) HepG2 and p53(-/-) Hep3B cells. However, only HepG2 cells showed increased G2/M phase arrest with concomitant up-regulation in p53 and p21 levels, suggesting that Cyr61 may play an active role in regulating HCC cell growth involving p53 as well as alternative pathways. In conclusion, we demonstrated that Cyr61 is a tumor suppressor in hepatocarcinogenesis and is involved in DNA damage response.
Feng
Ping
P
Laboratory of Cell and Medical Biology, Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome, 138672, Singapore.
Wang
Bei
B
Ren
Ee Chee
EC
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement; D049109:Cell Proliferation; D055515:Cysteine-Rich Protein 61 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D034741:RNA, Small Interfering; D013014:SOS Response, Genetics
C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D034741:RNA, Small Interfering