PIN1 gene overexpression and β-catenin gene mutation/expression in hepatocellular carcinoma and their significance

Abstract

The evolution of hepatocellular carcinoma (HCC) is a compound process which involves many kinds of genes and transductional pathways. The expression of the peptidyl-proplyl-isomerase PIN1 gene, the mutation in exon 3 of β-catenin and its correspondent abnormal expression and their roles in the hepatocellular carcinogeneisis were investigated. Among 29 pair cases of HCC and non-carcinoma tissues, the expression of PIN1 gene was detected by immunochemical staining. Mutations in exon 3 of β-catenin gene and differential expression of β-catenin gene were investigated by the methods of PCR-SSCP, direct sequencing and immunohistochemical technique as well. The results indicated: (1) 44.8% (13/29) cases of HCC presented higher level of PIN1 gene expression than non-cancerous tissues (x²=32.63, P<0.05), especially in cytoplasm and nucleus, while there was lower level of PIN1 expression in non-cancerous tissues; (2) 58.6% (17/29) HCC tissues showed β-catenin protein accumulation in cytoplasm and nucleus. 46.2% (6/13) HCC tissues indicated β-catenin protein accumulation with higher level of PIN1 expression, while 53.8% (7/13) HCC tissues indicated β-catenin protein accumulation with lower level or trace of PIN1 expression (x²=0.00, P>0.05); (3) 24.1% (7/29) of primary tumor lesions carried gene mutations in exon 3 of β-catenin, and accompanied by β-catenin protein accumulation. There was no mutation in non-cancerous tissues. All the mutation presented in tissues with low level of PIN1 expression. There was no mutation of β-catenin gene in tissues with high PIN1 expression level (x²=58.12, P<0.05). So it was postulated that the increase of PIN1 gene expression could promote hepatocellular carcinogenesis via a way different from β-catenin gene mutation.

Keywords

β-catenin / hepatocellular carcinoma / mutation

References

[1] KarimR., TseG., PuttiT., et al.. The significance of the Wnt pathway in the pathology of human cancers. Pathology, 2004, 36: 120-128

[2] RyoA., NakamuraM., WulfG., et al.. Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nat Cell Biol, 2001, 3: 793-801

[3] TorbensonM., KannangaiR., AbrahamS., et al.. Concurrent evaluation of p53, beta-catenin, and alphafetoprotein expression in human hepatocellular carcinoma. Am J Clin Pathol, 2004, 122: 377-382

[4] BrennanK. R., BrownA. M.. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia, 2004, 9: 119-131

[5] RyoA., LiouY. C., LuK. P., et al.. Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer. J Cell Sci, 2003, 116: 773-783

[6] CuiJ., ZhouX., LiuY., et al.. Wnt signaling in hepatocellular carcinoma: analysis of mutation and expression of beta-catenin, T-cell factor-4 and glycogen synthase kinase 3-beta genes. J Gastroenterol Hepatol, 2003, 18: 280-287

[7] WuW. X., ZhangX. H., YanX., et al.. Expressions of β-catenin, p53 and proliferating cell nuclear antigen in the carcinogensis of colorectal adenoma. Chin J Oncol (Chinese), 2002, 24: 264-267

[8] PangR., YuenJ., YuenM. F., et al.. PIN1 overexpression and b-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma. Oncogene, 2004, 23: 4182-4186

[9] EaswaranV., LeeS. H., IngeL.. Beta-catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res, 2003, 63: 3145-3153

[10] QiuZ. F., KeijiM., HanD. M., et al.. Correlation of the nuclear accumulation of CTNNB1 and colonic tumorigenesis. Chin Med J, 2006, 119(13): 1113-1117

[11] GotohJ., ObataM., YoshieM., et al.. Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. Carcinogenesis, 2003, 24: 435-442