Abstract
The G870A polymorphism in the exon 4/intron 4 boundary of CCND1 gene is thought to influence the generation of two mRNAs (cyclin D1a and cyclin D1b). The “A” allele codes for a truncated variant, cyclin D1b, which may have higher transforming activity. Herein, the tumor relevance of G870A polymorphism, the association between cyclin D1 variant expression and G870A genotype, and the oncogenic potential of cyclin D1 variants in HBV-related hepatocellular carcinoma (HCC) were examined. We found that there is no significant difference of G870A distribution among the HCC, chronic HBV (CHB) infection, cirrhotic CHB, and healthy control groups. Stratification analysis revealed that in younger patients (ages ≤ 50), cirrhotic CHB patients with AA genotype had an increased risk of developing HCC with odds ratio of 1.943 (95 % CI 1.022–3.694, p = 0.0411) as compared with AG/GG genotypes. The two variants were both transcripted from “A” and “G” alleles, and neither cyclin D1a nor D1b production was influenced by G870A genotype in HCC. The expression of both cyclins D1a and D1b decreased in HCC tissues (p = 0.003, p = 0.005), while increased in adjacent nontumor tissues as compared with normal liver tissues (p = 0.045, p = 0.034). Overexpression of cyclin D1a or D1b could promote the cell proliferation and cell-cycle progression in Huh-7 and LO2 cell lines. Collectively, our data suggest that G870A polymorphism has only very limited predictive value for HBV-related HCC. Both cyclins D1a and D1b could promote cell proliferation, which might contribute to the potential oncogenic role of cyclin D1 variants during the precancerous cirrhotic stage of hepatocarcinogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-015-3401-7) contains supplementary material, which is available to authorized users.
Highlights
Hepatocellular carcinoma (HCC) is the third cause of cancerrelated death worldwide [1] and the 5-year survival rate is only 5 % without treatment [2]
These findings indicated that the G870A polymorphism was, to some extent, associated with the HCC risk in this subgroup
A number of studies have described that the CCND1 870A allele is associated with susceptibility to various tumors [7,8,9,10], results of recent meta-analysis indicated that CCND1 G870A polymorphism is a potential risk factor only in the development of brain, lung, breast, and colorectal cancers [10, 19,20,21,22]
Summary
Hepatocellular carcinoma (HCC) is the third cause of cancerrelated death worldwide [1] and the 5-year survival rate is only 5 % without treatment [2]. The pathogenesis of HCC is characterized by sequential events including chronic inflammation, hepatocyte hyperplasia, and malignant transformation [3]. In China, the major risk factor for HCC is the chronic hepatitis B virus (HBV) infection and subsequent hepatic cirrhosis [4]. The surgical excision is still the most effective treatment so far, most HCC patients are diagnosed at late stage and cannot be treated surgically. Perturbations in the regulation of the core cell-cycle machinery are frequently observed in human cancers. As a key regulator of G1 reentry and progression, cyclin D1 is one of the most frequently altered cell-cycle factors in cancers [5].
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