Osteopontin promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma
Osteopontin promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma
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DOI：
10.1002/hep.26103
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发表时间：
2013-03-01
期刊：
影响因子：
13.5
通讯作者：
Qin, Lun-Xiu
中科院分区：
文献类型：
--
作者：
Dong, Qiong-Zhu;Zhang, Xiao-Fei;Qin, Lun-Xiu
骨桥蛋白（OPN）在肝细胞癌（HCC）转移中起重要作用。然而，关于OPN多态性对癌症进展的影响知之甚少。在这项研究中，我们首先确定了OPN启动子区的单核苷酸多态性（SNPs）的直接测序在30个肝癌，然后在两个大队列的826例肝癌患者的预后价值进行评估。使用体外和体内测定法对鉴定的SNP进行功能分析，并评估其与OPN水平的相关性。仅-443位点的SNP及其相关单倍型（Ht 2：-1748A/-616G/-443T/-155* [* 表示碱基缺失]; Ht 3：-1748A/-616G/-443C/-155*）与总生存期（OS）和复发时间（TTR）显著相关。携带-443TT/TC基因型或Ht 2的患者的OS和TTR较携带-443CC基因型或Ht 3的患者短。这在验证队列中得到了进一步证实。此外，这种相关性在小肝癌（5 cm）患者中仍然显著。多因素分析表明，-443基因型（OS，P = 0.031; TTR，P = 0.005）及其相关单倍型（OS，P = 0.002; TTR，P = 0.001）的预后表现与其他临床病理因素无关。与Ht 3和-443CC基因型相比，Ht 2和-443TT基因型可显著提高OPN启动子的转录活性和表达水平，并导致肝癌细胞体外侵袭和体内肿瘤生长及肺转移的显著增加（P < 0.05）。结论：OPN基因启动子-443位点的遗传变异在OPN表达调控和肝癌进展中起重要作用，是影响肝癌转移和预后的一个新的决定因素和靶点。（肝脏学2013）
Osteopontin (OPN) plays a crucial role in hepatocellular carcinoma (HCC) metastasis. However, little is known about the impact of OPN polymorphisms on cancer progression. In this study, we first identified the single nucleotide polymorphisms (SNPs) in the OPN promoter region by direct sequencing in 30 HCCs, and then evaluated the prognostic values of the selected ones in two large cohorts of 826 HCC patients. The identified SNPs were functionally analyzed using in vitro and in vivo assays and their correlations with OPN levels were also evaluated. Only SNP at locus -443 and their related haplotypes (Ht2: -1748A/-616G/-443T/-155* [*indicates base deletion]; Ht3: -1748A/-616G/-443C/-155*) were significantly associated with overall survival (OS) and time to recurrence (TTR). The patients with the -443TT/TC genotype or Ht2 had a shorter OS and TTR compared with those with -443CC genotype or Ht3. This was further confirmed in the validation cohort. Moreover, this correlation remained significant in patients with small HCCs (5 cm). Multivariate analyses indicated that the prognostic performance of the -443 genotypes (OS, P = 0.031; TTR, P = 0.005) and their related haplotypes (OS, P = 0.002; TTR, P = 0.001) was independent of other clinicopathological factors. The Ht2 and -443TT genotype could significantly increase the promoter transcriptional activity and expression level of OPN compared with the Ht3 or -443CC genotype, and lead to an obvious increase in both in vitro invasion and in vivo tumor growth and lung metastasis of HCC cells (P < 0.05). Conclusion: The genetic variation at locus -443 of the OPN promoter plays important roles in the regulation of OPN expression and cancer progression of HCCs, which is a novel determinant and target for HCC metastasis and prognosis. (HEPATOLOGY 2013)