Osteopontin promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma

Authors

  • Qiong-Zhu Dong,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Xiao-Fei Zhang,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Yue Zhao,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Hu-Liang Jia,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Hai-Jun Zhou,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Chun Dai,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Hai-Jing Sun,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Yi Qin,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Wei-De Zhang,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Ning Ren,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Qing-Hai Ye,

    Corresponding author
    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
    • Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
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    • fax: +86-21-5423 7960

  • Lun-Xiu Qin

    Corresponding author
    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
    • Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
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  • Potential conflict of interest: Nothing to report.

Abstract

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)

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