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Downregulation of betaine homocysteine methyltransferase (BHMT) in hepatocellular carcinoma associates with poor prognosis

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Tumor Biology

Abstract

Betaine homocysteine methyltransferase (BHMT) catalyzes the synthesis of methionine using betaine and homocysteine (Hcy), which is restricted to the liver and kidney. Impaired BHMT pathway has been associated with hepatocellular carcinogenesis in Bhmt−/− mice model, and decreased BHMT was observed in a small sample of human hepatocellular carcinoma (HCC) patients. However, the prognostic significance of BHMT in HCC has not been elucidated. This study aimed to examine the expression of BHMT in HCC and investigate the relationship between its expression and prognosis of HCC patients. BHMT expression was analyzed in 68 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), 115 paraffin-embedded HCC sections (primary cohort), and 65 paraffin-embedded HCC sections (validation cohort) using immunohistochemistry (IHC). The results of IHC analysis showed that BHMT was decreased in tumorous tissues in 85.2 % (58/68) of cases compared to the corresponding adjacent non-tumorous liver tissues. Further correlation analyses indicated that the decreased BHMT expression was closely correlated with serum α-fetoprotein (AFP) (p = 0.011), tumor size (p = 0.039), and vascular invasion (p = 0.017). Moreover, HCC patients with low BHMT expression had shorter overall survival (OS) and time to recurrence (TTR) than those with high BHMT expression in both primary cohort (p < 0.0001) and validation cohort (p < 0.05) assessed by the Kaplan–Meier method. In addition, multivariate analysis showed that BHMT was an independent prognostic factor for OS and TTR in the two cohorts (all p < 0.005). Collectively, our study demonstrated that BHMT could be served as a potential prognostic marker for HCC patients.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (no. 81100323, no. 81160256), the Fundamental Research Funds of Shan Dong University (Qilu Hospital Research Project) (2014QLKY18), and the Project Fund of Techpool (UF201330).

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    Authors and Affiliations

    1. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China

      Bin Jin, Zhiwei Gong & Sanyuan Hu

    2. Department of General Surgery, The Qingzhou City People’s hospital, Qingzhou, 262500, China

      Zhiwei Gong

    3. Department of General Surgery, The people’s Hospital of LingCheng, Dezhou, 253500, China

      Nongguo Yang

    4. Department of Pathology, Affiliated hospital of Guilin Medical University, Guilin, 541001, Guangxi, China

      Zhaoquan Huang & Sien Zeng

    5. Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, 541001, Guangxi, China

      Hui Chen

    6. Department of Hepatobiliary Surgery, The people’s hospital of Liuzhou, Liuzhou, 545001, Guangxi, China

      Guangdong Pan

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    1. Bin Jin
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    Correspondence to Sanyuan Hu.

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    Supplementary information

    Supplementary Figure 1, Supplementary Table 1–2.

    Additional information

    Bin Jin and Zhiwei Gong contributed equally to this work.

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    Supplementary Figure 1

    Correlation of low BHMT expression with unfavorable OS and TTR in primary cohort and validation cohort, respectively. Probabilities of OS (A) and TTR (B) of 115 HCC patients (primary cohort) were analyzed using Kaplan-Meier survival analysis (log-rank test). Probabilities of OS (C) and TTR (D) of 65 HCC patients (validation cohort) were analyzed using Kaplan-Meier survival analysis (log-rank test). (DOC 274 kb)

    Supplementary Table 1

    Univariate and multivariate analysis of different prognostic parameters in primary cohort by Cox regression analysis (n=115). (DOC 92 kb)

    Supplementary Table 2

    Univariate and multivariate analysis of different prognostic parameters in validation cohort by Cox regression analysis (n=65). (DOC 88 kb)

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    Jin, B., Gong, Z., Yang, N. et al. Downregulation of betaine homocysteine methyltransferase (BHMT) in hepatocellular carcinoma associates with poor prognosis. Tumor Biol. 37, 5911–5917 (2016). https://doi.org/10.1007/s13277-015-4443-6

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    • DOI: https://doi.org/10.1007/s13277-015-4443-6

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