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Role of the Hypoxia-Related Gene, JMJD1A, in Hepatocellular Carcinoma: Clinical Impact on Recurrence after Hepatic Resection

  • Translational Research and Biomarkers
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Abstract

Background and Aims

Intratumoral hypoxia affects every major aspect of cancer biology, but the relationship between hypoxia-induced genes and hepatocellular carcinoma has not been fully investigated. From a previously ranked microarray of hypoxia-inducible genes related to hepatocellular carcinoma, we focused on a histone H3 lysine 9 demethylase, known as Jumonji domain containing 1A. One function of this demethylase is to amplify hypoxia-inducible gene expression. We hypothesized that the demethylase would be a significant marker of hepatocellular carcinoma.

Methods

We examined Jumonji domain containing 1A expression in 110 hepatocellular carcinoma samples with quantitative real-time polymerase chain reaction and immunohistochemistry. We performed a small interfering RNA suppression analysis to determine the biological roles of the demethylase in proliferation, invasion, and the expression of epithelial–mesenchymal transition-related genes.

Results

The level of Jumonji domain containing 1A in cancer tissues was higher than in normal tissues (P < 0.0001). Protein expression was significantly related to gene expression (P < 0.0001). Samples with high Jumonji domain containing 1A expression (n = 47) had higher recurrence rates (P = 0.0006) than those with low expression. Multivariate Cox regression analysis revealed that Jumonji domain containing 1A expression was an independent predictor of recurrence (P = 0.0016), but was not significantly associated with any clinicopathological characteristics. Moreover, suppression of Jumonji domain containing 1A expression in hepatocellular carcinoma cell lines under hypoxic conditions reduced cell growth inhibition, reduced invasion ability, and arrested epithelial–mesenchymal transitions.

Conclusion

Jumonji domain containing 1A is a useful prognostic marker and may ameliorate malignant transformation in hepatocellular carcinoma.

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Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Daisaku Yamada MD, Shogo Kobayashi MD, PhD, Hirofumi Yamamoto MD, PhD, Yoshito Tomimaru MD, Takehiro Noda MD, PhD, Mamoru Uemura MD, PhD, Hiroshi Wada MD, PhD, Shigeru Marubashi MD, PhD, Hidetoshi Eguchi MD, PhD, Masahiro Tanemura MD, PhD, Yuichiro Doki MD, PhD, Masaki Mori MD, PhD & Hiroaki Nagano MD, PhD

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  1. Daisaku Yamada MD
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  2. Shogo Kobayashi MD, PhD
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  3. Hirofumi Yamamoto MD, PhD
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  5. Takehiro Noda MD, PhD
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Correspondence to Hiroaki Nagano MD, PhD.

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10434_2011_1797_MOESM1_ESM.tif

Supplemental Fig. 1 Receiver operating characteristics (ROC) curve analysis. JMJD1A protein reactivity (true positivity versus 1 – true negativity) was used to determine a cutoff value (line) for separating samples with high (>2.15-fold) and low (<2.15-fold) JMJD1A mRNA expression (TIF 65 kb)

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Yamada, D., Kobayashi, S., Yamamoto, H. et al. Role of the Hypoxia-Related Gene, JMJD1A, in Hepatocellular Carcinoma: Clinical Impact on Recurrence after Hepatic Resection. Ann Surg Oncol 19 (Suppl 3), 355–364 (2012). https://doi.org/10.1245/s10434-011-1797-x

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