Takano Nao, Hishida Mitsuhiro, Inokawa Yoshikuni, Hayashi Masamichi, Kanda Mitsuro, Nishikawa Yoko, Iwata Naoki, Kobayashi Daisuke, Tanaka Chie, Yamada Suguru, Nakayama Goro, Fujii Tsutomu, Sugimoto Hiroyuki, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro, Nomoto Shuji
Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
Department of Surgery, Aichi-Gakuin University School of Dentistry, Chikusa-ku, Nagoya 464-8651, Japan.
Int J Oncol. 2015 May;46(5):1963-70. doi: 10.3892/ijo.2015.2892. Epub 2015 Feb 11.
Hepatocellular carcinoma (HCC) has a high likelihood of recurrence and a poor prognosis. To detect cancer-related genes of HCC, we developed a new technique: triple combination array analysis, consisting of a methylation array, a gene expression array and a single nucleotide polymorphism array. A surgical specimen obtained from a 68-year-old female HCC patient was analyzed using triple combination array, which identified cyclin J (CCNJ) as a candidate cancer-related gene of HCC. Subsequently, samples from 85 HCC patients were evaluated for CCNJ promoter hypermethylation and expression status using methylation-specific PCR (MSP) and quantitative reverse transcriptase RT-PCR, respectively. CCNJ was found to be hypermethylated (methylation value, 0.906; range, 0-1.0) in cancer tissue, compared with adjacent non-cancerous tissue (0.112) using a methylation array. MSP revealed that CCNJ was hypermethylated in 67 (78.8%) of the tumor samples. CCNJ expression was significantly decreased in cases with hypermethylation (P<0.0001). Furthermore, cases with both promoter hypermethylation and decreased expression of CCNJ in the tumor tissue had a worse overall survival than the other cases (P=0.0383). In conclusion, our results indicated that CCNJ could be a novel prognostic marker of HCC, and this study indicated that triple combination array analysis was effective in detecting new tumor-related genes and their mechanisms.
肝细胞癌（HCC）复发可能性高且预后较差。为检测HCC的癌症相关基因，我们开发了一种新技术：三联组合阵列分析，它由甲基化阵列、基因表达阵列和单核苷酸多态性阵列组成。使用三联组合阵列对一名68岁女性HCC患者的手术标本进行分析，确定细胞周期蛋白J（CCNJ）为HCC的候选癌症相关基因。随后，分别使用甲基化特异性PCR（MSP）和定量逆转录RT-PCR对85例HCC患者的样本进行CCNJ启动子高甲基化和表达状态评估。使用甲基化阵列发现，与相邻非癌组织（0.112）相比，癌组织中CCNJ呈高甲基化（甲基化值为0.906；范围为0 - 1.0）。MSP显示，67例（78.8%）肿瘤样本中CCNJ呈高甲基化。CCNJ表达在高甲基化病例中显著降低（P<0.0001）。此外，肿瘤组织中启动子高甲基化且CCNJ表达降低的病例总生存期比其他病例更差（P = 0.0383）。总之，我们的结果表明CCNJ可能是HCC的一种新型预后标志物，本研究表明三联组合阵列分析在检测新的肿瘤相关基因及其机制方面是有效的。
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