Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, P. R. China.
Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, P. R. China.
Sci Rep. 2017 Mar 24;7(1):396. doi: 10.1038/s41598-017-00313-6.
Norcantharidin (NCTD), a demethylated analog of cantharidin derived from Chinese traditional medicine blister beetle, has been currently used as an anticancer drug for various cancers including hepatocellular carcinoma (HCC). In this study, for a more comprehensive understanding of the targets of NCTD in HCC, next-generation RNA-Seq was utilized. We revealed that the expression of FAM46C, which has been reported as a tumor suppressor for multiple myeloma, was enhanced after NCTD treatment. Re-analysis of TCGA (The Cancer Genome Atlas) LIHC (liver hepatocellular carcinoma) dataset demonstrated that FAM46C expression was significantly lower in HCC tissues than in normal liver tissues. NCTD injection or FAM46C overexpression could mitigate diethylnitrosamine (DEN)-initiated HCC in mice. Ectopic expression of FAM46C in two HCC cell lines, SMCC-7721 and SK-Hep-1, significantly repressed cell proliferation, and increased cells population in G2/M phase and cell apoptotic rate. We also found that FAM46C overexpression caused a notable decrease in Ras expression, MEK1/2 phosphorylation and ERK1/2 phosphorylation. More importantly, FAM46C knockdown significantly weakened the biological effects of NCTD on HCC cells, which suggested NCTD exerted the anticancer functions partially through up-regulating FAM46C. In conclusion, FAM46C, a tumor suppressor for HCC, is important for the anti-proliferation and proapoptotic effects of NCTD.
去甲基斑蝥素（NCTD）是一种从中药斑蝥中提取的斑蝥素去甲基类似物，目前已被用作多种癌症（包括肝细胞癌（HCC））的抗癌药物。在这项研究中，为了更全面地了解 NCTD 在 HCC 中的靶点，我们使用了下一代 RNA-Seq。我们发现，FAM46C 的表达在 NCTD 处理后增强，FAM46C 已被报道为多发性骨髓瘤的肿瘤抑制因子。对 TCGA（癌症基因组图谱）LIHC（肝肝细胞癌）数据集的重新分析表明，FAM46C 在 HCC 组织中的表达明显低于正常肝组织。NCTD 注射或 FAM46C 过表达可减轻二乙基亚硝胺（DEN）诱导的小鼠 HCC。FAM46C 在两种 HCC 细胞系 SMCC-7721 和 SK-Hep-1 中的异位表达显著抑制细胞增殖，并增加 G2/M 期细胞群体和细胞凋亡率。我们还发现，FAM46C 过表达导致 Ras 表达、MEK1/2 磷酸化和 ERK1/2 磷酸化显著减少。更重要的是，FAM46C 敲低显著削弱了 NCTD 对 HCC 细胞的生物学效应，这表明 NCTD 通过上调 FAM46C 发挥抗癌作用。总之，FAM46C 是 HCC 的肿瘤抑制因子，对 NCTD 的抗增殖和促凋亡作用很重要。
