Chen Chin-Chuan, Chen Chi-Yuan, Wang Shu-Huei, Yeh Chau-Ting, Su Shih-Chi, Ueng Shir-Hwa, Chuang Wen-Yu, Hsueh Chuen, Wang Tong-Hong
Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan.
Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan 33303, Taiwan.
Cancers (Basel). 2018 Sep 10;10(9):320. doi: 10.3390/cancers10090320.
DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC.
由于累积的突变，DNA修复系统在大多数肝细胞癌（HCC）细胞中异常活跃，导致DNA修复能力增强以及对化疗和放疗产生抗性。因此，靶向DNA修复机制是HCC中使癌细胞对DNA损伤敏感化的常用治疗方法。在本研究中，我们检测了褪黑素的抗HCC作用并阐明了其调控机制。功能试验结果表明，褪黑素除了抑制HCC细胞的增殖、迁移和侵袭能力外，还抑制其DNA修复能力，从而增强化疗和放疗的细胞毒性。全转录组以及功能获得和功能缺失分析表明，褪黑素诱导长链非编码RNA RAD51-AS1的表达，该长链非编码RNA与RAD51 mRNA结合以抑制其翻译，有效降低HCC细胞的DNA修复能力并增加其对化疗和放疗的敏感性。动物模型进一步证明，与单一疗法相比，褪黑素与化疗药物依托泊苷（VP16）联合使用可显著增强肿瘤生长抑制作用。我们的结果表明，褪黑素是HCC化疗和放疗的潜在辅助治疗药物。
