West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, People's Republic of China.
West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, People's Republic of China.
Eur J Pharmacol. 2020 Apr 5;872:172982. doi: 10.1016/j.ejphar.2020.172982. Epub 2020 Feb 1.
Arsenic trioxide is an effective drug in the treatment of hematologic malignancies, but it has no obvious therapeutic effect on liver cancer. Long non-coding RNA ROR is a newly found long-noncoding RNA that has been reported to get involved in the regulation of chemo-resistance in multiple cancers. However, whether and how long non-coding RNA ROR gets involved in the resistance to arsenic trioxide in liver cancer has not been explored. In this study, We found that cellular apoptosis was increased by arsenic trioxide in liver cancer HepG2 cells; P53 expression was also increased by arsenic trioxide at both mRNA level and protein level, indicating that P53-dependent apoptosis is the main mechanism for arsenic trioxide to induce cytotoxicity in liver cancer HepG2 cells. Meanwhile, we found an obvious increase in the level of long non-coding RNA ROR in arsenic trioxide-treated HepG2 cells. By measuring the level of reactive oxygen species, glutathione, superoxide dismutase, and malondialdehyde, the product of lipid peroxidation, we further demonstrated that oxidative stress was a potential factor for both the activation of P53 expression and the increase in long non-coding RNA ROR expression. Through the knock-down of long non-coding RNA ROR by siRNA, we revealed that the activated long non-coding RNA ROR ameliorated arsenic trioxide-induced apoptosis by inhibiting P53 expression. Together, our study reported that long non-coding RNA ROR conferred arsenic trioxide resistance to liver cancer cells through inhibiting P53 expression, and long non-coding RNA ROR might be a novel sensitizing target for liver cancer treatment.
三氧化二砷是治疗血液系统恶性肿瘤的有效药物，但对肝癌无明显治疗作用。长链非编码 RNA ROR 是一种新发现的长链非编码 RNA，已报道其参与多种癌症的化疗耐药调节。然而，长链非编码 RNA ROR 是否以及如何参与肝癌对三氧化二砷的耐药性尚未得到探索。在本研究中，我们发现三氧化二砷能增加肝癌 HepG2 细胞的细胞凋亡；三氧化二砷还能在 mRNA 水平和蛋白水平上增加 P53 的表达，表明 P53 依赖性凋亡是三氧化二砷诱导肝癌 HepG2 细胞细胞毒性的主要机制。同时，我们发现三氧化二砷处理的 HepG2 细胞中长链非编码 RNA ROR 的水平明显升高。通过测量活性氧、谷胱甘肽、超氧化物歧化酶和丙二醛（脂质过氧化的产物）的水平，我们进一步证明氧化应激是激活 P53 表达和增加长链非编码 RNA ROR 表达的潜在因素。通过 siRNA 敲低长链非编码 RNA ROR，我们揭示了激活的长链非编码 RNA ROR 通过抑制 P53 表达减轻了三氧化二砷诱导的细胞凋亡。综上所述，我们的研究表明，长链非编码 RNA ROR 通过抑制 P53 表达赋予肝癌细胞对三氧化二砷的耐药性，长链非编码 RNA ROR 可能是肝癌治疗的新敏化靶点。
