Department of Life Sciences, Unit of Pathology, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41124, Modena, Italy.
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
J Ovarian Res. 2019 Jul 10;12(1):62. doi: 10.1186/s13048-019-0536-y.
All-trans retinoic acid (ATRA) is currently being used to treat hematological malignancies, given the ability to inhibit cell proliferation. This effect seems to be related to epigenetic changes of the TERT (Telomerase Reverse Transcriptase) promoter. When hypomethylated, ATRA-inducible TERT repressors can bind the promoter, repressing transcription of TERT, the rate-limiting component of telomerase. Ovarian carcinomas are heterogeneous tumors characterized by several aberrantly methylated genes among which is TERT. We recently found a hypomethylation of TERT promoter in about one third of serous carcinoma, the most lethal histotype. Our aim was to investigate the potential role of ATRA as an anticancer drug in a sub-group of ovarian carcinoma where the TERT promoter was hypomethylated.
The potential antiproliferative and cytotoxic effect of ATRA was investigated in seven serous ovarian carcinoma and one teratocarcinoma cell lines and the results were compared to the methylation status of their TERT promoter.
The serous ovarian carcinoma cell line OVCAR3, harboring a hypomethylated TERT promoter, was the best and fastest responder. PA1 and SKOV3, two cell lines with an intermediate methylated promoter, revealed a weaker and delayed response. On the contrary, the other 5 cell lines with a highly methylated promoter did not respond to ATRA, indicative of ATRA-resistant cells.
Our results demonstrate an inverse correlation between the methylation level of TERT promoter and ATRA efficacy in ovarian carcinoma cell lines. Although these results are preliminary, ATRA treatment could become a new powerful, personalized therapy in serous ovarian carcinoma patients, but only in those with tumors harboring a hypomethylated TERT promoter.
全反式维甲酸（ATRA）目前被用于治疗血液系统恶性肿瘤，因为它能够抑制细胞增殖。这种作用似乎与 TERT（端粒酶逆转录酶）启动子的表观遗传变化有关。当 ATRA 诱导的 TERT 抑制剂去甲基化时，可以与启动子结合，抑制 TERT 的转录，TERT 是端粒酶的限速成分。卵巢癌是一种异质性肿瘤，其特征是存在几个异常甲基化的基因，其中包括 TERT。我们最近发现大约三分之一的浆液性癌存在 TERT 启动子的低甲基化，这是最致命的组织学类型。我们的目的是研究 ATRA 作为一种抗癌药物在 TERT 启动子低甲基化的卵巢癌亚组中的潜在作用。
我们研究了 ATRA 在七种浆液性卵巢癌和一种畸胎癌细胞系中的潜在增殖抑制和细胞毒性作用，并将结果与它们的 TERT 启动子甲基化状态进行了比较。
浆液性卵巢癌 OVCAR3 细胞系具有低甲基化的 TERT 启动子，是反应最好和最快的细胞系。PA1 和 SKOV3 是两个具有中等甲基化启动子的细胞系，表现出较弱和延迟的反应。相反，其他 5 个具有高度甲基化启动子的细胞系对 ATRA 没有反应，表明是 ATRA 耐药细胞。
我们的结果表明，TERT 启动子的甲基化水平与卵巢癌细胞系对 ATRA 的疗效呈负相关。尽管这些结果是初步的，但 ATRA 治疗可能成为浆液性卵巢癌患者的一种新的、强大的、个性化的治疗方法，但仅限于那些肿瘤具有低甲基化 TERT 启动子的患者。
