Wu Kai, Wang Qiang, Liu Yu-Lin, Xiang Zhuo, Wang Qing-Qing, Yin Li, Liu Shun-Li
Department of Burns and Plastic Surgery, People's Liberation Army (PLA) 960 Hospital, Jinan, China.
Oncology Department, Shandong Second Provincial General Hospital, Jinan, China.
Front Oncol. 2021 Mar 17;11:643613. doi: 10.3389/fonc.2021.643613. eCollection 2021.
Alkylating agents are critical therapeutic options for melanoma, while dacarbazine (DTIC)-based chemotherapy showed poor sensitivity in clinical trials. Long non-coding RNAs (lncRNAs) were highlighted in the progression of malignant tumors in recent years, whereas little was known about their involvement in melanoma. The functional role and molecular mechanism of lncRNA POU3F3 were evaluated on DTIC-resistant melanoma cells. Further studies analyzed its clinical role in the disease progression of melanoma. We observed elevated the expression of lncRNA POU3F3 in the DTIC-resistant melanoma cells. Gain-of-function assays showed that the overexpression of lncRNA POU3F3 maintained cell survival with DTIC treatment, while the knockdown of lncRNA POU3F3 restored cell sensitivity to DTIC. A positive correlation of the expression O6-methylguanine-DNA-methyltransferase (MGMT) was observed with lncRNA POU3F3 and . Bioinformatic analyses predicted that miR-650 was involved in the lncRNA POU3F3-regulated MGMT expression. Molecular analysis indicated that lncRNA POU3F3 worked as a competitive endogenous RNA to regulate the levels of miR-650, and the lncRNA POU3F3/miR-650 axis determined the transcription of MGMT in melanoma cells to a greater extent. Further clinical studies supported that lncRNA POU3F3 was a risk factor for the disease progression of melanoma. LncRNA POU3F3 upregulated the expression of MGMT by sponging miR-650, which is a crucial way for DTIC resistance in melanoma. Our results indicated that lncRNA POU3F3 was a valuable biomarker for the disease progression of melanoma.
烷化剂是黑色素瘤的关键治疗选择，而基于达卡巴嗪（DTIC）的化疗在临床试验中显示出较差的敏感性。长链非编码RNA（lncRNAs）近年来在恶性肿瘤进展中受到关注，而其在黑色素瘤中的作用却知之甚少。本研究评估了lncRNA POU3F3在DTIC耐药黑色素瘤细胞中的功能作用和分子机制。进一步研究分析了其在黑色素瘤疾病进展中的临床作用。我们观察到lncRNA POU3F3在DTIC耐药黑色素瘤细胞中的表达升高。功能获得实验表明，lncRNA POU3F3的过表达可使细胞在DTIC处理下维持存活，而敲低lncRNA POU3F3可恢复细胞对DTIC的敏感性。观察到O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的表达与lncRNA POU3F3呈正相关。生物信息学分析预测miR-650参与lncRNA POU3F3调控的MGMT表达。分子分析表明，lncRNA POU3F3作为竞争性内源RNA调节miR-650的水平，lncRNA POU3F3/miR-650轴在很大程度上决定了黑色素瘤细胞中MGMT的转录。进一步的临床研究支持lncRNA POU3F3是黑色素瘤疾病进展的危险因素。lncRNA POU3F3通过海绵吸附miR-650上调MGMT的表达，这是黑色素瘤对DTIC耐药的关键途径。我们的结果表明，lncRNA POU3F3是黑色素瘤疾病进展的一个有价值的生物标志物。
