Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, PR China.
Collaborative innovation platform for modernization and industrialization of regional characteristic traditional Chinese medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, PR China.
Cell Death Dis. 2022 Apr 7;13(4):314. doi: 10.1038/s41419-022-04736-6.
Emerging evidence has shown that long non-coding RNAs (lncRNAs) play an important role in inhibiting tumor cell proliferation and inducing differentiation. In this study, integrative analysis of whole transcriptome sequencing data demonstrated that lncRNA-Gm31932 is significantly decreased in all-trans retinoic acid (ATRA)-induced and sodium 4-phenylbutanoate (PB-4)-induced mouse melanoma B16 cells. Silencing lncRNA-Gm31932 could inhibit B16 cell proliferation, with cell cycle arrest at the G0/G1 phase and obvious differentiation characteristics, e.g., increased cell volume, melanin content and tyrosinase (Tyr) activity. Furthermore, a series of experiments (luciferase reporter assay, RNA pull-down assay, and western blotting) showed that lncRNA-Gm3932 down-regulated Prc1 and Nuf2 by competitively sponging miR-344d-3-5p, which subsequently reduced the expression of cell cycle-related proteins CDK2, CDC2, and Cyclin B1, and increased the expression of P21 and P27. Moreover, silencing lncRNA-Gm31932 could significantly inhibit tumor growth in B16 melanoma-bearing mice. Taken together, these results indicate that as a possible signaling pathway for ATRA and PB-4, lncRNA-Gm31932 can induce cell cycle arrest and differentiation via miR-344d-3-5p/Prc1 (and Nuf2) axis.
越来越多的证据表明，长链非编码 RNA（lncRNA）在抑制肿瘤细胞增殖和诱导分化方面发挥着重要作用。本研究通过整合全转录组测序数据分析发现，全反式视黄酸（ATRA）和 4-苯丁酸（PB-4）诱导的小鼠黑色素瘤 B16 细胞中 lncRNA-Gm31932 表达显著下调。沉默 lncRNA-Gm31932 可抑制 B16 细胞增殖，细胞周期停滞在 G0/G1 期，并表现出明显的分化特征，如细胞体积增大、黑色素含量增加和酪氨酸酶（Tyr）活性增强。进一步的实验（荧光素酶报告基因检测、RNA 下拉实验和 Western blot 分析）表明，lncRNA-Gm3932 通过竞争性结合 miR-344d-3-5p 下调 Prc1 和 Nuf2，进而降低细胞周期相关蛋白 CDK2、CDC2 和 Cyclin B1 的表达水平，增加 P21 和 P27 的表达水平。此外，沉默 lncRNA-Gm31932 可显著抑制 B16 黑素瘤荷瘤小鼠的肿瘤生长。综上所述，这些结果表明，lncRNA-Gm31932 可能作为 ATRA 和 PB-4 的信号通路，通过 miR-344d-3-5p/Prc1（和 Nuf2）轴诱导细胞周期停滞和分化。
