Su Shih-Chi, Yeh Chia-Ming, Lin Chiao-Wen, Hsieh Yi-Hsien, Chuang Chun-Yi, Tang Chih-Hsin, Lee Yi-Chan, Yang Shun-Fa
Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan.
J Pineal Res. 2021 Oct;71(3):e12760. doi: 10.1111/jpi.12760. Epub 2021 Aug 26.
The inhibitory effect of melatonin on cancer cell dissemination is well established, yet the functional involvement of lncRNAs in melatonin signaling remains poorly understood. In this study, we identified a melatonin-attenuated lncRNA acting as a potential melatonin-regulated oral cancer stimulator (MROS-1). Downregulation of MROS-1 by melatonin suppressed TPA-induced oral cancer migration through replenishing the protein expression of prune homolog 2 (PRUNE2), which functioned as a tumor suppressor in oral cancer. Melatonin-mediated MROS-1/PRUNE2 expression and cell motility in oral cancer were regulated largely through the activation of JAK-STAT pathway. In addition, MROS-1, preferentially localized in the nuclei, promoted oral cancer migration in an epigenetic mechanism in which it modulates PRUNE2 expression by interacting with a member of the DNA methylation machinery, DNA methyltransferase 3A (DNMT3A). Higher methylation levels of PRUNE2 promoter were associated with nodal metastases and inversely correlated with PRUNE2 expression in head and neck cancer. Collectively, these findings suggest that MROS-1, serving as a functional mediator of melatonin signaling, could predispose patients with oral cancer to metastasize and may be implicated as a potential target for antimetastatic therapies.
褪黑素对癌细胞扩散的抑制作用已得到充分证实，然而，lncRNAs在褪黑素信号传导中的功能作用仍知之甚少。在本研究中，我们鉴定出一种受褪黑素抑制的lncRNA，它作为一种潜在的褪黑素调节的口腔癌刺激因子（MROS-1）。褪黑素下调MROS-1可通过补充在口腔癌中起肿瘤抑制作用的果蝇Prune同源物2（PRUNE2）的蛋白表达来抑制佛波酯（TPA）诱导的口腔癌迁移。褪黑素介导的口腔癌中MROS-1/PRUNE2的表达和细胞运动主要通过JAK-STAT通路的激活来调节。此外，MROS-1优先定位于细胞核，通过与DNA甲基化机制成员DNA甲基转移酶3A（DNMT3A）相互作用调节PRUNE2表达，以一种表观遗传机制促进口腔癌迁移。PRUNE2启动子的高甲基化水平与头颈部癌的淋巴结转移相关，且与PRUNE2表达呈负相关。总的来说，这些发现表明，MROS-1作为褪黑素信号传导的功能介质，可能使口腔癌患者易于发生转移，并可能作为抗转移治疗的潜在靶点。
