The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial–mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis. Amongst the different existing types of the EMT, type 3 is directly involved in carcinogenesis. A type 3 EMT occurs in neoplastic cells that have previously acquired genetic and epigenetic alterations, specifically affecting genes involved in promoting clonal outgrowth and invasion. Markers such as E-cadherin; N-cadherin; vimentin; and transcription factors (TFs) like Twist, Snail and ZEB are considered key molecules in the transition. The EMT process is also regulated by microRNA expression. Many miRNAs have been reported to repress EMT-TFs. Thus, Snail 1 is repressed by miR-29, miR-30a and miR-34a; miR-200b downregulates Slug; and ZEB1 and ZEB2 are repressed by miR-200 and miR-205, respectively. Occasionally, some microRNA target genes act downstream of the EMT master TFs; thus, Twist1 upregulates the levels of miR-10b. Melatonin is an endogenously produced hormone released mainly by the pineal gland. It is widely accepted that melatonin exerts oncostatic actions in a large variety of tumors, inhibiting the initiation, progression and invasion phases of tumorigenesis. The molecular mechanisms underlying these inhibitory actions are complex and involve a great number of processes. In this review, we will focus our attention on the ability of melatonin to regulate some key EMT-related markers, transcription factors and micro-RNAs, summarizing the multiple ways by which this hormone can regulate the EMT. Since melatonin has no known toxic side effects and is also known to help overcome drug resistance, it is a good candidate to be considered as an adjuvant drug to conventional cancer therapies.
上皮-间质转化（EMT）是一种细胞生物学程序，在多种生理过程进展中发生，也可在诸如癌变等病理状态下出现。该程序通过有序激活一系列细胞内信号通路，驱动上皮细胞获得沿上皮-间质轴分布的多重中间表型状态。这些表型特征包括癌细胞运动性、构型、极性和功能性的改变，最终促使细胞获得干性特征，增强侵袭能力，产生放化疗抵抗并形成肿瘤转移。在现有EMT分型中，3型EMT直接参与癌变过程，发生于已获得遗传学和表观遗传学改变（特别是影响克隆增殖与侵袭相关基因）的肿瘤细胞。E-钙黏蛋白、N-钙黏蛋白、波形蛋白等标志物及Twist、Snail、ZEB等转录因子被视为该转化过程的关键分子。EMT进程同时受microRNA表达调控，多种miRNA可抑制EMT相关转录因子：miR-29、miR-30a与miR-34a抑制Snail1；miR-200b下调Slug；miR-200与miR-205分别抑制ZEB1和ZEB2。部分microRNA靶基因偶尔作为EMT主调控转录因子的下游效应分子，如Twist1可上调miR-10b水平。褪黑素是主要由松果体分泌的内源性激素，其在多种肿瘤中发挥抑癌作用已获广泛认可，能抑制肿瘤发生的起始、进展及侵袭阶段。这些抑制作用的分子机制极为复杂，涉及众多生物学过程。本综述将聚焦褪黑素调控EMT关键标志物、转录因子及micro-RNA的能力，系统阐述该激素调控EMT的多重途径。鉴于褪黑素无已知毒副作用且能帮助克服耐药性，其有望成为常规癌症治疗的辅助药物。
Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer
肿瘤(癌症)患者之家