上皮间充质转化（EMT）是一种复杂的过程，在细胞转化中起着原始作用。此过程中，上皮细胞转化并获得间充质表型。这种转化在肿瘤进程和自我更新中发挥关键作用，同时加剧了对细胞凋亡和化疗的抵抗。EMT可以通过非正常的致癌信号通路、缺氧以及肿瘤微环境中的细胞启动和促进，导致上皮细胞极性、细胞间粘附以及增强的浸润/迁移性质的流失。多种转录调节因子如Snail、Slug、Twist和ZEB1/ZEB2通过下调上皮标志物和上调间充质标志物诱导EMT。此外，信号通路如Wnt/β-catenin、Notch、Sonic Hedgehog、核因子kappa B、受体酪氨酸激酶、PI3K/AKT/mTOR、Hippo和转化生长因子β通路调节EMT，在癌症中常常失调，导致异常的EMT。此外，非编码RNA、肿瘤源性外泌体和表观遗传改变也参与EMT的调节。因此，调节EMT是控制肿瘤细胞侵袭性转移特征的至关重要的策略。尽管EMT在癌症进展中有大量的临床前数据，但在治疗层面缺乏临床转化。在本综述中，我们全面讨论了上述转录因子、非编码RNA（microRNA、长链非编码RNA、环状RNA）、信号通路、表观遗传修饰和肿瘤源性外泌体在癌症中调节EMT的作用。我们还强调了EMT对药物抵抗的贡献以及使用植物来源的天然产物、其半合成衍生物和纳米制剂作为有前途的EMT阻断剂的可能治疗干预。©2023 Wiley Periodicals LLC.

Epithelial-mesenchymal transition (EMT) is a complex process with a primordial role in cellular transformation whereby an epithelial cell transforms and acquires a mesenchymal phenotype. This transformation plays a pivotal role in tumor progression and self-renewal, and exacerbates resistance to apoptosis and chemotherapy. EMT can be initiated and promoted by deregulated oncogenic signaling pathways, hypoxia, and cells in the tumor microenvironment, resulting in a loss-of-epithelial cell polarity, cell-cell adhesion, and enhanced invasive/migratory properties. Numerous transcriptional regulators, such as Snail, Slug, Twist, and ZEB1/ZEB2 induce EMT through the downregulation of epithelial markers and gain-of-expression of the mesenchymal markers. Additionally, signaling cascades such as Wnt/β-catenin, Notch, Sonic hedgehog, nuclear factor kappa B, receptor tyrosine kinases, PI3K/AKT/mTOR, Hippo, and transforming growth factor-β pathways regulate EMT whereas they are often deregulated in cancers leading to aberrant EMT. Furthermore, noncoding RNAs, tumor-derived exosomes, and epigenetic alterations are also involved in the modulation of EMT. Therefore, the regulation of EMT is a vital strategy to control the aggressive metastatic characteristics of tumor cells. Despite the vast amount of preclinical data on EMT in cancer progression, there is a lack of clinical translation at the therapeutic level. In this review, we have discussed thoroughly the role of the aforementioned transcription factors, noncoding RNAs (microRNAs, long noncoding RNA, circular RNA), signaling pathways, epigenetic modifications, and tumor-derived exosomes in the regulation of EMT in cancers. We have also emphasized the contribution of EMT to drug resistance and possible therapeutic interventions using plant-derived natural products, their semi-synthetic derivatives, and nano-formulations that are described as promising EMT blockers.© 2023 Wiley Periodicals LLC.