Abstract
Human uveal melanoma (UM) is a major ocular malignant tumor with high risk of metastasis and requires multiple oncogenic factors for progression. ZEB1 is a zinc finger E-box binding transcription factor known for participating epithelial-mesenchymal transition (EMT), a critical cellular event for metastasis of malignant tumors of epithelium origin. ZEB1 is also expressed in UM and high expression of ZEB1 correlates with UM advancement, but has little effect on cell morphology. We show that spindle UM cells can become epithelioid but not vice versa; and ZEB1 exerts its tumorigenic effects by promoting cell dedifferentiation, proliferation, invasiveness, and dissemination. We provide evidence that ZEB1 binds not only to repress critical genes involving in pigment synthesis, mitosis, adherent junctions, but also to transactivate genes involving in matrix degradation and cellular locomotion to propel UM progression towards metastasis. We conclude that ZEB1 is a major oncogenic factor required for UM progression and could be a potential therapeutic target for treating UM in the clinic.
Highlights
It appears that epithelial-mesenchymal transition (EMT)-TFs are important for uveal melanoma (UM) tumorigenesis and progression but not necessarily through EMT morphology switch
Within 25 days after cell into the vitreous (IV) injection, ZEB1high C918-grafted tumors disseminated to the liver as compared to no dissemination in the ZEB1low OCM1-grafted mice though knockdown of ZEB1 in C918 seemingly had no significant effect on metastasis (Fig. 8J,K, insert 8K1, Supplemental Table 5). It is well documented in many malignant tumors of epithelium origin that EMT is critical for tumor cells to acquire more advanced capacities of local invasion, distant dissemination, and regeneration because EMT
EMT may not be as important for non-epithelium origin tumor, the EMT-TFs still play an important role in their progression
Summary
It appears that EMT-TFs are important for UM tumorigenesis and progression but not necessarily through EMT morphology switch. We hypothesize that these EMT-TFs and other factors regulate EMT morphology and www.nature.com/scientificreports/. Tumor progression independently through distinct pathways and their combined action results in UM transformation and progression regardless of EMT morphology manifestation. We provide evidence that spindle UM cells can convert to epithelioid UM cells both in vivo and in vitro and that higher levels of ZEB1 propel UM progression by promoting cell dedifferentiation, proliferation, local migration and invasion, and distant dissemination though has little effect on EMT morphology. We conclude that ZEB1 is an oncogenic factor required for UM growth and metastasis
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