Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
Institute of Experimental Endocrinology and Oncology (IEOS) G. Salvatore, CNR, 80131 Naples, Italy.
Hum Mol Genet. 2021 Nov 1;30(22):2100-2109. doi: 10.1093/hmg/ddab173.
The zinc finger protein ZNF224 plays a dual role in cancer, operating as both tumour suppressor and oncogenic factor depending on cellular and molecular partners. In this research we investigated the role of ZNF224 in melanoma, a highly invasive and metastatic cancer, and provided evidence for the involvement of ZNF224 in the TGF-β signalling as a mediator of the TGF-β pro-oncogenic function. Our results showed that ZNF224, whose expression increased in melanoma cell lines after TGF-β stimulation, potentiated the activation induced by TGF-β on its target genes involved in epithelial-mesenchymal transition (EMT). Accordingly, overexpression of ZNF224 enhanced the tumourigenic properties of melanoma cells, promoting cell proliferation and invasiveness, whereas ZNF224 knockdown had the opposite effect. Moreover, ZNF224 positively modulates the expression of TGF-β itself and its type 1 and 2 receptors (TβR1 and TβR2), thus highlighting a possible mechanism by which ZNF224 could enhance the endogenous TGFβ/Smad signalling. Our findings unveil a positive regulatory loop between TGF-β and ZNF224 to promote EMT, consequently increasing the tumour metastatic potential.
锌指蛋白 ZNF224 在癌症中发挥双重作用，根据细胞和分子伴侣的不同，它既可以作为肿瘤抑制因子，也可以作为致癌因子。在这项研究中，我们研究了 ZNF224 在黑色素瘤中的作用，黑色素瘤是一种高度侵袭性和转移性的癌症，并为 ZNF224 参与 TGF-β 信号作为 TGF-β 致癌功能的介质提供了证据。我们的结果表明，ZNF224 的表达在 TGF-β 刺激后增加黑色素瘤细胞系，增强 TGF-β 对其参与上皮-间充质转化（EMT）的靶基因的激活。因此，ZNF224 的过表达增强了黑色素瘤细胞的致瘤特性，促进了细胞增殖和侵袭性，而 ZNF224 的敲低则产生了相反的效果。此外，ZNF224 还正向调节 TGF-β 本身及其 1 型和 2 型受体（TβR1 和 TβR2）的表达，从而突出了 ZNF224 可能增强内源性 TGFβ/Smad 信号的可能机制。我们的研究结果揭示了 TGF-β 和 ZNF224 之间的正反馈环，以促进 EMT，从而增加肿瘤转移潜力。
