Dalle Carbonare Luca, Minoia Arianna, Vareschi Anna, Piritore Francesca Cristiana, Zouari Sharazed, Gandini Alberto, Meneghel Mirko, Elia Rossella, Lorenzi Pamela, Antoniazzi Franco, Pessoa João, Zipeto Donato, Romanelli Maria Grazia, Guardavaccaro Daniele, Valenti Maria Teresa
Department of Engineering for Innovative Medicine, University of Verona, 37134 Verona, Italy.
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.
Cells. 2024 Feb 27;13(5):408. doi: 10.3390/cells13050408.
Overexpression of the Runt-related transcription factor 2 () has been reported in several cancer types, and the C-X-C motif chemokine receptor 4 () has an important role in tumour progression. However, the interplay between and in melanoma cells remains poorly understood. In the present study, we used melanoma cells and a knockout (-KO) in vitro model to assess the influence of on CXCR4 protein levels along with its effects on markers associated with cell invasion and autophagy. Osteotropism was assessed using a 3D microfluidic model. Moreover, we assessed the impact of CXCR4 on the cellular levels of key cellular signalling proteins involved in autophagy. We observed that melanoma cells express both and . Restored expression in KO cells increased the expression levels of and proteins associated with the metastatic process. The protein markers of autophagy LC3 and beclin were upregulated in response to increased levels. The CXCR4 inhibitor WZ811 reduced osteotropism and activated the mTOR and p70-S6 cell signalling proteins. Our data indicate that the RUNX2 transcription factor promotes the expression of the CXCR4 chemokine receptor on melanoma cells, which in turn promotes autophagy, cell invasiveness, and osteotropism, through the inhibition of the mTOR signalling pathway. Our data suggest that promotes melanoma progression by upregulating , and we identify the latter as a key player in melanoma-related osteotropism.
已有报道称，Runt相关转录因子2（RUNX2）在多种癌症类型中过表达，而C-X-C基序趋化因子受体4（CXCR4）在肿瘤进展中起重要作用。然而，RUNX2与CXCR4在黑色素瘤细胞中的相互作用仍知之甚少。在本研究中，我们使用黑色素瘤细胞和RUNX2基因敲除（RUNX2-KO）体外模型，评估RUNX2对CXCR4蛋白水平的影响及其对与细胞侵袭和自噬相关标志物的作用。使用三维微流控模型评估向骨性。此外，我们评估了CXCR4对参与自噬的关键细胞信号蛋白细胞水平的影响。我们观察到黑色素瘤细胞同时表达RUNX2和CXCR4。在RUNX2 KO细胞中恢复RUNX2表达可增加CXCR4及与转移过程相关蛋白的表达水平。自噬蛋白标志物LC3和贝克林（beclin）响应RUNX2水平升高而上调。CXCR4抑制剂WZ811降低向骨性并激活mTOR和p70-S6细胞信号蛋白。我们的数据表明，RUNX2转录因子促进黑色素瘤细胞上CXCR4趋化因子受体的表达，进而通过抑制mTOR信号通路促进自噬、细胞侵袭和向骨性。我们的数据表明，RUNX2通过上调CXCR4促进黑色素瘤进展，并且我们确定CXCR4是黑色素瘤相关向骨性的关键参与者。
