Tyumentseva Anna, Averchuk Anton, Palkina Nadezhda, Zinchenko Ivan, Moshev Anton, Savchenko Andrey, Ruksha Tatiana
Department of Pathophysiology, Krasnoyarsk State Medical University, Krasnoyarsk, Russia.
Federal Research Center Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk, Russia.
Front Oncol. 2021 Dec 3;11:732501. doi: 10.3389/fonc.2021.732501. eCollection 2021.
Melanoma is highly heterogeneous type of malignant neoplasm that is responsible for the majority of deaths among other types of skin cancer. In the present study, we screened a list of differentially expressed genes in two primary, drug-naïve melanoma cell lines derived from patients with melanoma following treatment of the cells with the chemotherapeutic agent dacarbazine. The aim was to determine the transcriptomic profiles and associated alterations in the cell phenotype. We found the vascular endothelial growth factor A/vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase/protein kinase B and focal adhesion signaling pathways to be top altered after dacarbazine treatment. In addition, we observed the expression levels of genes associated with tumor dissemination, integrin β8 and matrix metalloproteinase-1, to be diminished in both cell lines studied, the results of which were confirmed by reverse transcription-quantitative polymerase chain reaction. By contrast, plexin A2 expression was found to be upregulated in K2303 cells, where reduced migration and invasion were also observed, following dacarbazine treatment. Plexin A2 downregulation was associated with the promotion of migrative and invasive capacities in B0404 melanoma cells. Since plexin A2 is semaphorin co-receptor that is involved in focal adhesion and cell migration regulation, the present study suggested that plexin A2 may be implicated in the dacarbazine-mediated phenotypic shift of melanoma cells. We propose that the signature of cancer cell invasiveness can be revealed by using a combination of transcriptomic and functional approaches, which should be applied in the development of personalized therapeutic strategies for each patient with melanoma.
黑色素瘤是一种高度异质性的恶性肿瘤，在其他类型的皮肤癌中导致了大多数死亡。在本研究中，我们筛选了两个原发性、未接受过药物治疗的黑色素瘤细胞系中的差异表达基因列表，这两个细胞系来自黑色素瘤患者，在使用化疗药物达卡巴嗪处理细胞后进行筛选。目的是确定转录组图谱以及细胞表型的相关改变。我们发现，达卡巴嗪处理后，血管内皮生长因子A/血管内皮生长因子受体2、磷酸肌醇3激酶/蛋白激酶B和粘着斑信号通路的改变最为显著。此外，我们观察到在研究的两个细胞系中，与肿瘤播散相关的基因整合素β8和基质金属蛋白酶-1的表达水平均降低，逆转录-定量聚合酶链反应证实了这一结果。相比之下，在K2303细胞中发现，达卡巴嗪处理后，丛状蛋白A2表达上调，同时细胞迁移和侵袭能力降低。在B0404黑色素瘤细胞中，丛状蛋白A2下调与迁移和侵袭能力的增强有关。由于丛状蛋白A2是一种信号素共受体，参与粘着斑和细胞迁移调控，因此本研究表明，丛状蛋白A2可能与达卡巴嗪介导的黑色素瘤细胞表型转变有关。我们建议，通过结合转录组学和功能学方法可以揭示癌细胞侵袭的特征，这应该应用于为每位黑色素瘤患者制定个性化治疗策略。
