Growth and Differentiation Factor 3 Induces Expression of Genes Related to Differentiation in a Model of Cancer Stem Cells and Protects Them from Retinoic Acid-Induced Apoptosis

Misexpression of growth factors, particularly those related to stem cell-like phenotype, is often observed in several cancer types. It has been found to influence parameters of disease progression like cell proliferation, differentiation, maintenance of undifferentiated phenotype and modulation of the immune system. GDF3 is a TGFB family member associated with pluripotency and differentiation during embryonic development that has been previously reported to be re-expressed in a number of cancer types. However, its role in tumor development and progression has not been clarified yet. In this study we decipher the role of GDF3 in an in vitro model of cancer stem cells, NCCIT cells. By classical approach to study protein function combined with high-throughput technique for transcriptome analysis and differentiation assays we evaluated GDF3 as a potential therapeutic target. We observed that GDF3 robustly induces a panel of genes related to differentiation, including several potent tumor suppressors, without impacting the proliferative capacity. Moreover, we report for the first time the protective effect of GDF3 against retinoic acid-induced apoptosis in cells with stem cell-like properties. Our study implies that blocking of GDF3 combined with retinoic acid-treatment of solid cancers is a compelling direction for further investigations, which can lead to re-design of cancer differentiation therapies.

生长因子的异常表达，尤其是与干细胞样表型相关的生长因子，在多种癌症类型中屡见不鲜。现有研究证实，此类异常表达可影响疾病进展的多项核心参数，包括细胞增殖、分化、未分化表型维持以及免疫系统调控。GDF3（growth differentiation factor 3）属于转化生长因子β（TGF-β）家族成员，与胚胎发育过程中的多能性调控及细胞分化进程密切相关，既往已有研究报道其在多种癌症类型中出现重表达现象。然而，其在肿瘤发生与进展中的具体作用尚未阐明。本研究以癌症干细胞体外模型NCCIT细胞为研究对象，解析了GDF3的生物学功能。我们结合经典蛋白质功能研究方法与高通量转录组分析、分化实验技术，评估了GDF3作为潜在治疗靶点的可行性。实验结果显示，GDF3可显著诱导一批与分化相关的基因表达，其中包含多种强效肿瘤抑制因子，且未对细胞增殖能力造成影响。此外，本研究首次报道了GDF3对具有干细胞样特性的细胞抵御视黄酸诱导凋亡的保护作用。本研究提示，联合阻断GDF3与视黄酸治疗实体瘤是极具前景的研究方向，有望推动癌症分化治疗方案的重新设计。