背景:炎症无疑是癌症发展的标志。对其在肿瘤中的维持以及对疾病侵袭性的后果的理解不足。
方法:从TCGA和GEO数据库下载27个肿瘤实体(约5000个样品)的数据。对这些数据和内部数据进行了多项分析,以研究肿瘤侵袭性的分子决定因素。使用分子功能损失数据,研究了炎症诱导肿瘤侵袭性的机制基础.随后使用患者样本和体内疾病模型来验证发现。
结果:体细胞拷贝数改变(sCNAs)与肿瘤侵袭性之间存在显著关联。SOX2扩增是新的和已知的侵袭性相关改变中最重要的特征。机械上,SOX2调节一组基因,特别是AP1转录因子FOSL2,以维持促炎信号通路,如IL6-JAK-STAT3、TNFA和IL17。发现FOSL2在特异性侵袭性癌症的肿瘤切片中过表达。因此,如侵袭性肿瘤中相关突变特征所证明的,延长的炎症诱导免疫抑制并激活胞苷脱氨基,从而激活DNA损伤。DNA损伤会影响肿瘤抑制基因,如TP53,与侵袭性较低的肿瘤相比,TP53是侵袭性肿瘤中突变最多的基因(38%vs14%)。从而释放细胞周期控制。通过分析来自各种肿瘤类型的组织和体内研究证实了这些结果。
结论:我们的数据表明SOX2通过FOSL2/IL6维持炎症,促进DNA损伤和基因组不稳定,导致肿瘤侵袭性。
Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and the consequences on disease aggressiveness are insufficiently understood.
Data of 27 tumor entities (about 5000 samples) were downloaded from the TCGA and GEO databases. Multi-omic analyses were performed on these and in-house data to investigate molecular determinants of tumor aggressiveness. Using molecular loss-of-function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness were addressed. Patient specimens and in vivo disease models were subsequently used to validate findings.
There was significant association between somatic copy number alterations (sCNAs) and tumor aggressiveness. SOX2 amplification was the most important feature among novel and known aggressiveness-associated alterations. Mechanistically, SOX2 regulates a group of genes, in particular the AP1 transcription factor FOSL2, to sustain pro-inflammatory signaling pathways, such as IL6-JAK-STAT3, TNFA and IL17. FOSL2 was found overexpressed in tumor sections of specifically aggressive cancers. In consequence, prolonged inflammation induces immunosuppression and activates cytidine deamination and thus DNA damage as evidenced by related mutational signatures in aggressive tumors. The DNA damage affects tumor suppressor genes such as TP53, which is the most mutated gene in aggressive tumors compared to less aggressive ones (38% vs 14%), thereby releasing cell cycle control. These results were confirmed by analyzing tissues from various tumor types and in vivo studies.
Our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.