Hou Jie, Wang Zhan, Li Hong, Zhang Hongzhi, Luo Lan
The People's Hospital of Baoan Shenzhen, The 8th people's Hospital of Shenzhen, The Affiliated Baoan Hospital of Southern Medical University, Shenzhen, China.
Front Genet. 2020 Jul 10;11:522. doi: 10.3389/fgene.2020.00522. eCollection 2020.
Pancreatic cancer (PC) has a very poor prognosis and is usually diagnosed only at an advanced stage. The discovery of new biomarkers for PC will help in early diagnosis and a better prognosis for patients. Recently, N6-methyladenosine (mA) RNA modifications and their regulators have been implicated in the development of many cancers. To investigate the functions and mechanisms of mA modifications in the development of PC, 19 mA regulators, including mA-methyltransferases (ZC3H13, RBM15/15B, WTAP, KIAA1429, and METTL3/14), demethylases (FTO and ALKBH5), and binding proteins (YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, HNRNPC, and HNRNPA2B1) were analyzed in 178 PC tissues from the cancer genome atlas (TCGA) database. The results were verified in PC cell lines Mia-PaCa-2, BXPC-3, and the control cell line HDE-CT. The mA regulators-based sample clusters were significantly related to overall survival (OS). Further, lasso regression identified a six-mA-regulator-signature prognostic model (KIAA1429, HNRNPC, METTL3, YTHDF1, IGF2BP2, and IGF2BP3). Model-based high-risk and low-risk groups were significantly correlated with OS and clinical traits (pathologic M, N, and clinical stages and vital status). The risk signature was verified as an independent prognostic marker for patients with PC. Finally, gene set enrichment analysis revealed mA regulators (KIAA1429, HNRNPC, and IGF2BP2) were related to multiple biological behaviors in PC, including adipocytokine signaling, the well vs. poorly differentiated tumor pathway, tumor metastasis pathway, epithelial mesenchymal transition pathway, gemcitabine resistance pathway, and stemness pathway. In summary, the m6A regulatory factors which related to clinical characteristics can be involved in the malignant progression of PC, and the constructed risk markers may be a promising prognostic biomarker that can guide the individualized treatment of PC patients.
胰腺癌（PC）的预后非常差，通常在晚期才被诊断出来。发现胰腺癌的新生物标志物将有助于早期诊断并改善患者的预后。最近，N6-甲基腺苷（m⁶A）RNA修饰及其调节因子与许多癌症的发生发展有关。为了研究m⁶A修饰在胰腺癌发生发展中的功能和机制，我们在癌症基因组图谱（TCGA）数据库的178例胰腺癌组织中分析了19种m⁶A调节因子，包括m⁶A甲基转移酶（ZC3H13、RBM15/15B、WTAP、KIAA1429和METTL3/14）、去甲基酶（FTO和ALKBH5）以及结合蛋白（YTHDF1/2/3、YTHDC1/2、IGF2BP1/2/3、HNRNPC和HNRNPA2B1）。结果在胰腺癌细胞系Mia-PaCa-2、BXPC-3以及对照细胞系HDE-CT中得到验证。基于m⁶A调节因子的样本聚类与总生存期（OS）显著相关。此外，套索回归确定了一个由六种m⁶A调节因子组成的预后模型（KIAA1429、HNRNPC、METTL3、YTHDF1、IGF2BP2和IGF2BP3）。基于模型的高危和低危组与总生存期及临床特征（病理M、N分期、临床分期和生存状态）显著相关。该风险特征被验证为胰腺癌患者的独立预后标志物。最后，基因集富集分析表明，m⁶A调节因子（KIAA1429、HNRNPC和IGF2BP2）与胰腺癌的多种生物学行为有关，包括脂肪细胞因子信号传导、高分化与低分化肿瘤途径、肿瘤转移途径、上皮-间质转化途径、吉西他滨耐药途径和干性途径。总之，与临床特征相关的m⁶A调节因子可能参与了胰腺癌的恶性进展，构建的风险标志物可能是一种有前景的预后生物标志物，可指导胰腺癌患者的个体化治疗。
