Zhang Jie, Sun Wenxue, Wu Wenda, Qin Zihui, Wei Ben, Li Tushuai
School of Biology and Food Engineering, Changshu Institute of Technology, Suzhou, 215500, People's Republic of China.
Jining First People's Hospital, Jining Medical University, Jining, 272000, People's Republic of China.
Cell Mol Life Sci. 2025 Mar 27;82(1):132. doi: 10.1007/s00018-025-05653-5.
Pancreatic cancer is highly lethal and has a poor prognosis. Research has highlighted the role of circular RNAs and m6A methylation in cancer progression. METTL3, a key m6A methyltransferase, is linked to various cancers, but its interaction with circular RNAs in pancreatic cancer is unclear. This study examined the role of circCEACAM5 in pancreatic cancer, particularly its regulation by METTL3-mediated m6A methylation and interaction with effectors such as DKC1.
circCEACAM5 expression in pancreatic cancer tissues and cell lines was evaluated via RT‒qPCR. Its characteristics were validated through Sanger sequencing, stability assays, and FISH. Functional assays (CCK-8, EdU, Transwell, and flow cytometry) were conducted in AsPC-1 cells, and in vivo tumor models were established. m6A modification was analyzed via bioinformatics tools and m6A-specific immunoprecipitation, while RNA pull-down assays were used to examine the interaction of circCEACAM5 with METTL3 and DKC1.
circCEACAM5 was significantly upregulated in pancreatic cancer and correlated with poor clinical outcomes. CircCEACAM5 promoted cell proliferation, invasion, and migration while inhibiting apoptosis both in vitro and in vivo. METTL3-mediated m6A methylation of circCEACAM5 was confirmed, and METTL3 knockdown reversed the effects of circCEACAM5 silencing on the malignant behavior of pancreatic cancer cells. circCEACAM5 interacted with DKC1, and DKC1 overexpression reversed the effects of circCEACAM5 knockdown on the malignant behavior of pancreatic cancer cells.
METTL3-mediated m6A methylation of circCEACAM5 drives pancreatic cancer progression by increasing DKC1 expression, suggesting potential new therapeutic targets for this aggressive malignancy.
胰腺癌具有高度致死性，预后较差。研究突出了环状RNA和m6A甲基化在癌症进展中的作用。METTL3作为一种关键的m6A甲基转移酶，与多种癌症相关，但其在胰腺癌中与环状RNA的相互作用尚不清楚。本研究探讨了circCEACAM5在胰腺癌中的作用，特别是其受METTL3介导的m6A甲基化调控以及与DKC1等效应分子的相互作用。
通过RT-qPCR评估circCEACAM5在胰腺癌组织和细胞系中的表达。通过Sanger测序、稳定性分析和FISH验证其特征。在AsPC-1细胞中进行功能分析（CCK-8、EdU、Transwell和流式细胞术），并建立体内肿瘤模型。通过生物信息学工具和m6A特异性免疫沉淀分析m6A修饰，同时使用RNA下拉分析检测circCEACAM5与METTL3和DKC1的相互作用。
circCEACAM5在胰腺癌中显著上调，且与不良临床结局相关。circCEACAM5在体外和体内均促进细胞增殖、侵袭和迁移，同时抑制细胞凋亡。证实了METTL3介导的circCEACAM5的m6A甲基化，METTL3敲低逆转了circCEACAM5沉默对胰腺癌细胞恶性行为的影响。circCEACAM5与DKC1相互作用，DKC1过表达逆转了circCEACAM5敲低对胰腺癌细胞恶性行为的影响。
METTL3介导的circCEACAM5的m6A甲基化通过增加DKC1表达驱动胰腺癌进展，提示这种侵袭性恶性肿瘤可能有新的治疗靶点。
