Ding Ying, Li Xinying, Wang Wenlong, Cai Lei
Department of Breast Thyroid Surgery, Third Xiangya Hospital, Central South University, No.138, Tongzipo Road, Changsha, 410013, Hunan, China.
Postdoctoral Station of Medical Aspects of Specific Environments, The Third Xiangya Hospital, Central South University, Changsha, China.
Sci Rep. 2025 Feb 5;15(1):4405. doi: 10.1038/s41598-025-88657-2.
Emerging evidence has indicated that m5C modification plays a vital role in cancer development. However, the function of m5C-lncRNAs in PTC has never been reported. This study aims to explore the regulation mechanism of m5C RNA methylation-related long noncoding RNAs (m5C-lncRNAs) in papillary thyroid cancer (PTC). Bioinformatics analysis was used to investigate the role of m5C-lncRNAs in the prognosis and tumor immune microenvironment of PTC. Subsequently, we preliminarily verified the regulation mechanisms of m5C-lncRNAs in vivo and in vitro experiments. A total of six m5C-lncRNAs and five immune cell types were selected to construct the risk score and immune risk score (IRS) model, respectively. Patients with a high-risk score had a worse prognosis and the ROC indicated a reliable prediction performance (AUC = 0.796). As expected, the ESTIMATE and immune scores were higher (P < 0.001) and the tumor purity (P < 0.05) was significantly lower in the low-risk subgroup. CIBERSORT analysis showed Tregs, M0 macrophages, dendritic cells resting, and eosinophils were positively correlated to the risk score. Moreover, the expression levels of PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, and KLRB1 were lower in the high-risk subgroup. Importantly, patients in high-risk subgroup tended to have a better response to immunotherapy than those in low-risk subgroup (P = 0.022). Similar to the above risk score, the IRS model also showed favorable prognosis predictive performance (AUC = 0.764). An integrated nomogram combining risk score, IRS, and age exhibited good prognostic predictive performance. Additionally, we validate the downregulation of PPP1R12A-AS1 promotes proliferation and metastasis by activating the MAPK signaling pathway. Our research confirms that m5C-lncRNAs not only contribute to evaluating the prognosis of patients with PTC but also help predict immune cell infiltration and immunotherapy response.
新出现的证据表明，m5C修饰在癌症发展中起着至关重要的作用。然而，m5C长链非编码RNA（m5C-lncRNAs）在甲状腺乳头状癌（PTC）中的功能尚未见报道。本研究旨在探讨m5C RNA甲基化相关长链非编码RNA（m5C-lncRNAs）在甲状腺乳头状癌（PTC）中的调控机制。采用生物信息学分析方法研究m5C-lncRNAs在PTC预后和肿瘤免疫微环境中的作用。随后，我们在体内和体外实验中初步验证了m5C-lncRNAs的调控机制。分别选取6个m5C-lncRNAs和5种免疫细胞类型构建风险评分和免疫风险评分（IRS）模型。高风险评分的患者预后较差，ROC曲线显示预测性能可靠（AUC = 0.796）。正如预期的那样，低风险亚组的ESTIMATE评分和免疫评分较高（P < 0.001），肿瘤纯度显著较低（P < 0.05）。CIBERSORT分析显示调节性T细胞、M0巨噬细胞、静息树突状细胞和嗜酸性粒细胞与风险评分呈正相关。此外，高风险亚组中PD-1、PD-L1、CTLA-4、TIM-3、LAG-3和KLRB1的表达水平较低。重要的是，高风险亚组的患者比低风险亚组的患者对免疫治疗的反应更好（P = 0.022）。与上述风险评分相似，IRS模型也显示出良好的预后预测性能（AUC = 0.764）。结合风险评分、IRS和年龄的综合列线图显示出良好的预后预测性能。此外，我们验证了PPP1R12A-AS1的下调通过激活MAPK信号通路促进增殖和转移。我们的研究证实，m5C-lncRNAs不仅有助于评估PTC患者的预后，还有助于预测免疫细胞浸润和免疫治疗反应。
