Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, China.
Front Immunol. 2022 Mar 8;13:740960. doi: 10.3389/fimmu.2022.740960. eCollection 2022.
N6-methyladenosine (mA) and 5-methylcytosine (mC) can modify long non-coding RNAs (lncRNAs), thereby affecting tumorigenesis and tumor progression. However, there is a lack of knowledge regarding the potential roles and cross-talk of mA- and mC-related lncRNAs in the tumor microenvironment (TME) and their effect on prognosis.
We systematically evaluated the expression patterns of mA- and mC-related lncRNAs in 1358 colorectal cancer (CRC) samples from four datasets. Consensus clustering was conducted to identify molecular subtypes of CRC, and the clinical significance, TME, tumor-infiltrating immune cells (TIICs), and immune checkpoints in the different molecular subtypes were analyzed. Finally, we established a mA- and mC-related lncRNA signature and a prognostic nomogram.
We identified 141 mA- and mC-related lncRNAs by co-expression analysis, among which 23 lncRNAs were significantly associated with the overall survival (OS) of CRC patients. Two distinct molecular subtypes (cluster A and cluster B) were identified, and these two distinct molecular subtypes could predict clinicopathological features, prognosis, TME stromal activity, TIICs, immune checkpoints. Next, a mA- and mC-related lncRNA signature for predicting OS was constructed, and its predictive capability in CRC patients was validated. We then constructed a highly accurate nomogram for improving the clinical applicability of the signature. Analyses of clinicopathological features, prognosis, TIICs, cancer stem cell (CSC), and drug response revealed significant differences between two risk groups. In addition, we found that patients with a low-risk score exhibited enhanced response to anti-PD-1/L1 immunotherapy. Functional enrichment analysis showed that these lncRNAs related to the high-risk group were involved in the development and progression of CRC.
We conducted a comprehensive analysis of mA- and mC-related lncRNAs in CRC and revealed their potential functions in predicting tumor-immune-stromal microenvironment, clinicopathological features, and prognosis, and determined their role in immunotherapy. These findings may improve our understanding of the cross-talk between mA- and mC-related lncRNAs in CRC and pave a new road for prognosis assessment and more effective immunotherapy strategies.
N6-甲基腺苷（mA）和 5-甲基胞嘧啶（mC）可以修饰长非编码 RNA（lncRNA），从而影响肿瘤的发生和发展。然而，关于 mA 和 mC 相关 lncRNA 在肿瘤微环境（TME）中的潜在作用及其对预后的影响知之甚少。
我们系统地评估了四个数据集的 1358 个结直肠癌（CRC）样本中 mA 和 mC 相关 lncRNA 的表达模式。进行一致性聚类以识别 CRC 的分子亚型，并分析不同分子亚型的临床意义、TME、肿瘤浸润免疫细胞（TIIC）和免疫检查点。最后，我们建立了 mA 和 mC 相关 lncRNA 特征和预后列线图。
通过共表达分析，我们确定了 141 个 mA 和 mC 相关 lncRNA，其中 23 个 lncRNA与 CRC 患者的总生存（OS）显著相关。鉴定出两个不同的分子亚型（cluster A 和 cluster B），这两个不同的分子亚型可以预测临床病理特征、预后、TME 基质活性、TIIC、免疫检查点。接下来，构建了一个用于预测 OS 的 mA 和 mC 相关 lncRNA 特征，并验证了其在 CRC 患者中的预测能力。然后构建了一个高度准确的列线图，以提高特征的临床适用性。分析临床病理特征、预后、TIIC、癌症干细胞（CSC）和药物反应发现两个风险组之间存在显著差异。此外，我们发现低风险评分的患者对抗 PD-1/L1 免疫治疗的反应增强。功能富集分析表明，这些与高风险组相关的 lncRNA 参与了 CRC 的发生和发展。
我们对 CRC 中的 mA 和 mC 相关 lncRNA 进行了全面分析，揭示了它们在预测肿瘤免疫基质微环境、临床病理特征和预后方面的潜在功能，并确定了它们在免疫治疗中的作用。这些发现可能会提高我们对 CRC 中 mA 和 mC 相关 lncRNA 相互作用的理解，并为预后评估和更有效的免疫治疗策略开辟新的道路。
