Liu Weisha, Zhou Hanxiao, Qi Yue, Wang Peng, Ning Shangwei, Huang Yue, Wang Liuying, Cao Lei, Li Kang
Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin 150081, China.
Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin 150081, China.
J Cancer. 2025 Jan 1;16(3):720-734. doi: 10.7150/jca.102148. eCollection 2025.
Platinum resistance is a common cause of chemotherapy failure in lung adenocarcinoma (LUAD). Competing endogenous RNAs (ceRNAs), which function by competitively binding to miRNAs, can influence drug response. However, the regulatory mechanisms of ceRNAs underlying chemoresistance in LUAD remain largely unknown. Here, we proposed an integrated pipeline combining limma algorithm, miRNA binding prediction algorithm, expression correlation model and experimental support to identify functional lncRNA-miRNA-mRNA competing triplets associated with resistance, which showed variable competing patterns between resistant and sensitive cells. We found that a minority of altered ceRNAs overlapped in multiple types of cisplatin-resistant LUAD cell lines and were involved in biological processes known to mediate cancer drug response. We identified them as core resistance factors, forming a novel lncRNA-mediated resistance-related ceRNA network, which indicated a potential mechanism. Single-cell analysis revealed that these resistance-related ceRNAs regulated the functional states of LUAD cells, and survival analysis showed that they contributed to the prognosis of LUAD patients. The lncRNA regulators and were found to correlate with cisplatin activity in LUAD cell lines, and dysregulation of their expression triggered disorders of cisplatin response-related functions through multiple ceRNA regulatory axes in this network, suggesting them as potential resistance biomarkers and therapeutic targets. In summary, the integrated pipeline and the resulting data serve as a valuable resource for understanding the ceRNA mechanisms of chemoresistance and improving chemotherapy response.
铂耐药是肺腺癌（LUAD）化疗失败的常见原因。竞争性内源性RNA（ceRNA）通过竞争性结合miRNA发挥作用，可影响药物反应。然而，LUAD中ceRNA介导化疗耐药的调控机制在很大程度上仍不清楚。在此，我们提出了一种整合的流程，结合limma算法、miRNA结合预测算法、表达相关模型和实验支持，以识别与耐药相关的功能性lncRNA-miRNA-mRNA竞争性三联体，其在耐药和敏感细胞之间呈现出不同的竞争模式。我们发现少数改变的ceRNA在多种顺铂耐药的LUAD细胞系中重叠，并参与已知介导癌症药物反应的生物学过程。我们将它们鉴定为核心耐药因子，形成了一个新的lncRNA介导的耐药相关ceRNA网络，这表明了一种潜在机制。单细胞分析显示，这些与耐药相关的ceRNA调节LUAD细胞的功能状态，生存分析表明它们有助于LUAD患者的预后。发现lncRNA调节因子 和 与LUAD细胞系中的顺铂活性相关，它们表达的失调通过该网络中的多个ceRNA调节轴引发顺铂反应相关功能的紊乱，表明它们是潜在的耐药生物标志物和治疗靶点。总之，整合的流程和所得数据是理解化疗耐药的ceRNA机制和改善化疗反应的宝贵资源。
