Wang Tianxiao, Zhang Wenxin, Liu Jiafeng, Mao Xiang, Wang Xinhai, Li Jiyifan, Huang Yuxin, Wu Zimei, Chen Haifei, Shi Huanying, Qi Huijie, Chen Lu, Li Qunyi
Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China.
Cell Death Discov. 2025 Jul 2;11(1):299. doi: 10.1038/s41420-025-02561-2.
The Warburg effect, which is aerobic glycolysis, constitutes a major driver of various cancer progression. Therefore, we aimed to examine the role of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC1α) and its competing endogenous RNA (ceRNA) network in colorectal cancer (CRC) metabolic reprogramming. We used bioinformatics analysis and dual-luciferase reporter gene experiments and identified the DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA network. Additionally, we investigate the impact of PGC1α expression alterations on CRC proliferation and metabolic reprogramming. Moreover, we studied the influence of PGC1α on pyruvate kinase M2 (PKM2), and CRC malignant behavior manifestation. Our study has uncovered a significant association between the DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA network and CRC patient prognosis. Additionally, PGC1α overexpression impeded CRC growth, reduced glycolytic capacity, and enhanced anti-PD-1 therapy efficacy. PGC1α inhibited tumor cell glycolysis by downregulating the WNT/β-catenin pathway depending on peroxisome proliferator-activated receptor gamma (PPARγ), thereby suppressing PKM2. The PPARγ agonist rosiglitazone could hinder CRC proliferation and glycolytic activity. Combined with the PGC1α agonist ZLN005, it exhibits synergistic effects for treating CRC. Moreover, we verified that ZLN005 significantly potentiated PD-1 induced tumor suppression in xenograft mice. Finally, we demonstrated that PGC1α and PKM2 expression patterns in tumor tissues were closely related to patient prognosis. Moreover, we constructed a predictive model to predict the 5-year survival events in CRC patients using random forest model. Our results offer novel perspectives on the role of DNMBP-AS1/hsa-miR-30a-5p/PGC1α network in controlling CRC proliferation, metabolism and immune responses. Furthermore, our investigation reveals that using rosiglitazone combined with PGC1α agonist presents a promising therapeutic approach for managing CRC.
瓦博格效应即有氧糖酵解，是多种癌症进展的主要驱动因素。因此，我们旨在研究过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC1α）及其竞争性内源性RNA（ceRNA）网络在结直肠癌（CRC）代谢重编程中的作用。我们运用生物信息学分析和双荧光素酶报告基因实验，鉴定出了DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA网络。此外，我们研究了PGC1α表达改变对CRC增殖和代谢重编程的影响。而且，我们研究了PGC1α对丙酮酸激酶M2（PKM2）以及CRC恶性行为表现的影响。我们的研究揭示了DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA网络与CRC患者预后之间存在显著关联。此外，PGC1α过表达抑制了CRC生长，降低了糖酵解能力，并增强了抗PD-1治疗效果。PGC1α通过依赖过氧化物酶体增殖物激活受体γ（PPARγ）下调WNT/β-连环蛋白通路来抑制肿瘤细胞糖酵解，从而抑制PKM2。PPARγ激动剂罗格列酮可阻碍CRC增殖和糖酵解活性。与PGC1α激动剂ZLN005联合使用时，它在治疗CRC方面表现出协同效应。此外，我们证实ZLN005显著增强了PD-1在异种移植小鼠中诱导的肿瘤抑制作用。最后，我们证明肿瘤组织中PGC1α和PKM2的表达模式与患者预后密切相关。而且，我们构建了一个预测模型，使用随机森林模型来预测CRC患者的5年生存情况。我们的研究结果为DNMBP-AS1/hsa-miR-30a-5p/PGC1α网络在控制CRC增殖、代谢和免疫反应中的作用提供了新的视角。此外，我们的研究表明，使用罗格列酮联合PGC1α激动剂为管理CRC提供了一种有前景的治疗方法。
