Huang Liyong, Tong Yixin, Li Xu, Wang Wei, Wang Zhen, Chen Bingchen, E Jifu, Zhou Ruzhen, Wang Hantao, He Jinghu
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, No.270 Dongan Road, Xuhui District, Shanghai, 200032, China.
Department of GI Surgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China.
Mol Med. 2025 Jun 15;31(1):239. doi: 10.1186/s10020-025-01252-z.
Colorectal cancer (CRC) remains a significant health challenge globally, demanding a comprehensive understanding of its molecular underpinnings for effective management. In this study, we investigated the role of Aldolase C (ALDOC), a glycolytic enzyme, in CRC pathogenesis. Transcriptomic analysis of CRC tissues from The Cancer Genome Atlas (TCGA) revealed a substantial upregulation of ALDOC, correlating with adverse clinical outcomes. Immunohistochemical (IHC) staining of locally collected patient-derived tissues corroborated these findings, demonstrating elevated ALDOC expression in tumor tissues, particularly in advanced stages. Functional studies elucidated the regulatory role of ALDOC in CRC cell phenotypes. ALDOC knockdown significantly inhibited cell proliferation, induced apoptosis, arrested cell cycle progression, and suppressed cell migration in vitro. Moreover, in vivo studies using xenograft models confirmed that ALDOC knockdown attenuated tumor growth. Mechanistically, ALDOC was found to interact with hypoxia-inducible factor 1 alpha (HIF1A) and enhance its transcriptional activity on phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme. Dual-luciferase reporter assays and chromatin immunoprecipitation experiments validated the ALDOC-mediated transcriptional activation of PGK1. Further functional rescue experiments revealed a synergistic interplay between ALDOC and PGK1 in regulating CRC cell phenotypes. Additionally, ALDOC was implicated in promoting aerobic glycolysis in CRC cells, potentially through PGK1 regulation. Collectively, our findings unveil ALDOC as a critical regulator of CRC pathogenesis, offering insights into its potential as a therapeutic target and highlighting the ALDOC/PGK1 axis as a promising avenue for further investigation in CRC.
结直肠癌（CRC）在全球范围内仍然是一项重大的健康挑战，需要全面了解其分子基础以进行有效管理。在本研究中，我们调查了糖酵解酶醛缩酶C（ALDOC）在CRC发病机制中的作用。对来自癌症基因组图谱（TCGA）的CRC组织进行转录组分析发现，ALDOC显著上调，这与不良临床结果相关。对本地收集的患者来源组织进行的免疫组织化学（IHC）染色证实了这些发现，表明肿瘤组织中ALDOC表达升高，尤其是在晚期。功能研究阐明了ALDOC在CRC细胞表型中的调节作用。在体外，敲低ALDOC可显著抑制细胞增殖、诱导细胞凋亡、阻止细胞周期进程并抑制细胞迁移。此外，使用异种移植模型的体内研究证实，敲低ALDOC可减弱肿瘤生长。机制上，发现ALDOC与缺氧诱导因子1α（HIF1A）相互作用，并增强其对关键糖酵解酶磷酸甘油酸激酶1（PGK1）的转录活性。双荧光素酶报告基因测定和染色质免疫沉淀实验验证了ALDOC介导的PGK1转录激活。进一步的功能挽救实验揭示了ALDOC和PGK1在调节CRC细胞表型方面的协同相互作用。此外，ALDOC可能通过调节PGK1促进CRC细胞中的有氧糖酵解。总体而言，我们的研究结果揭示了ALDOC是CRC发病机制的关键调节因子，为其作为治疗靶点的潜力提供了见解，并突出了ALDOC/PGK1轴作为CRC进一步研究的有希望的途径。
