Chen Yiyi, Zhao Ningning, Xu Lingna, Jia Xiya, Liu Fang, Huang Jian, Li Xuhua, Wang Yunfei, Lai Chuanxi, Shen Yanbin, Wang Fei, Lv Yiming, Huang Xuefeng, Zhang Fan, Gu Hongcang, Dai Sheng
Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.
Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
Mol Cancer. 2025 Jun 6;24(1):164. doi: 10.1186/s12943-025-02359-x.
Colorectal cancer (CRC) is a major global health concern, characterized by high morbidity and mortality rates. CRC progression involves intricate molecular networks that remain incompletely understood. In this study, we conducted an integrative multi-omics analysis of transcriptomic, proteomic, and metabolomic profiles from CRC tissues and matched normal adjacent tissues (NATs). Our analysis revealed 1,394 differentially expressed long non-Coding RNAs (lncRNAs), 2,788 genes, 548 proteins, and 91 metabolites. A significant interaction network comprising 22 lncRNAs, 14 mRNAs/proteins, and 9 metabolites was identified, among which lncRNA 60967.1 emerged as a pivotal regulator. Functional validation demonstrated that lncRNA 60967.1 is markedly downregulated in CRC cell lines and patient tissues. Overexpression of lncRNA 60967.1 restored expression of the tumor suppressor PLCD4 and increased levels of all-trans retinoic acid (ATRA). This modulation enhanced IFN-γ-induced apoptosis and increased expression of the IFN-γ receptor subunit IFNGR1, thereby partially reversing IFN-γ resistance. In murine models, lncRNA 60967.1 overexpression promoted immune cell infiltration and synergized with anti-PD-1 therapy to inhibit tumor growth. Collectively, our findings uncover a novel lncRNA-mRNA/protein-metabolite network, the lncRNA 60967.1-PLCD4-ATRA axis, that plays a critical role in CRC progression and immune modulation, offering promising therapeutic targets for improved treatment efficacy.
结直肠癌（CRC）是一个重大的全球健康问题，其发病率和死亡率都很高。CRC的进展涉及复杂的分子网络，目前仍未完全了解。在本研究中，我们对CRC组织和匹配的正常相邻组织（NATs）进行了转录组、蛋白质组和代谢组学的综合多组学分析。我们的分析揭示了1394个差异表达的长链非编码RNA（lncRNAs）、2788个基因、548种蛋白质和91种代谢物。我们鉴定出了一个由22个lncRNAs、14个mRNA/蛋白质和9种代谢物组成的重要相互作用网络，其中lncRNA 60967.1成为关键调节因子。功能验证表明，lncRNA 60967.1在CRC细胞系和患者组织中明显下调。lncRNA 60967.1的过表达恢复了肿瘤抑制因子PLCD4的表达，并增加了全反式维甲酸（ATRA）的水平。这种调节增强了IFN-γ诱导的细胞凋亡，并增加了IFN-γ受体亚基IFNGR1的表达，从而部分逆转了IFN-γ耐药性。在小鼠模型中，lncRNA 60967.1的过表达促进了免疫细胞浸润，并与抗PD-1治疗协同抑制肿瘤生长。总的来说，我们的研究结果揭示了一个新的lncRNA-mRNA/蛋白质-代谢物网络，即lncRNA 60967.1-PLCD4-ATRA轴，它在CRC进展和免疫调节中起关键作用，为提高治疗效果提供了有前景的治疗靶点。
