Guo Huimin, Zheng Guiwen, Li Jia, Yao Shuzhan, Jia Qiang, Tan Jian, Meng Zhaowei
Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Department of Nuclear Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
Discov Oncol. 2025 Aug 25;16(1):1624. doi: 10.1007/s12672-025-03468-1.
Colorectal neuroendocrine neoplasms (CrNENs) are rare malignancies with limited therapeutic options and poorly understood molecular mechanisms. The roles of genetic, epigenetic, and immune factors in CrNEN progression remain largely unknown.
We employed an integrative multi-omics approach combining two-sample Mendelian randomization, Bayesian colocalization, methylation quantitative trait loci (mQTLs), cis-expression QTLs (cis-eQTLs), protein QTLs (pQTLs), summary data-based Mendelian randomization, mediation analyses, immunohistochemistry validation, and pan-cancer validation using TCGA and GTEx data, including DNA methylation profiling using the SMART, UALCAN, UCSC Xena and MethSurv platforms to provide integrative insights into potential epigenetic regulation in oncogenesis. Molecular docking was performed to identify candidate therapeutic compounds that targeted the genes.
Our analyses identified TREM1 as a robust therapeutic candidate, with elevated TREM1 expression promoting the progression of CrNEN. Epigenetic analysis revealed that hypomethylation at the cg04451353 locus was associated with increased TREM1 expression, mediating approximately 74% of the CrNEN risk attributable to this epigenetic mechanism. Immune mediation analysis suggested that increased TREM1 expression may influence the infiltration of specific immune subsets (CD14 + CD16- monocytes, CD25 + + CD8br Tregs, CD3 on Tregs, CD3 on CD39 + secreting Tregs, CD3 on CD8br Tregs, and CD28 on CD39 + CD8br Tregs), with each subset contributing approximately 1-4% to the total 16.65% increase in CrNEN risk. Pan-cancer validation underscored the oncogenic potential and prognostic significance of TREM1 across various malignancies, with particular relevance in the colorectal cancer. Molecular docking analysis suggested favorable binding affinities between TREM1 and bioactive natural compounds, such as artemisinin and quercetin, which may support their potential as therapeutic candidates.
Multi-omics analysis suggests that TREM1 may play a role in CrNEN pathogenesis, with potential implications as a therapeutic target. Further validation and research are needed to confirm its clinical relevance and therapeutic potential.
结直肠神经内分泌肿瘤（CrNENs）是罕见的恶性肿瘤，治疗选择有限，分子机制尚不清楚。遗传、表观遗传和免疫因素在CrNEN进展中的作用仍 largely 未知。
我们采用了一种综合多组学方法，结合两样本孟德尔随机化、贝叶斯共定位、甲基化数量性状位点（mQTLs）、顺式表达数量性状位点（cis-eQTLs）、蛋白质数量性状位点（pQTLs）、基于汇总数据的孟德尔随机化、中介分析、免疫组化验证以及使用TCGA和GTEx数据进行泛癌验证，包括使用SMART、UALCAN、UCSC Xena和MethSurv平台进行DNA甲基化谱分析，以提供对肿瘤发生中潜在表观遗传调控的综合见解。进行分子对接以鉴定靶向这些基因的候选治疗化合物。
我们的分析确定TREM1是一个有力的治疗候选物，TREM1表达升高促进CrNEN的进展。表观遗传分析表明，cg04451353位点的低甲基化与TREM1表达增加相关，介导了约74%的CrNEN风险归因于这种表观遗传机制。免疫中介分析表明，TREM1表达增加可能影响特定免疫亚群（CD14+CD16-单核细胞、CD25++CD8br调节性T细胞、调节性T细胞上的CD3、CD39+分泌调节性T细胞上的CD3、CD8br调节性T细胞上的CD3以及CD39+CD8br调节性T细胞上的CD28）的浸润，每个亚群对CrNEN风险总增加的16.65%贡献约1-4%。泛癌验证强调了TREM1在各种恶性肿瘤中的致癌潜力和预后意义，在结直肠癌中尤为相关。分子对接分析表明TREM1与生物活性天然化合物（如青蒿素和槲皮素）之间具有良好的结合亲和力，这可能支持它们作为治疗候选物的潜力。
多组学分析表明TREM1可能在CrNEN发病机制中起作用，具有作为治疗靶点的潜在意义。需要进一步验证和研究以确认其临床相关性和治疗潜力。
