PDF(Pubmed)
Abstract：
Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing ApcMin/+ mice with Cul4bΔIEC mice to achieve specific deletion of Cul4b in the gut epithelium against an ApcMin/+ background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited ApcMin/+ adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted ApcMin/+ adenomas. Furthermore, the addition of MDSCs to in vitro cultured ApcMin/+; Cul4bΔIEC adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating ApcMin/+ adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.
摘要：
结直肠癌（CRC）是全球普遍存在的恶性肿瘤。CRC发病机制中的一个关键事件涉及APC基因的功能缺失突变，导致良性息肉的形成。尽管APC的作用已经确立，对于CUL4B在肿瘤前阶段对CRC启动的贡献仍然知之甚少.在这次调查中,我们通过将ApcMin/+小鼠与Cul4bΔIEC小鼠交叉以在ApcMin/+背景下实现肠上皮中Cul4b的特异性缺失来产生小鼠模型。通过采用组织学方法，RNA测序（RNA-seq），和流式细胞术，我们评估了改变并表征了免疫微环境。我们的结果揭示了肠上皮中的CUL4B缺乏加速了ApcMin/腺瘤的形成。值得注意的是,腺瘤中的CUL4B抑制了肿瘤浸润性髓源性抑制细胞（MDSC）的积累。MDSC的体内抑制显著延迟了CUL4B缺失的ApcMin/+腺瘤的生长。此外，向体外培养的ApcMin/+;Cul4bΔIEC腺瘤类器官中添加MDSCs减轻了它们的改变。机械上,CUL4B通过与PRC2协调，直接与Csf3的启动子相互作用，Csf3是编码粒细胞集落刺激因子（G-CSF）的基因。抑制CUL4B表观遗传激活G-CSF的表达，促进招募MDSCs。这些发现为CUL4B在调节ApcMin/+腺瘤中的肿瘤抑制因子样作用提供了新的见解。提示在激活的Wnt信号背景下，CRC起始和进展的潜在治疗策略。
