"Partitioning defective 3（Par3）是一种在建立上皮细胞极性和紧密连接（TJ）中起关键作用的极性蛋白。肠道上皮屏障的功能障碍与溃疡性结肠炎相关的结直肠癌（CRC）进展密切相关。根据GEO和TCGA数据库的分析，我们首先观察到Par3在CRC患者身上的表达受到了抑制。为了了解Par3与CRC的关系，我们采用了体内遗传方法研究了Par3在CRC发展中的作用。我们的研究结果表明，肠道上皮特异性PAR3缺失小鼠在异环丙甲烷/右硫糖苷酸钠（AOM/DSS）治疗背景下展示出更严重的CRC表型，伴随肿瘤数量增加和炎性细胞因子谱的变化。在机制上，Par3的丧失破坏了肠道上皮的TJ，并增加了粘膜屏障的渗透性。Par3与ZO-1的相互作用阻止了ZO-1蛋白内分子间的相互作用，并促进occludin与ZO-1的结合，从而保持了TJ的完整性。我们的研究结果表明，Par3缺失允许病原菌及其内毒素穿透肠道粘膜下层并激活TLR4/MyD88/NF-κB信号通路，促进了炎症驱动的CRC发展，并且Par3可能是早期CRC诊断的一种新潜在分子标志物。© 2023 Wiley Periodicals LLC."

Partitioning defective 3 (Par3) is a polarity protein critical in establishing epithelial cell polarity and tight junctions (TJs). Impaired intestinal epithelial barrier integrity is closely associated with colitis-associated colorectal cancer (CRC) progression. According to the GEO and TCGA database analyses, we first observed that the expression of Par3 was reduced in CRC patients. To understand how Par3 is related to CRC, we investigated the role of Par3 in the development of CRC using an in vivo genetic approach. Our results show that the intestinal epithelium-specific PAR3 deletion mice demonstrated a more severe CRC phenotype in the context of azoxymethane/dextran sodium sulfate (AOM/DSS) treatment, with a corresponding increase in tumor number and inflammatory cytokines profile. Mechanistically, loss of Par3 disrupts the TJs of the intestinal epithelium and increases mucosal barrier permeability. The interaction of Par3 with ZO-1 prevents intramolecular interactions within ZO-1 protein and facilitates the binding of occludin to ZO-1, hence preserving TJs integrity. Our results suggest that Par3 deficiency permits pathogenic bacteria and their endotoxins to penetrate the intestinal submucosa and activate TLR4/MyD88/NF-κB signaling, promoting inflammation-driven CRC development and that Par3 may be a novel potential molecular marker for the diagnosis of early-stage CRC.© 2023 Wiley Periodicals LLC.