Department of Radiology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
Biomol Biomed. 2024 Jan 20;24(4):968-981. doi: 10.17305/bb.2024.10119.
Colorectal cancer (CRC) presents a landscape of intricate molecular dynamics. In this study, we focused on the role of the leukotriene B4 receptor (LTB4R) in CRC, exploring its significance in the disease's progression and potential therapeutic approaches. Using bioinformatics analysis of the GSE164191 and the Cancer Genome Atlas-colorectal adenocarcinoma (TCGA-COAD) datasets, we identified LTB4R as a hub gene influencing CRC prognosis. Subsequently, we examined the relationship between LTB4R expression, apoptosis, and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway through cellular and mice experiments. Our findings revealed that LTB4R is highly expressed in CRC samples and is pivotal for determining prognosis. In vitro experiments demonstrated that silencing LTB4R significantly impeded CRC cell viability, migration, invasion, and colony formation. Correspondingly, in vivo tests indicated that LTB4R knockdown led to markedly slower tumor growth in mice models. Further in-depth investigation revealed that LTB4R knockdown significantly amplified the apoptosis in CRC cells and upregulated the expression of apoptosis-related proteins, such as caspase-3 and caspase-9, while diminishing p53 expression. Interestingly, silencing LTB4R also resulted in a significant downregulation of the PI3K/AKT/mTOR signaling pathway. Moreover, pretreatment with the PI3K activator 740Y-P only partially attenuated the effects of LTB4R knockdown on CRC cell behavior, emphasizing LTB4R's dominant influence in CRC cell dynamics and signaling pathways. LTB4R stands out as a critical factor in CRC progression, profoundly affecting cellular behavior, apoptotic responses, and the PI3K/AKT/mTOR signaling pathway. These findings not only shed light on LTB4R's role in CRC but also establish it as a potential diagnostic biomarker and a promising target for therapeutic intervention.
结直肠癌（CRC）呈现出复杂的分子动态景观。在这项研究中，我们专注于白三烯 B4 受体（LTB4R）在 CRC 中的作用，探索其在疾病进展中的意义和潜在的治疗方法。通过对 GSE164191 和癌症基因组图谱-结直肠腺癌（TCGA-COAD）数据集进行生物信息学分析，我们确定 LTB4R 是影响 CRC 预后的关键基因。随后，我们通过细胞和小鼠实验研究了 LTB4R 表达、细胞凋亡和磷酸肌醇 3-激酶/蛋白激酶 B/雷帕霉素靶蛋白（PI3K/AKT/mTOR）信号通路之间的关系。我们的研究结果表明，LTB4R 在 CRC 样本中高表达，对确定预后至关重要。体外实验表明，沉默 LTB4R 可显著抑制 CRC 细胞活力、迁移、侵袭和集落形成。相应地，体内试验表明，LTB4R 敲低导致小鼠模型中肿瘤生长明显减缓。进一步深入研究表明，LTB4R 敲低显著增强了 CRC 细胞的凋亡，并上调了凋亡相关蛋白如 caspase-3 和 caspase-9 的表达，同时降低了 p53 的表达。有趣的是，沉默 LTB4R 也导致 PI3K/AKT/mTOR 信号通路的显著下调。此外，用 PI3K 激活剂 740Y-P 预处理仅部分减弱了 LTB4R 敲低对 CRC 细胞行为的影响，这强调了 LTB4R 在 CRC 细胞动力学和信号通路中的主导作用。LTB4R 是 CRC 进展的关键因素，它深刻影响细胞行为、凋亡反应和 PI3K/AKT/mTOR 信号通路。这些发现不仅揭示了 LTB4R 在 CRC 中的作用，还将其确立为潜在的诊断生物标志物和治疗干预的有前途的靶点。
