Wang Yuyao, Yang Zhengbo, Li Ziqun, Huang Linglong, Hou Shuangshuang, Wang Jiaqi, Yu Yang, Yin Jiajun, Wu Ju
Dalian Medical University, Dalian, China.
Department of Gastrointestinal Surgery, Chengdu Sixth People's Hospital, Chengdu, China.
BMC Cancer. 2025 Mar 15;25(1):480. doi: 10.1186/s12885-025-13882-x.
This study aimed to identify molecular markers that influence liver metastasis in colorectal cancer (CRC) and assess their clinical relevance.
Proteomic analysis compared differential protein expression between CRC patients with liver metastasis (CRLM) and those without (CRNLM). Bioinformatics and survival analyses identified key proteins and validated them using the TCGA database for expression and clinical significance. Clinical and pathological data, along with tissue samples from our center, were used to create tissue microarrays for immunohistochemistry. Logistic regression assessed odds ratios (OR) for molecular markers linked to liver metastasis post-CRC surgery. Stable LCAT knockdown and overexpression CRC cell lines were constructed, and Transwell assays assessed the impact LCAT on cell migration. Nile red staining of these cells validated the effect LCAT on lipid metabolism in CRC cells.
Proteomic analysis identified 383 differentially expressed proteins between the CRLM and CRNLM groups (212 upregulated, 171 downregulated). Enrichment analysis linked these proteins to steroid and alcohol metabolism, inflammation, lipoproteins, and HDL particles, with key pathways in cholesterol and retinol metabolism. Lecithin cholesterol acyltransferase (LCAT), an important enzyme in this process, showed higher expression in CRC tissues, with increased LCAT linked to poorer 5-year OS, DSS, and PFI. LCAT expression also increased with tumor stage. Among 119 patients with CRC, preoperative complications, tumor staging, and LCAT scores differed significantly between patients with and without liver metastasis within 3 years post-surgery. LCAT and postoperative CEA levels were independent risk factors for liver metastasis (LCAT OR, 10.221; P = 0.002; CEA OR, 1.296; P = 0.014). Western blotting confirmed significantly higher LCAT expression in CRC tissues with liver metastasis. Transwell assays showed that LCAT overexpression enhanced migratory ability, while knockdown inhibited it. Nile red staining revealed increased lipid droplet accumulation in LCAT-overexpressing CRC cells, which was reduced by LCAT knockdown.
LCAT, which is involved in lipid metabolism, is an independent risk factor for liver metastasis following CRC surgery, suggesting its potential as a therapeutic target.
本研究旨在鉴定影响结直肠癌（CRC）肝转移的分子标志物，并评估其临床相关性。
蛋白质组学分析比较了有肝转移的CRC患者（CRLM）和无肝转移的患者（CRNLM）之间的差异蛋白表达。生物信息学和生存分析确定了关键蛋白，并使用TCGA数据库对其表达和临床意义进行了验证。利用本中心的临床和病理数据以及组织样本制作组织芯片用于免疫组化。逻辑回归评估了CRC手术后与肝转移相关的分子标志物的比值比（OR）。构建了稳定敲低和过表达LCAT的CRC细胞系，Transwell实验评估了LCAT对细胞迁移的影响。对这些细胞进行尼罗红染色验证了LCAT对CRC细胞脂质代谢的影响。
蛋白质组学分析确定CRLM组和CRNLM组之间有383种差异表达蛋白（212种上调，171种下调）。富集分析将这些蛋白与类固醇和酒精代谢、炎症、脂蛋白及高密度脂蛋白颗粒联系起来，关键途径涉及胆固醇和视黄醇代谢。卵磷脂胆固醇酰基转移酶（LCAT）是这一过程中的一种重要酶，在CRC组织中表达较高，LCAT升高与较差的5年总生存期、疾病特异性生存期和无进展生存期相关。LCAT表达也随肿瘤分期增加。在119例CRC患者中，术前并发症、肿瘤分期和LCAT评分在术后3年内有肝转移和无肝转移患者之间存在显著差异。LCAT和术后CEA水平是肝转移的独立危险因素（LCAT的OR为10.221；P = 0.002；CEA的OR为1.296；P = 0.014）。蛋白质印迹法证实有肝转移的CRC组织中LCAT表达显著更高。Transwell实验表明，LCAT过表达增强迁移能力，而敲低则抑制迁移能力。尼罗红染色显示LCAT过表达的CRC细胞中脂滴积累增加，而LCAT敲低则减少了脂滴积累。
参与脂质代谢的LCAT是CRC手术后肝转移的独立危险因素，提示其作为治疗靶点的潜力。
