Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Malaga, Spain.
Institute of Biomedical Research in Malaga (IBIMA)-Bionand Platform, University of Malaga, 29010, Malaga, Spain.
J Transl Med. 2024 May 27;22(1):509. doi: 10.1186/s12967-024-05329-x.
Several studies have suggested secreted frizzled-related protein 2 (SFRP2) gene as a potential clinical biomarker in colorectal cancer (CRC). However, its diagnostic role remains unclear. In this study, we aimed to investigate the significance of SFRP2 methylation levels in a large cohort of biological specimens (including blood, adipose and colonic tissues) from patients with CRC, thereby potentially identifying new biomarker utility.
We examined the expression (by qPCR) and methylation status (by 450 K DNA array and DNA pyrosequencing) of the SFRP2 gene in healthy participants (N = 110, aged as 53.7 (14.2), 48/62 males/females) and patients with CRC (N = 85, aged 67.7 (10.5), 61/24 males/females), across different biological tissues, and assessing its potential as a biomarker for CRC. Additionally, we investigated the effect of recombinant human SFRP2 (rhSFRP2) as a therapeutic target, on cell proliferation, migration, and the expression of key genes related to carcinogenesis and the Wnt pathway.
Our findings revealed that SFRP2 promoter methylation in whole blood could predict cancer stage (I + II vs. III + IV) (AUC = 0.653), lymph node invasion (AUC = 0.692), and CRC recurrence (AUC = 0.699) in patients with CRC (all with p < 0.05). Furthermore, we observed a global hypomethylation of SFRP2 in tumors compared to the adjacent area (p < 0.001). This observation was validated in the TCGA-COAD and TCGA-READ cohorts, demonstrating overall hypermethylation (both with p < 0.001) and low expression (p < 0.001), as shown in publicly available scRNA-Seq data. Notably, neoadjuvant-treated CRC patients exhibited lower SFRP2 methylation levels compared to untreated patients (p < 0.05) and low promoter SFRP2 methylation in untreated patients was associated with poor overall survival (p < 0.05), when compared to high methylation. Finally, treatment with 5 µg of rhSFRP2 treatment in CRC cells (HCT116 cells) inhibited cell proliferation (p < 0.001) and migration (p < 0.05), and downregulated the expression of AXIN2 (p < 0.01), a gene involved in Wnt signaling pathway.
These findings establish promoter methylation of the SFRP2 gene as a prognostic candidate in CRC when assessed in blood, and as a therapeutic prognostic candidate in tumors, potentially valuable in clinical practice. SFRP2 also emerges as a therapeutic option, providing new clinical and therapeutical avenues.
几项研究表明，分泌型卷曲相关蛋白 2（SFRP2）基因作为结直肠癌（CRC）的潜在临床生物标志物。然而，其诊断作用仍不清楚。在这项研究中，我们旨在研究 SFRP2 甲基化水平在 CRC 患者的大量生物样本（包括血液、脂肪和结肠组织）中的意义，从而可能确定新的生物标志物用途。
我们通过 qPCR 检查了健康参与者（N=110，年龄为 53.7（14.2），48/62 名男性/女性）和 CRC 患者（N=85，年龄为 67.7（10.5），61/24 名男性/女性）中 SFRP2 基因的表达（qPCR）和甲基化状态（450K DNA 阵列和 DNA 焦磷酸测序），并在不同的生物组织中评估了其作为 CRC 生物标志物的潜力。此外，我们研究了重组人 SFRP2（rhSFRP2）作为治疗靶标对细胞增殖、迁移以及与癌变和 Wnt 通路相关的关键基因表达的影响。
我们的研究结果表明，全血中 SFRP2 启动子甲基化可预测 CRC 患者的癌症分期（I+II 期 vs. III+IV 期）（AUC=0.653）、淋巴结侵犯（AUC=0.692）和 CRC 复发（AUC=0.699）（均 p<0.05）。此外，我们观察到肿瘤中的 SFRP2 整体低甲基化与邻近区域相比（p<0.001）。这一观察结果在 TCGA-COAD 和 TCGA-READ 队列中得到了验证，表明总体上高甲基化（均 p<0.001）和低表达（p<0.001），正如公开的 scRNA-Seq 数据所示。值得注意的是，与未经治疗的患者相比，接受新辅助治疗的 CRC 患者的 SFRP2 甲基化水平较低（p<0.05），并且未经治疗的患者中 SFRP2 启动子的低甲基化与总生存期较差相关（p<0.05），与高甲基化相比。最后，用 5μg rhSFRP2 处理 CRC 细胞（HCT116 细胞）抑制细胞增殖（p<0.001）和迁移（p<0.05），并下调 Wnt 信号通路相关基因 AXIN2 的表达（p<0.01）。
这些发现确立了 SFRP2 基因启动子甲基化作为血液中 CRC 的预后候选物，并作为肿瘤中的治疗预后候选物，在临床实践中可能具有重要价值。SFRP2 也可作为一种治疗选择，为临床和治疗提供新的途径。
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