Department of Medical Science and Technology, Hiroshima International University, Higashi-hiroshima, Hiroshima, 739-2695, Japan.
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Biochem Biophys Res Commun. 2022 Jun 30;611:146-150. doi: 10.1016/j.bbrc.2022.04.069. Epub 2022 Apr 20.
Netrin-1, the protein product of the NTN1 gene, is an axon guidance molecule implicated in regulation of cell survival and tumorigenesis. Expression of the netrin-1 receptors deleted in colorectal cancer (DCC) and uncoordinated 5 homolog (UNC5H) is frequently silenced in colorectal cancer (CRC) by either loss of heterozygosity or epigenetic mechanisms. However, netrin-1 expression and regulation in CRC are mostly unknown. Here, we report that NTN1 expression is significantly reduced in most CRC tissues compared to the adjacent normal intestinal mucosa, and that NTN1 DNA methylation is significantly higher in CRCs (24.6%) than in the adjacent normal intestinal mucosa (4.0%). In 6 CRC cell lines, NTN1 expression is low. Treatment with 5-Aza-2'-deoxycytidine increased expression of NTN1 in CRC cell lines, indicating that DNA methylation represses NTN1 transcription in CRCs. NTN1 DNA hypermethylation was significantly associated with advanced CRC disease. Median netrin-1 serum levels were significantly decreased in CRC patients (330.1 pg/mL) compared with normal individuals (438.6 pg/mL). Our results suggest that netrin-1 is a candidate biomarker for CRC.
轴突导向分子 netrin-1 是 NTN1 基因的蛋白产物，其表达与细胞存活和肿瘤发生有关。在结直肠癌（CRC）中，netrin-1 受体 deleted in colorectal cancer（DCC）和 uncoordinated 5 homolog（UNC5H）的表达常常因杂合子缺失或表观遗传机制而沉默。然而，CRC 中 netrin-1 的表达和调控仍知之甚少。在这里，我们报告 NTN1 在大多数 CRC 组织中的表达明显低于相邻的正常肠黏膜，CRC 中 NTN1 的 DNA 甲基化水平（24.6%）显著高于相邻的正常肠黏膜（4.0%）。在 6 种 CRC 细胞系中，NTN1 的表达水平较低。5-Aza-2'-deoxycytidine 处理可增加 CRC 细胞系中 NTN1 的表达，表明 DNA 甲基化抑制 CRC 中 NTN1 的转录。NTN1 DNA 高甲基化与晚期 CRC 疾病显著相关。CRC 患者的 netrin-1 血清水平中位数（330.1 pg/mL）明显低于正常个体（438.6 pg/mL）。我们的研究结果表明，netrin-1 是 CRC 的候选生物标志物。
