Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
Asian Pac J Cancer Prev. 2023 Dec 1;24(12):4285-4292. doi: 10.31557/APJCP.2023.24.12.4285.
Angiogenesis contributes to hepatocellular carcinoma (HCC) progression by promoting tumor growth and metastasis. Netrin-4 (NTN4) is a secreted glycoprotein that has been reported to control angiogenesis and preserve endothelial homeostasis. Macrovascular invasion of the portal vein, referred to as portal vein invasion (PVI) is associated with poor prognosis in HCC patients. In this work, we sought to understand more about the systemic and hepatic level expression of NTN4 and its receptors in HCC patients with and without portal vein invasion.
A total of 154 patients with HCC, and 90 healthy volunteers were recruited in this case-control study. Patients with HCC were further subdivided into those with portal vein invasion (PVI) (n=68), and those without portal vein invasion (NPVI) (n=86). Clinical characteristics and liver function parameters were recorded among the study subjects PVI and NPVI. The serum levels of NTN4 (pg/ml) were estimated by ELISA. HCC tissues and normal non-tumorous liver tissues (controls) were collected for gene expression analysis of NTN4 and its receptors.
ALT, ALP, and GGT levels were significantly elevated in the serum of HCC patients with PVI compared to NPVI and control subjects. Systemic NTN4 was significantly reduced in both PVI and NPVI patients compared to control subjects. At the tissue level, the hepatic NTN4 followed a similar trend with significantly lower mRNA expression in both patients with PVI and NPVI compared to control subjects.
Systemic and hepatic NTN4 levels were reduced in both PVI and NPVI subjects. The hepatic expression of NTN4 receptors Neogenin and UNC5B were markedly elevated in patients with HCC with PVI compared to NPVI. Future experimental studies might shed the role of NTN4 and its receptors in the development of PVI in HCC.
血管生成通过促进肿瘤生长和转移促进肝细胞癌（HCC）的进展。轴突导向因子 4（NTN4）是一种分泌的糖蛋白，据报道它可以控制血管生成并维持内皮细胞的稳态。门静脉的大血管侵犯，称为门静脉侵犯（PVI），与 HCC 患者的预后不良相关。在这项工作中，我们试图更多地了解 HCC 患者伴或不伴门静脉侵犯时 NTN4 及其受体在全身和肝脏水平的表达情况。
本病例对照研究共纳入 154 例 HCC 患者和 90 名健康志愿者。将 HCC 患者进一步分为伴有门静脉侵犯（PVI）（n=68）和不伴有门静脉侵犯（NPVI）（n=86）的患者。记录研究对象 PVI 和 NPVI 的临床特征和肝功能参数。通过 ELISA 测定血清 NTN4（pg/ml）水平。收集 HCC 组织和正常非肿瘤性肝组织（对照）进行 NTN4 及其受体的基因表达分析。
与 NPVI 和对照受试者相比，PVI 患者的血清 ALT、ALP 和 GGT 水平显著升高。与对照受试者相比，PVI 和 NPVI 患者的全身 NTN4 水平均显著降低。在组织水平上，肝 NTN4 也呈现出相似的趋势，与对照受试者相比，PVI 和 NPVI 患者的肝组织中 NTN4 的 mRNA 表达均显著降低。
PVI 和 NPVI 患者的全身和肝 NTN4 水平均降低。与 NPVI 患者相比，伴有 PVI 的 HCC 患者的肝 NTN4 受体 Neogenin 和 UNC5B 的表达明显升高。未来的实验研究可能会揭示 NTN4 及其受体在 HCC 中 PVI 发展中的作用。
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