Department of Medicine II, Liver Centre Munich, University Hospital, LMU Munich, Germany.
Digestive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
Clin Transl Gastroenterol. 2020 Jan;11(1):e00124. doi: 10.14309/ctg.0000000000000124.
Hepatocellular carcinoma (HCC) is a leading cancer-related cause of death. Unfortunately, recurrence is common even after curative treatment of early-stage patients, and no adjuvant treatment has yet been established. Aberrant expression of OLFM4 in human cancers has been reported; yet, its specific function during tumor development remains poorly understood, and its role in HCC is unknown. The purpose of this study is to examine the prognostic significance of OLFM4 and its functional relevance in determining recurrence in patients with early-stage HCC.
Immunohistochemical staining to assess expression, cellular distribution, and prognostic significance of OLFM4 was performed in a tissue microarray comprising 157 HCC tissues and matched nontumor tissues. In addition, expression of OLFM4-coding mRNA was assessed in a separate patients' cohort. The findings were validated by in vitro functional studies using siRNA directed against OLFM4 to assess its effect on cell motility and proliferation.
The fraction of HCC samples exhibiting positive OLFM4 staining was higher in comparison with that observed in hepatocytes from matched nontumor tissue (61% vs 39%). However, cytoplasmic-only staining for OLFM4 was associated with vascular invasion (P = 0.048), MMP-7 expression (P = 0.002), and poorer survival (P = 0.008). A multivariate analysis confirmed the independent significance of OLFM4 in determining patients' outcome (5-year survival [58.3% vs 17.3%; HR: 2.135 {95% confidence interval: 1.135-4.015}; P = 0.019]). Correspondingly, inhibition of OLFM4 by siRNA modulated the expression of MMP-7 and E-cadherin, causing inhibition of cell proliferation, motility, and migration.
To the best of our knowledge, we provide the first report on the prognostic significance of OLFM4 in HCC and identify its mechanistic role as crucial mediator of MMP family protein and E-Cadherin in determining cell invasion and metastasis formation.
肝细胞癌（HCC）是导致癌症相关死亡的主要原因。不幸的是，即使对早期患者进行了根治性治疗，复发也很常见，而且尚未建立辅助治疗方法。已经报道了 OLFM4 在人类癌症中的异常表达；然而，其在肿瘤发展过程中的具体功能仍知之甚少，其在 HCC 中的作用尚不清楚。本研究旨在探讨 OLFM4 的预后意义及其在决定早期 HCC 患者复发中的功能相关性。
采用组织微阵列免疫组化染色法检测 157 例 HCC 组织及其配对非肿瘤组织中 OLFM4 的表达、细胞分布及预后意义。此外，还评估了另一个患者队列中 OLFM4 编码 mRNA 的表达。通过针对 OLFM4 的 siRNA 进行体外功能研究来验证这些发现，以评估其对细胞迁移和增殖的影响。
与匹配的非肿瘤组织中的肝细胞相比，表现出 OLFM4 阳性染色的 HCC 样本比例更高（61%比 39%）。然而，OLFM4 仅存在于细胞质中的染色与血管侵犯（P = 0.048）、MMP-7 表达（P = 0.002）和较差的生存相关（P = 0.008）。多变量分析证实 OLFM4 对确定患者预后具有独立意义（5 年生存率[58.3%比 17.3%；HR：2.135（95%置信区间：1.135-4.015）；P = 0.019]）。相应地，siRNA 抑制 OLFM4 可调节 MMP-7 和 E-钙黏蛋白的表达，从而抑制细胞增殖、迁移和迁移。
据我们所知，我们首次报道了 OLFM4 在 HCC 中的预后意义，并确定了其作为 MMP 家族蛋白和 E-钙黏蛋白的关键介质在决定细胞侵袭和转移形成中的机制作用。
