OBJECTIVES 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. METHODS 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. RESULTS 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. DISCUSSION 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.

中文翻译：

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嗅觉蛋白 4 在早期肝细胞癌中的预后意义和功能相关性。

目的 肝细胞癌 (HCC) 是癌症相关的主要死因。不幸的是，即使在对早期患者进行治愈性治疗后，复发也很常见，并且尚未建立辅助治疗。已报道 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然知之甚少，其在 HCC 中的作用尚不清楚。本研究的目的是检查 OLFM4 的预后意义及其在确定早期 HCC 患者复发中的功能相关性。方法 在包含 157 个 HCC 组织和匹配的非肿瘤组织的组织微阵列中进行免疫组织化学染色以评估 OLFM4 的表达、细胞分布和预后意义。此外，在单独的患者队列中评估 OLFM4 编码 mRNA 的表达。使用针对 OLFM4 的 siRNA 以评估其对细胞运动和增殖的影响，通过体外功能研究验证了这些发现。结果 与匹配的非肿瘤组织的肝细胞中观察到的相比，表现出阳性 OLFM4 染色的 HCC 样本比例更高（61% 对 39%）。然而，OLFM4 的仅细胞质染色与血管侵袭（P = 0.048）、MMP-7 表达（P = 0.002）和较差的存活率（P = 0.008）相关。多变量分析证实了 OLFM4 在确定患者预后方面的独立意义（5 年生存率 [58.3% 对 17.3%；HR：2.135 {95% 置信区间：1.135-4.015}；P = 0.019]）。相应地，siRNA 对 OLFM4 的抑制调节了 MMP-7 和 E-cadherin 的表达，从而抑制了细胞增殖、运动和迁移。讨论 据我们所知，我们提供了关于 OLFM4 在 HCC 中的预后意义的第一份报告，并确定了其作为 MMP 家族蛋白和 E-Cadherin 在确定细胞侵袭和转移形成中的关键介质的机制作用。