Yeung Bonnie H Y, Shek Felix H, Lee Nikki P, Wong Chris K C
Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
PLoS One. 2015 Oct 15;10(10):e0139977. doi: 10.1371/journal.pone.0139977. eCollection 2015.
Growing evidence has revealed high expression levels of stanniocalcin-1 (STC1) in different types of human cancers. Numerous experimental studies using cancer cell lines demonstrated the involvement of STC1 in inflammatory and apoptotic processes; however the role of STC1 in carcinogenesis remains elusive. Hepatocellular carcinoma (HCC) an exemplified model of inflammation-related cancer, represents a paradigm of studying the association between STC1 and tumor development. Therefore, we conducted a statistical analysis on the expression levels of STC1 using clinicopathological data from 216 HCC patients. We found that STC1 was upregulated in the tumor tissues and its expression levels was positively correlated with the levels of interleukin (IL)-6 and IL-8. Intriguingly tumors with greater expression levels of STC1 (tumor/normal ≥ 2) were significantly smaller than the lower level (tumor/normal<2) samples (p = 0.008). A pharmacological approach was implemented to reveal the functional correlation between STC1 and the ILs in the HCC cell-lines. IL-6 and IL-8 treatment of Hep3B cells induced STC1 expression. Lentiviral-based STC1 overexpression in Hep3B and MHCC-97L cells however showed inhibitory action on the pro-migratory effects of IL-6 and IL-8 and reduced size of tumor spheroids. The inhibitory effect of STC1 on tumor growth was confirmed in vivo using the stable STC1-overexpressing 97L cells on a mouse xenograft model. Genetic analysis of the xenografts derived from the STC1-overexpressing 97L cells, showed upregulation of the pro-apoptotic genes interleukin-12 and NOD-like receptor family, pyrin domain-containing 3. Collectively, the anti-inflammatory and pro-apoptotic functions of STC1 were suggested to relate its inhibitory effect on the growth of HCC cells. This study supports the notion that STC1 may be a potential therapeutic target for inflammatory tumors in HCC patients.
越来越多的证据表明，在不同类型的人类癌症中，鲽源钙调蛋白-1（STC1）表达水平较高。众多使用癌细胞系的实验研究表明，STC1参与炎症和凋亡过程；然而，STC1在致癌作用中的作用仍不明确。肝细胞癌（HCC）作为炎症相关癌症的典型模型，是研究STC1与肿瘤发展之间关联的范例。因此，我们利用216例HCC患者的临床病理数据对STC1的表达水平进行了统计分析。我们发现，STC1在肿瘤组织中上调，其表达水平与白细胞介素（IL）-6和IL-8水平呈正相关。有趣的是，STC1表达水平较高（肿瘤/正常≥2）的肿瘤明显小于表达水平较低（肿瘤/正常<2）的样本（p = 0.008）。采用药理学方法揭示HCC细胞系中STC1与白细胞介素之间的功能相关性。用IL-6和IL-8处理Hep3B细胞可诱导STC1表达。然而，在Hep3B和MHCC-97L细胞中基于慢病毒的STC1过表达对IL-6和IL-8的促迁移作用具有抑制作用，并减小了肿瘤球体的大小。使用稳定过表达STC1的97L细胞在小鼠异种移植模型上进行体内实验，证实了STC1对肿瘤生长的抑制作用。对来自过表达STC1的97L细胞的异种移植瘤进行基因分析，结果显示促凋亡基因白细胞介素-12和含pyrin结构域的NOD样受体家族3上调。总体而言，STC1的抗炎和促凋亡功能与其对HCC细胞生长的抑制作用有关。这项研究支持了STC1可能是HCC患者炎症性肿瘤潜在治疗靶点的观点。
