Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachi-dori 1, Chuo-ku, Niigata 951-8510, Japan.
Int J Oncol. 2010 Jan;36(1):245-54.
Liver-intestine cadherin (LI-cadherin) represents a novel type of cadherin within the cadherin superfamily that comprises seven cadherin repeats and a short cytoplasmic domain. In this study, we first examined LI-cadherin expression immunohistochemically in 34 specimens of human intrahepatic cholangiocarcinoma (ICC). LI-cadherin expression was positive (defined as positivity in > or = 10% of cells) in 18 of the ICCs (52.9%). LI-cadherin negativity was significantly correlated with tumor dedifferentiation (P=0.026) and vascular invasion (P=0.015). The cumulative survival rate of patients with LI-cadherin-negative ICC was significantly shorter than that of patients with LI-cadherin-positive ICC (P=0.021). Multivariate analysis identified the extent of LI-cadherin staining as an independent prognostic factor for ICC survival (P=0.027). Next, to elucidate the mechanism of loss of LI-cadherin-mediated aggressiveness in ICC, we knocked down LI-cadherin expression in an ICC cell line using small interfering RNA (siRNA) technology, and screened for genes that were expressed differentially between these cells and ICC cells transfected with scrambled siRNA using microarray analysis with real-time polymerase chain reaction confirmation. Among 21 identified genes, we focused on metal-responsive transcription factor-1 (MTF-1), whose target genes might contribute to tumor aggressiveness. Expression of placental growth factor (PlGF), one of the MTF-1 target genes, was up-regulated in the ICC cells transfected with LI-cadherin siRNA. Likewise, PlGF expression was up-regulated in LI-cadherin-negative ICC specimens. There was a significant inverse relationship between these expressions (P=0.033). Furthermore, the microvessel density of LI-cadherin-negative ICC specimens was higher than that of LI-cadherin-positive specimens. These findings suggest that loss of LI-cadherin in ICC is associated with tumor dedifferentiation and vascular invasion, and thus poor prognosis. Loss of LI-cadherin results in up-regulation of MTF-1 and PlGF, thereby regulating angiogenesis in ICC.
肝肠钙黏蛋白（LI-cadherin）代表钙黏蛋白超家族中的一种新型钙黏蛋白，它由七个钙黏蛋白重复序列和一个短的细胞质结构域组成。在这项研究中，我们首先通过免疫组织化学方法检测了 34 例人肝内胆管癌（ICC）标本中 LI-cadherin 的表达。在 18 例 ICC 中（52.9%）LI-cadherin 表达阳性（定义为> = 10%的细胞阳性）。LI-cadherin 阴性与肿瘤去分化（P=0.026）和血管侵犯（P=0.015）显著相关。LI-cadherin 阴性 ICC 患者的累积生存率明显短于 LI-cadherin 阳性 ICC 患者（P=0.021）。多因素分析确定 LI-cadherin 染色程度是 ICC 生存的独立预后因素（P=0.027）。接下来，为了阐明 ICC 中 LI-cadherin 介导的侵袭性丧失的机制，我们使用小干扰 RNA（siRNA）技术在 ICC 细胞系中敲低 LI-cadherin 表达，并用微阵列分析和实时聚合酶链反应确认筛选这些细胞与转染 scrambled siRNA 的 ICC 细胞之间差异表达的基因。在 21 个鉴定的基因中，我们集中研究金属反应转录因子-1（MTF-1），其靶基因可能有助于肿瘤侵袭性。胎盘生长因子（PlGF）是 MTF-1 的靶基因之一，在转染 LI-cadherin siRNA 的 ICC 细胞中表达上调。同样，LI-cadherin 阴性 ICC 标本中 PlGF 的表达也上调。这些表达之间存在显著的负相关关系（P=0.033）。此外，LI-cadherin 阴性 ICC 标本的微血管密度高于 LI-cadherin 阳性标本。这些发现表明，ICC 中 LI-cadherin 的缺失与肿瘤去分化和血管侵犯有关，从而导致预后不良。LI-cadherin 的缺失导致 MTF-1 和 PlGF 的上调，从而调节 ICC 的血管生成。
