PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection
PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection
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DOI：
10.1111/j.1478-3231.2011.02619.x
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发表时间：
2012-01-01
影响因子：
6.7
通讯作者：
Nagano, Hiroaki
中科院分区：
文献类型：
--
作者：
Noda, Takehiro;Yamamoto, Hirofumi;Nagano, Hiroaki
背景：在缺氧条件下，肿瘤细胞发生遗传和适应性变化，使其生存。以前，我们报道过低氧诱导因子（HIF）-1的高表达是肝细胞癌（HCC）复发的一个重要预测因子。缺氧还通过HIF-1途径刺激前胶原-赖氨酸、2-酮戊二酸5-双加氧酶（PLOD）基因的表达。目的：本研究的目的是评估缺氧应激与肝癌PLOD基因表达之间的关系，并确定一种新的肝癌患者预后标志物。研究方法：PLOD 2的表达评估缺氧条件下的肝癌细胞系和特点，在139个肝癌样本肝切除术后，使用微阵列实验，定量RT-PCR和免疫组化。采用单因素和多因素分析评估HCC患者的预后因素。结果：缺氧诱导PLOD 2表达。与低表达组相比，肝癌患者PLOD 2高表达组的无病生存期显著缩短（P = 0.002）。在一部分肝癌组织中，我们发现PLOD 2的表达与定量RT-PCR和免疫组化结果相关。在临床病理因素中，PLOD 2表达与肿瘤大小（P = 0.022）和肉眼可见的肝内转移（P = 0.049）显著相关。在单因素分析中，六个预后因素（肿瘤多样性，宏观肝内转移，组织学分级，显微镜下门静脉浸润，显微镜下肝内转移和PLOD 2表达）对无病生存率有意义。PLOD 2表达是预后不良的独立因素（P = 0.013）。结论：PLOD 2是一个潜在的新的肝癌患者手术后的预后因素。
Background: Under hypoxia, tumour cells undergo genetic and adaptive changes that allow their survival. Previously, we reported that high expression of hypoxia-inducible factor (HIF)-1 was a significant predictive factor for recurrence in hepatocellular carcinoma (HCC). Hypoxia also stimulates expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) genes via the HIF-1 pathway. Aims: The aim was to evaluate the relationship between hypoxia stress and expression of PLOD genes in HCC in vitro and to identify a new prognostic marker in HCC patients. Methods: The PLOD2 expression was assessed under hypoxia in hepatoma cell lines and characterized in 139 HCC samples following hepatic resection using microarray experiments, quantitative RT-PCR and immunohistochemistry. Prognostic factors in HCC patients were assessed using univariate and multivariate analyses. Results: The PLOD2 expression was induced under the hypoxia in vitro. Disease-free survival in the high PLOD2 expression group of HCC patients was significantly shorter when compared with the low-expression group (P = 0.002). In a subset of HCCs, we found that the PLOD2 expression of microarray was correlated with data of quantitative RT-PCR and immunohistochemistry. Of clinicopathological factors, PLOD2 expression was significantly correlated with tumour size (P = 0.022) and macroscopic intrahepatic metastasis (P = 0.049). In univariate analysis, six prognostic factors (tumour multiplicity, macroscopic intrahepatic metastasis, histological grade, microscopic portal invasion, microscopic intrahepatic metastasis and PLOD2 expression) were significant for disease-free survival. PLOD2 expression was identified as a significant, independent factor of poor prognosis (P = 0.013). Conclusions: PLOD2 is a potential novel prognostic factor for HCC patients following surgery.