Potential Prognostic Biomarkers for Bone Metastasis from Hepatocellular Carcinoma
Potential Prognostic Biomarkers for Bone Metastasis from Hepatocellular Carcinoma
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肝细胞癌骨转移的潜在预后生物标志物
DOI：
10.1634/theoncologist.2010-0358
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发表时间：
2011-07-01
期刊：
影响因子：
5.8
通讯作者：
Zhu, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Xiang, Zuo-Lin;Zeng, Zhao-Chong;Zhu, Xiao-Dong
背景。肝细胞癌 (HCC) 最常见于病毒感染患者，尤其是乙型肝炎病毒 (HBV) 感染者和慢性肝病患者。患有骨转移 (BM) 的 HCC 患者会遭受疼痛和其他症状，从而显着降低他们的生活质量。在接受潜在的 HCC 治愈性治疗后，识别 BM 高风险患者仍然具有挑战性。在这里，我们的目的是鉴定 HCC BM 相关基因和蛋白质，以建立预测生物标志物。方法。从有或没有 BM 的 HCC 患者的 48 对瘤内和瘤周福尔马林固定、石蜡包埋的组织中提取 RNA。使用包含 502 个癌症相关基因的 cDNA 介导的退火、选择、延伸和连接测定来鉴定新的 BM 相关基因。另一项对 350 名接受肝切除术的 HCC 患者进行的独立研究，利用组织微阵列 (TMA) 上的免疫组织化学评估蛋白质水平上候选基因的表达。 350 名患者中，273 名（78.0%）感染了 HBV。结果。 BM患者中有7个瘤内基因和17个瘤周基因过表达，而BM患者中有15个瘤内基因和28个瘤周基因表达不足。我们选择以下四个基因进行进一步分析，因为它们在癌症基因特异性微阵列中存在差异表达，并且之前报道与BM相关：结缔组织生长因子（CTGF）、基质金属蛋白酶-1（MMP-1）、转化生长因子β1（TGF-β1）和白介素-11（IL-11）。我们使用 TMA（包括 350 个 HCC 患者样本）的免疫组织化学方法评估了这些选定基因的蛋白质表达。我们确定瘤内 CTGF、瘤内 IL-11 和瘤周 MMP-1 的表达是 HCC 患者发生 BM 的独立预后因素。瘤内 CTGF 和 IL-11 表达相结合也是 BM 发生的独立危险因素。结论。有和没有 BM 的 HCC 患者中有 67 个基因存在差异表达。瘤内高 CTGF、阳性 IL-11 和瘤周 MMP-1 表达与肝切除后的 BM 相关。瘤内 CTGF 表达与 IL-11 表达相结合可能作为 HCC BM 的有用预测生物标志物。肿瘤学家 2011 年；16：1028-1039
Background. Hepatocellular carcinoma (HCC) most commonly develops in patients who have a viral infection, especially in the case of hepatitis B virus (HBV), and in patients with a chronic liver disease. HCC patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. Identification of patients who are at high risk for BM after undergoing potentially curative treatment for HCC remains challenging. Here, we aimed to identify HCC BM-related genes and proteins to establish prediction biomarkers.Methods. RNA was extracted from 48 pairs of intratumoral and peritumoral formalin-fixed, paraffin-embedded tissue from HCC patients with and without BM. A cDNA-mediated annealing, selection, extension and ligation assay containing 502 cancer-related genes was used to identify novel BM-associated genes. An additional independent study with 350 HCC patients who had undergone hepatectomy was conducted to evaluate the expression of candidate genes at the protein level using immunohistochemistry on tissue microarrays (TMAs). Of the 350 patients, 273 (78.0%) were infected with HBV.Results. Seven intratumoral genes and 17 peritumoral genes were overexpressed in patients with BM, whereas 15 intratumoral genes and 28 peritumoral genes were underexpressed in patients with BM. We selected the following four genes for further analysis because they were differentially expressed in the cancer gene-specific microarray and were previously reported to be associated with BM: connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), transforming growth factor beta 1 (TGF-beta 1), and interleukin-11 (IL-11). We assessed the protein expression of these selected genes using immunohistochemistry on TMAs including 350 HCC patient specimens. We determined that expression of intratumoral CTGF, intratumoral IL-11, and peritumoral MMP-1 were independent prognostic factors for developing BM in HCC patients. Combining intratumoral CTGF and IL-11 expression was also an independent risk factor for BM development.Conclusions. Sixty-seven genes were differentially expressed in HCC patients with and without BM. High intratumoral CTGF, positive IL-11, and high peritumoral MMP-1 expression were associated with BM after hepatectomy. Intratumoral CTGF expression combined with IL-11 expression may serve as a useful predictive biomarker for HCC BM. The Oncologist 2011;16:1028-1039