Daveau Maryvonne, Scotte Michel, François Arnaud, Coulouarn Cédric, Ros Gilles, Tallet Yveline, Hiron Martine, Hellot Marie-France, Salier Jean-Philippe
INSERM Unité 519 and Institut Fédératif de Recherches Multidisciplinaires sur les Peptides, Faculté de Médecine-Pharmacie, Rouen France.
Mol Carcinog. 2003 Mar;36(3):130-41. doi: 10.1002/mc.10103.
A change in the balance between proliferation and apoptosis in the course of hepatocellular carcinoma (HCC) development and progression has been suspected. We wanted to identify related genes whose mRNA levels could provide markers of severity and prognosis after resection. The extent of cell apoptosis, proliferation, and differentiation was measured with a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick-end labeling assay, and the Ki-67 index was determined in paired tumor and cirrhotic tissue samples from patients who had undergone HCC resection after diagnosis of hepatitis C-related or alcoholism-related cirrhosis. These patients included two groups with highly versus poorly differentiated tumor cells, and the latter was split into two subgroups of those with versus without early recurrence. The mRNA levels for various apoptosis-related or proliferation-related genes and those for the growth factor/receptor systems were measured by quantitative reverse transcriptase-polymerase chain reaction in paired tumor and cirrhotic liver samples from every patient, and some of the corresponding proteins were detected by immunohistochemistry. In all instances, protein expression was highly heterogeneous within groups and similar between groups. In contrast, some differences in mRNA level between tumor and cirrhotic tissues were quite informative. Low levels of hepatocyte growth factor and transforming growth factor alpha mRNAs were found concomitantly in highly differentiated tumors, whereas overexpression of mRNAs for the cognate receptors c-met and epidermal growth factor receptor were found in poorly differentiated tumors and primarily in patients with early tumor recurrence. These results argue for growth factor-dependent HCC development and provide novel and combined prognosis markers after HCC surgery.
肝细胞癌（HCC）发生和发展过程中增殖与凋亡之间的平衡变化已受到怀疑。我们希望鉴定出相关基因，其mRNA水平可作为切除术后严重程度和预后的标志物。通过末端脱氧核苷酸转移酶介导的脱氧尿苷5-三磷酸生物素缺口末端标记法检测细胞凋亡、增殖和分化程度，并在诊断为丙型肝炎相关或酒精性肝硬化后接受HCC切除的患者的配对肿瘤和肝硬化组织样本中测定Ki-67指数。这些患者包括两组肿瘤细胞高分化与低分化的患者，后者又分为有早期复发和无早期复发的两个亚组。通过定量逆转录聚合酶链反应在每位患者的配对肿瘤和肝硬化肝脏样本中测量各种凋亡相关或增殖相关基因以及生长因子/受体系统的mRNA水平，并通过免疫组织化学检测一些相应的蛋白质。在所有情况下，组内蛋白质表达高度异质性，组间相似。相比之下，肿瘤组织和肝硬化组织之间mRNA水平的一些差异很有信息量。在高分化肿瘤中同时发现肝细胞生长因子和转化生长因子α mRNA水平较低，而在低分化肿瘤中，主要是在早期肿瘤复发患者中发现同源受体c-met和表皮生长因子受体的mRNA过表达。这些结果支持生长因子依赖性HCC的发生，并为HCC手术后提供了新的联合预后标志物。
