Wong Nathalie, Yeo Winnie, Wong Wai-Lap, Wong Navy L-Y, Chan Kathy Y-Y, Mo Frankie K-F, Koh Jane, Chan Stephan Lam, Chan Anthony T-C, Lai Paul B-S, Ching Arthur K-K, Tong Joanna H-M, Ng Ho-Keung, Johnson Philip J, To Ka-Fai
Department of Anatomical and Cellular Pathology, Li Ka-Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China.
Int J Cancer. 2009 Feb 1;124(3):644-52. doi: 10.1002/ijc.23968.
Genomic gain represents an important mechanism in the activation of proto-oncogenes. In many instances, induced oncogenes hold clinical implications both as prognostic markers and targets for therapeutic design. In hepatocellular carcinoma (HCC), although chromosomal gains are common, information on underlying oncogenes induced remains minimal. Here, we examined 7 causal sites of HCC for overexpressed genes by array-based transcriptional mapping. In 22 HCC cell lines and early passages of cultures studied, clusters of up-regulated genes were indicated, where TOP2A expression ranked the highest. Distinct TOP2A transcriptions were confirmed in an independent series of HCC tumors relative to adjacent non-tumoral liver (p=0.0018). By tissue microarray analysis of 172 HCC, we found TOP2A expressions correlated with advance histological grading (p<0.001), microvascular invasion (p=0.004) and an early age onset of the malignancy (<or=40 years; p=0.007). In conjunction with P-gp and MRP1, TOP2A were further assessed for its association with chemotherapy responsiveness and survival in 148 patients who entered our recently reported Phase III prospective randomized study. In 73 chemoresistant and 75 nonresistant patients, only TOP2A positivity correlated with chemoresistance (p=0.029) and shorter patients survival (p<0.0001). The potential therapeutic value in targeting TOP2A by Etoposide, as a single agent, and in combination with Doxorubicin was also explored. In vitro cytotoxic studies suggested Etoposide at IC20 readily reduced IC50 values of Doxorubicin by a magnitude of approximately 3.5 to 10-fold compared to Doxorubicin alone (p<0.028). Our study highlighted for the first time the prognostic value of TOP2A in HCC and the potential use of TOP2A reactive agents in therapy.
基因组扩增是原癌基因激活的重要机制。在许多情况下，诱导产生的癌基因作为预后标志物和治疗设计靶点均具有临床意义。在肝细胞癌（HCC）中，虽然染色体扩增很常见，但关于所诱导的潜在癌基因的信息仍然很少。在此，我们通过基于阵列的转录图谱分析检查了7个HCC致病位点的过表达基因。在所研究的22个HCC细胞系和早期传代培养物中，发现了上调基因簇，其中TOP2A表达排名最高。相对于相邻的非肿瘤性肝组织，在一系列独立的HCC肿瘤中证实了明显的TOP2A转录（p = 0.0018）。通过对172例HCC进行组织微阵列分析，我们发现TOP2A表达与组织学分级进展（p <0.001）、微血管侵犯（p = 0.004）以及恶性肿瘤的早发年龄（≤40岁；p = 0.007）相关。结合P-糖蛋白和多药耐药相关蛋白1（MRP1），在148例进入我们最近报道的III期前瞻性随机研究的患者中，进一步评估了TOP2A与化疗反应性和生存率的关系。在73例化疗耐药和75例非耐药患者中，只有TOP2A阳性与化疗耐药（p = 0.029）和患者较短生存期（p <0.0001）相关。还探索了依托泊苷作为单一药物靶向TOP2A以及与多柔比星联合使用的潜在治疗价值。体外细胞毒性研究表明，与单独使用多柔比星相比，依托泊苷在IC20时能使多柔比星的IC50值轻松降低约3.5至10倍（p <0.028）。我们的研究首次强调了TOP2A在HCC中的预后价值以及TOP2A反应性药物在治疗中的潜在用途。
