Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
Mol Aspects Med. 2010 Apr;31(2):179-93. doi: 10.1016/j.mam.2010.02.007. Epub 2010 Feb 20.
Hepatocellular carcinoma (HCC) is the fifth most frequent human cancer and a fatal disease. Therapies with pharmacological agents do not improve the prognosis of patients with unresectable HCC. This emphasizes the need to identify new targets for early diagnosis, chemoprevention, and treatment of the disease. Available evidence indicates that clinical outcome of HCC could reflect the genetic predisposition to cancer development and progression. Numerous loci controlling HCC progression have been identified in rodents. In this review, we describe results of recent studies on effector mechanisms of susceptibility/resistance genes, responsible for HCC progression, aimed at identifying new putative prognostic markers and therapeutic targets of this tumor. Highest c-myc amplification and overexpression, alterations of iNOS crosstalk with IKK/NF-kB and RAS/ERK signaling, ubiquitination of ERK and cell cycle inhibitors, and deregulation of FOXM1 and cell cycle key genes occur in rapidly progressing dysplastic nodules and HCC, induced in genetic susceptible rat strains, compared to the lesions of resistant rats. Notably, alterations of these mechanisms in human HCC subtypes with poorer or better prognosis, are similar to those present in genetically susceptible and resistant rats, respectively, and function as prognostic markers and therapeutic targets. Attempts to cure advanced HCC by molecular therapy directed against specific targets led to modest survival benefit. Thus, efforts are necessary to identify and test, in pre-clinical and clinical studies, new therapeutic targets for combined molecular treatments of HCC. They may take advantage from the comparative analysis of signal transduction in HCCs differently prone to progress, in rats and humans.
肝细胞癌 (HCC) 是第五种最常见的人类癌症，也是一种致命的疾病。用药物治疗并不能改善不可切除 HCC 患者的预后。这强调了需要确定新的靶点，以进行早期诊断、化学预防和治疗这种疾病。现有证据表明，HCC 的临床结果可以反映癌症发展和进展的遗传倾向。在啮齿动物中已经确定了许多控制 HCC 进展的基因座。在这篇综述中，我们描述了最近关于负责 HCC 进展的易感/抗性基因效应机制的研究结果，旨在确定这种肿瘤的新的潜在预后标志物和治疗靶点。在遗传易感大鼠诱导的快速进展性发育不良结节和 HCC 中，c-myc 扩增和过度表达最高，iNOS 与 IKK/NF-kB 和 RAS/ERK 信号的串扰改变，ERK 和细胞周期抑制剂的泛素化，以及 FOXM1 和细胞周期关键基因的失调，与抗性大鼠的病变相比。值得注意的是，这些机制在人类 HCC 亚型中预后较差或较好的改变，分别与遗传易感和抗性大鼠中的改变相似，并作为预后标志物和治疗靶点。针对特定靶点的分子治疗试图治愈晚期 HCC ，仅导致适度的生存获益。因此，有必要在临床前和临床研究中，确定和测试新的治疗靶点，用于 HCC 的联合分子治疗。它们可以从对大鼠和人类中不同易进展 HCC 的信号转导的比较分析中获益。
