Role of the RB Tumor Suppression in Liver Tumorigenesis

 描述(申请人提供)：肝细胞癌是一个主要的健康问题。目前，这种疾病是全球第三大癌症死亡原因，每年新增诊断病例超过50万例。肝细胞癌的高发病率可归因于环境污染，从接触致癌物、病毒感染到代谢紊乱。在肝癌中发现的关键遗传损伤之一是失活的 视网膜母细胞瘤肿瘤抑制因子(Rb)途径。在大多数肝脏肿瘤中，这一途径是通过一些离散的机制被破坏的，包括Rb基因的丢失或蛋白磷酸化的解除调控(例如，p16INK4a丢失)。在上一个资助周期中，我们广泛询问了RB丢失是如何促进肿瘤发展的。在小鼠模型中，我们发现在没有致癌压力的情况下，Rb的丢失不足以促进肿瘤的发展。这是由于RB缺乏状态的广泛补偿，并导致我们探索RB的独特功能，这些功能不受补偿过程的影响。这些分析证明了Rb在特定致癌压力下维持转录控制和细胞周期退出的新功能。一致的是，在这种情况下，Rb缺乏与显著增加的肿瘤发展有关。这些综合的发现为充分理解RB状态如何影响应激条件下的转录过程以及与驱动肿瘤发展的基因组完整性相关的特定后果提供了基础(目标1)。有趣的是，在这些研究的过程中，我们发现在小鼠模型中，Rb的丢失与快速增殖和进展到晚期肿瘤分级有关。对小鼠和人类肝癌的分子分析表明，Rb在细胞周期和其他过程(如黏附和EMT)中发挥着复杂的作用，这些过程与疾病进展相关，并与不良预后相关。肝细胞癌存活率低的部分原因是未能有效治疗晚期疾病。鉴于Rb在肿瘤病因学/进展中的关键作用，我们调查了激活Rb途径作为一种治疗策略的能力。这些研究的结果表明，使用特定的CDK4/6抑制剂在治疗上恢复Rb通路是可能的，该抑制剂正在进行临床试验。这些综合的发现为确定RB如何调节疾病进展以及如何系统地靶向RB途径治疗肝细胞癌提供了基础(目标2)。

 DESCRIPTION (provided by applicant): Hepatocellular Carcinoma is a major health concern. Currently, this disease is the 3rd leading cause of cancer deaths worldwide with over 500,000 new diagnoses each year. This high incidence of hepatocellular carcinoma development is attributed to environmental insults ranging from exposure to hepatocarcinogens, viral infections, to metabolic disorders. One of the key genetic lesions found in liver cancer is inactivation of the retinoblastoma tumor suppressor (RB) pathway. This pathway is disrupted in most liver tumors via a number of discrete mechanisms including loss of RB gene or deregulation of protein phosphorylation (e.g., p16ink4a loss). Over the last funding cycle we extensively interrogated how RB loss contributes to tumor development. In mouse models, we found that in the absence of carcinogenic stress RB loss is insufficient for tumor development. This is due to extensive compensation of the RB-deficient state and led us to explore unique functions of RB that are not subject to compensatory processes. These analyses demonstrated a novel function of RB in maintaining transcriptional control and cell cycle exit in the presence of specific carcinogenic stresses. Consonantly, RB-deficiency was associated with significantly increased tumor development under such conditions. These combined findings provide the basis for fully understanding how RB-status impinges on transcriptional processes under stress conditions and the specific consequence related to genome integrity driving tumor development (Aim 1). Interestingly, in the course of these studies we found that RB loss is associated with rapid proliferation and progression to advanced tumor grade in mouse models. Molecular analysis of mouse and human HCC tumors revealed that RB plays a complex role on cell cycle and other processes (e.g., adhesion and EMT) that are relevant for disease progression and associate with poor prognosis. The poor survival of HCC is due, in part, to failure to effectively treat advanced disease. Given the key role of RB in tumor etiology/progression, we investigated the ability to activate the RB-pathway as a therapeutic strategy. The findings from these studies indicated that it is possible to therapeutically reinstate the RB-pathway using specific CDK4/6 inhibitors, which are being tested in clinical trials. These combined findings provide the basis fo determining how RB modulates disease progression and how to systematically target the RB-pathway therapeutically in the treatment of HCC (Aim 2).