Novel Role(s) of Nrf2 in the Growth of Post-Transplantation Cancer

Nrf2 在移植后癌症生长中的新作用

• 批准号: 9027248
• 负责人: Soumitro Pal
• 金额: $ 41.12万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027248
• 关键词: 1-Phosphatidylinositol 3-Kinase; Allografting; Antioxidants; Apoptosis; Apoptotic; Attenuated; Calcineurin inhibitor; Cancer cell line; Cell Cycle Progression; Down-Regulation; Drug usage; Effectiveness; Endothelial Cells; Equilibrium; Event; Goals; Growth; HGF gene; Immunosuppressive Agents; In Vitro; Kidney; Kidney Neoplasms; Lead; Ligands; MAP Kinase Gene; MAPK11 gene; MAPK3 gene; Malignant Neoplasms; Mediating; Modeling; Molecular Profiling; Morphogenesis; Oncogenes; Organ Transplantation; Oxidation-Reduction; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Ras/Raf; Receptor Protein-Tyrosine Kinases; Regulation; Renal Cell Carcinoma; Renal carcinoma; Resistance; Role; Signal Transduction; Solid; Testing; Therapeutic immunosuppression; Tissues; Transcription Repressor/Corepressor; Transplant Recipients; Transplantation; Tumor Tissue; Xenograft Model; activating transcription factor; angiogenesis; cancer therapy; cancer transplantation; cell killing; chemotherapeutic agent; chemotherapy; design; heme oxygenase-1; in vivo; inhibitor/antagonist; killings; knock-down; meetings; migration; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; prevent; public health relevance; rapid growth; rho; targeted treatment; transcription factor; tumor; tumor growth; tumor xenograft; tumorigenesis

 DESCRIPTION (provided by applicant): There are limited treatment options for advanced renal cell carcinoma (RCC). Interestingly, kidney cancer is also a critical problem in organ transplant patients receiving immunosuppressive therapy, particularly with calcineurin inhibitors (CNIs). Thus, the accelerated rate of cancer in transplant recipients can serve as a unique model to understand the mechanism(s) of renal tumor growth. We discovered that in CNI-induced renal cancer, the Ras-Raf pathway is highly activated to promote over-expression of the anti-oxidant and cytoprotective molecule heme oxygenase-1 (HO-1). HO-1 mediates a rapid growth and survival of renal cancer cells, and it can lead to resistance against chemotherapeutic treatments. The apoptotic effects of commonly used drugs for renal cancer treatment were markedly enhanced upon HO-1 knockdown. We recently identified that the transcription factor Nrf2 is highly activated in RCC through the induction of Ras-Raf pathway, and it mediates HO-1 over-expression. One of the possible mechanism(s) for hyper activation of the Ras-Raf pathway in RCC is due to the signaling through upstream receptor tyrosine kinases (RTKs). The RTK c-MET is over-expressed in RCC; and in preliminary studies, we observed that the induction of c-MET activates the Ras pathway and induces Nrf2/HO-1. As discussed, kidney cancer is one of the most common cancers in patients having solid organ transplantation. Oncogenes, including ras, become activated during post-transplantation period. We have demonstrated that although CNIs are very good immunosuppressive agents to prolong allograft survival, they can promote a rapid progression of post-transplantation cancer; and CNI-induced tumors were associated with Ras/Raf-1/Nrf2 activation, HO-1 over-expression and angiogenesis. Interestingly, we also observed that the CNI treatment can promote an increased phosphorylation of c-MET; and thus c-MET can possibly be a critical molecule for CNI-induced and Ras-Nrf2-mediated renal tumor growth. Together, Nrf2 has a great potential to be considered as a novel therapeutic target in RCC. We hypothesize that targeting the c-MET-Ras-Nrf2 pathway and the inhibition of HO-1 will attenuate the growth, angiogenesis and progression of renal cancer (with importance to CNI-induced post-transplantation cancer), and it will significantly promote the tumor killing efficienc of chemotherapeutic agents. In our specific aims, we will study: 1) roles of CNI- and c- MET-induced pathway(s) in the regulation of Ras-mediated Nrf2 activation/stabilization in renal cancer cells (Aim-1); 2) role(s) of Nrf2 in regulating CNI- and c-MET-induced growth of renal cancer cells (Aim-2); and 3) roles of c-MET/Raf-1 and Nrf2 in CNI-induced renal cancer growth after organ transplantation in murine model; and to evaluate the expression of Nrf2 and HO-1 in renal tumor tissues from transplant and non-transplant patients (Aim-3). Together, our studies should identify the c-MET-Ras-Nrf2-HO-1 tumor-promoting pathway as a new and novel therapeutic target in RCC, with particular importance to CNI-induced post-transplantation cancer. It should lead to a paradigm shift for current therapies in renal cancer.

 描述（适用提供）：晚期肾细胞癌（RCC）的治疗方案有限。有趣的是，在接受免疫抑制治疗的器官移植患者中，肾癌也是一个关键问题，尤其是钙调神经磷酸酶抑制剂（CNIS）。这就是移植受者中癌症的加速率可以作为了解肾脏肿瘤生长机制的独特模型。我们发现，在CNI诱导的肾脏癌中，RAS-RAF途径被高度激活，以促进抗氧化剂和细胞保护分子血红素氧酶-1（HO-1）的过表达。 HO-1介导了肾脏癌细胞的快速生长和存活，并可能导致对化学治疗的抗性。 HO-1敲低时，常用药物用于肾癌治疗的凋亡作用显着增强。我们最近确定，通过诱导RAS-RAF途径，转录因子NRF2在RCC中被高度激活，并且它介导HO-1过表达。 RCC中RAS-RAF途径过度激活的可能机制之一是由于通过上游受体酪氨酸激酶（RTK）信号传导引起的。 RTK C-MET在RCC中过表达；在初步研究中，我们观察到C-MET的诱导会激活RAS途径并诱导NRF2/HO-1。如所讨论的，肾癌是具有固体器官移植的患者中最常见的癌症之一。包括RAS在内的癌基因在移植后期被激活。我们已经证明，尽管CNIS是延长同种异体移植生存的非常好的免疫抑制剂，但它们可以促进移植后癌症的快速发展。 CNI诱导的肿瘤与RAS/RAF-1/NRF2激活，HO-1过表达和血管生成有关。有趣的是，我们还观察到CNI处理可以促进C-MET磷酸化的增加。因此，C-MET可能是CNI诱导和RAS-NRF2介导的肾肿瘤生长的关键分子。总之，NRF2具有将其视为RCC中新型治疗靶标的巨大潜力。我们假设针对C-MET-RAS-NRF2途径和HO-1抑制作用将减轻肾脏癌的生长，血管生成和进展（对于CNI诱导的转移后癌症至关重要），它将显着促进化学治疗剂的肿瘤杀伤效率。在我们的具体目标中，我们将研究：1）CNI-和C-MET诱导的途径在肾脏癌细胞中RAS介导的NRF2激活/稳定性调节中的作用（AIM-1）； 2）NRF2在控制CNI-和C-MET诱导的肾癌细胞生长中的作用（AIM-2）； 3）C-MET/RAF-1和NRF2在鼠模型中器官移植后CNI诱导的肾脏癌生长中的作用；并评估来自移植和非移植患者的肾脏肿瘤组织中NRF2和HO-1的表达（AIM-3）。总之，我们的研究应确定C-MET-RAS-NRF2-HO-1肿瘤促进途径是RCC中的新型治疗靶标，对于CNI诱导的移植后癌症特别重要。它应该导致肾癌当前疗法的范式转变。