Mixed Lineage Kinase 3 and cytokine signaling axis in hepatocellular carcinoma

肝细胞癌中的混合谱系激酶 3 和细胞因子信号轴

• 批准号: 10527344
• 负责人: BASABI RANA
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10527344
• 关键词: Apoptosis; Apoptotic; Attenuated; BAY 54-9085; Biochemical; Biological; Biological Assay; Breast; CEP 1347; Cancer Etiology; Carcinogens; Cause of Death; Cell Cycle Arrest; Cell Survival; Cells; Cessation of life; Colorectal Cancer; Cytokine Signaling; Data; Detection; Development; Event; Family; Family member; Feedback; Future; Gene Expression; Gene Expression Profile; Genetic Models; Goals; Hepatocarcinogenesis; Human; IL6 gene; Immunohistochemistry; Inflammatory; Interleukin-1 beta; Interleukin-11; Interleukin-6; Knockout Mice; Link; Liver; MAP Kinase Gene; MAPK8 gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Mediating; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular; Mus; Nodule; Oncogenic; Outcome; Outcome Study; Pharmaceutical Preparations; Phosphotransferases; Primary carcinoma of the liver cells; Proliferating; RAS genes; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Stains; Stomach; TNF gene; Therapeutic; Therapeutic Intervention; Tissue Microarray; United States; Up-Regulation; Wild Type Mouse; antagonist; beta catenin; carcinogenicity; chemokine; combat; cytokine; design; in vivo; inhibitor; insight; knock-down; liver cancer model; member; mixed lineage kinase 3; mortality; mouse model; novel; overexpression; pharmacologic; pre-clinical; preclinical efficacy; therapeutically effective; tumor; tumor progression; upstream kinase

Summary/Abstract: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide including the United States due to late detection and limited effective therapeutic options. It is imperative to obtain a better understanding of the molecular events underlying the progression of HCC, so that rational therapeutic strategies can be designed. The current proposal focuses on a key signaling molecule, Mixed-Lineage Kinase 3 (MLK3), a member of the MAPK Kinase kinase (MAP3K) family to determine its role in HCC. Using a carcinogen-induced HCC model, we found that MLK3 knockout (KO) mice are protected from developing liver cancer and showed reduced proliferation compared to wild-type (WT) mice. MLK3 expression was induced in a panel of human HCC samples. In addition, in cell-based assays, treatment of various HCC cells with the pan-MLK inhibitor CEP-1347 reduced cell survival, promoted cell cycle arrest and apoptosis, suggesting a potential role of MLK3 in mediating these. Furthermore, overexpression of MLK3 increased the expression and release of cytokines, which in turn promoted MLK3 activity, indicating the presence of a potential positive feedback loop between MLK3 and cytokine signaling axis during HCC progression. Based on these preliminary data, we hypothesize that MLK3 represents a novel target involved in mediating liver tumorigenesis via a crosstalk with cytokine signaling, and targeting of MLK3- cytokine axis by the available pharmacological inhibitors might be a viable means of antagonizing HCC progression. The current proposal is aimed towards establishing MLK3’s role in HCC progression, while elucidating the underlying mechanisms by which this is accomplished, to achieve a mechanistic insight towards MLK3-induced HCC. As a proof-of principle, we will examine the feasibility of pharmacological inhibition of MLK3 on HCC progression using preclinical mouse models. The following specific aims are proposed to achieve our goals: (1) Elucidate the molecular mechanism underlying MLK3-mediated HCC progression, 2) Establish that a crosstalk between MLK3 and cytokine axis promotes HCC progression, and 3) Determine whether pharmacological inhibition of MLK3 and cytokine signaling mitigates liver cancer progression. While studies in Aims 1 and 2 are expected to provide a mechanistic insight towards the signaling pathway by which MLK3 promotes HCC and identify potential downstream targets, those in Aim 3 will provide important proof-of-principle preclinical information on the in vivo efficacy of the pharmacological inhibitor of MLK axis (CEP-1347) and IL-11 antagonist in antagonizing HCC progression. Successful outcome of the proposed studies will not only provide newer insights towards understanding the mechanism by which MLK3 mediates HCC progression, but also provide information on the preclinical efficacy of MLK3 inhibitor combination, which can be utilized towards developing effective MLK3-based therapeutic strategies for targeting HCC in the future.

摘要/摘要： 肝细胞癌（HCC）是包括美国在内的全球癌症相关死亡的主要原因 由于较晚的检测和有效的治疗选择。必须更好地理解 HCC进展为基础的分子事件，因此可以设计合理的治疗策略。 当前的建议着重于关键信号分子，混合细胞激酶3（MLK3），该成员的成员 MAPK激酶激酶（MAP3K）家族确定其在HCC中的作用。使用致癌物诱导的HCC模型，我们 发现MLK3敲除（KO）小鼠受到保护免受肝癌的影响，显示出降低 与野生型（WT）小鼠相比，增殖。在人类HCC样品小组中诱导MLK3表达。 此外，在基于细胞的测定中，用PAN-MLK抑制剂CEP-1347降低了各种HCC细胞的处理 细胞存活，促进细胞周期停滞和凋亡，表明MLK3在介导这些中的潜在作用。 此外，MLK3的过表达增加了细胞因子的表达和释放，进而促进 MLK3活性，表明MLK3和细胞因子信号之间存在潜在的正反馈回路 HCC进展过程中的轴。基于这些初步数据，我们假设MLK3代表了一种新颖 通过与细胞因子信号传导的串扰和MLK3-靶向介导肝肿瘤发生的靶标 可用的药物抑制剂的细胞因子轴可能是对抗HCC的可行手段 进展。当前的提案旨在确立MLK3在HCC进展中的作用，而 阐明实现这一目标的基本机制，以实现机械洞察力 MLK3诱导的HCC。作为原则证明，我们将研究MLK3药物抑制的可行性 使用临床前小鼠模型进行HCC进展。提出了以下特定目标以实现我们的 目标：（1）阐明MLK3介导的HCC进展的分子机制，2）确定A MLK3和细胞因子轴之间的串扰会促进HCC的进展，3）确定是否确定是否是否 MLK3和细胞因子信号传导的药理抑制可减轻肝癌的进展。同时研究 目的1和2有望为MLK3提供的信号传导途径提供机械洞察力 促进HCC并确定潜在的下游目标，AIM 3中的目标将提供重要的原理证明 有关MLK轴（CEP-1347）和IL-111的药物抑制剂体内效率的临床前信息 拮抗HCC进展的拮抗剂。拟议研究的成功结果不仅将提供 对了解MLK3介导HCC进展的机制的新见解，也是 提供有关MLK3抑制剂组合的临床前效率的信息，可用于 开发有效的基于MLK3的治疗策略来靶向HCC。