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: 10365639
• 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/10365639
• 关键词: Apoptosis; 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; Pharmacology; Phosphotransferases; Primary carcinoma of the liver cells; 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; base; 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; 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.

总结/摘要： 肝细胞癌（HCC）是包括美国在内的世界范围内癌症相关死亡的主要原因 这是由于检测较晚和有效治疗选择有限。必须更好地了解 肝癌进展的分子基础事件，以便设计合理的治疗策略。 目前的建议集中在一个关键的信号分子，混合谱系激酶3（MLK 3），一个成员， MAPK激酶激酶（MAP 3 K）家族，以确定其在HCC中的作用。使用致癌物诱导的HCC模型，我们 发现MLK 3基因敲除（KO）小鼠可以防止发生肝癌，并显示出降低的 与野生型（WT）小鼠相比，在一组人HCC样品中诱导MLK 3表达。 此外，在基于细胞的测定中，用泛MLK抑制剂CEP-1347处理各种HCC细胞降低了细胞凋亡。 细胞存活，促进细胞周期停滞和凋亡，表明MLK 3在介导这些中的潜在作用。 此外，MLK 3的过表达增加了细胞因子的表达和释放，这反过来又促进了细胞增殖。 MLK 3活性，表明MLK 3和细胞因子信号传导之间存在潜在的正反馈环 轴在HCC进展期间。基于这些初步数据，我们假设MLK 3代表了一种新的 通过与细胞因子信号传导的串扰参与介导肝肿瘤发生的靶点，以及MLK 3- 细胞因子轴的药理学抑制剂可能是一个可行的手段，拮抗肝癌 进展目前的提案旨在确定MLK 3在HCC进展中的作用， 阐明实现这一目标的基本机制，以实现对 MLK 3诱导的HCC。作为原理证明，我们将检查MLK 3的药理学抑制的可行性。 对HCC进展的影响。为了实现我们的目标，我们提出了以下具体目标： 目的：（1）阐明MLK 3介导的HCC进展的分子机制，2）建立一种新的肿瘤标志物， MLK 3和细胞因子轴之间的串扰促进HCC进展，和3）确定是否 MLK 3和细胞因子信号传导的药理学抑制减轻了肝癌进展。虽然研究在 目的1和2预计将提供一个机制的见解信号转导途径，MLK 3 促进HCC并确定潜在的下游目标，目标3中的目标将提供重要的原理证明 MLK轴药理学抑制剂（CEP-1347）和IL-11体内疗效的临床前信息 拮抗剂拮抗HCC进展。研究的成功结果不仅将提供 对了解MLK 3介导HCC进展的机制的新见解， 提供MLK 3抑制剂组合的临床前疗效信息，可用于 开发有效的基于MLK 3的治疗策略，用于未来靶向HCC。