ERK3 Kinase Signaling in Lung Cancer

肺癌中的 ERK3 激酶信号转导

• 批准号: 9070693
• 负责人: Weiwen Long
• 金额: $ 33.86万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070693
• 关键词: Cancer Cell Growth; Cellular Morphology; Coculture Techniques; Data; Drug Targeting; FRAP1 gene; Gene Expression; Genes; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Human; In Vitro; JUN gene; Knock-out; Knockout Mice; Lung; Lung Neoplasms; MAP3K7 gene; MAPK3 gene; Macrophage Colony-Stimulating Factor; Malignant neoplasm of lung; Matrix Metalloproteinases; Mediating; Metalloproteinase Gene; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; Pathway Analysis; Phosphorylation; Phosphotransferases; Pilot Projects; Proteins; Regulation; Role; STK11 gene; Signal Pathway; Signal Transduction; Staging; Stimulus; Structure of parenchyma of lung; System; Testing; Therapeutic; Transforming Growth Factor beta; Tumor Cell Invasion; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; Work; base; cancer cell; cell motility; diagnostic biomarker; extracellular signal-regulated kinase 3; in vivo; knock-down; macrophage; mouse model; neoplastic cell; novel; novel diagnostics; overexpression; p53 Signaling Pathway; research study; response; rho GTP-Binding Proteins; rhoB p20 GDI; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): Tumor suppressor gene LKB1 is frequently inactivated by mutations in lung cancer, which is often associated with concomitant activating KRas mutation. LKB1 inactivation is positively associated with advanced tumor progression and metastasis. While it is well-documented that LKB1 regulates cancer cell growth mainly through targeting AMPK/mTOR and p53 signaling pathways, the molecular mechanisms underlying the regulation of tumor invasion and metastasis by LKB1 are poorly understood. Interestingly, upon the loss of LKB1, ERK3, an atypical MAP kinase, is highly upregulated in KRasG12D-induced tumors and in human lung cancer cells. ERK3 was recently shown to be overexpressed in lung cancer and promote lung cancer cell migration and invasion by upregulating matrix metalloproteinase (MMP) gene expression. In contrast to the well-studied classic MAPKs, such as ERK1/2, little is known about the molecular regulation of ERK3 signaling (gene expression and kinase activation). Importantly, ingenuity pathway analysis of ERK3 interacting proteins identified in our pilot study shows that ERK3 is highly associated with TGFß (or Wnt)/TAK1 signaling and RhoGDI signaling. In addition, preliminary data from in vitro co-culture experiments demonstrate that depletion of LKB1 in lung cancer cells facilitates the conversion of MФs to M2 type; M2 MФs then produce high levels of TGFß1 and Wnt2 that may in turn act on tumors in activating TAK1 and ERK3. Based on these findings, we hypothesize that ERK3 signaling is upregulated upon the loss of LKB1 in lung tumor microenvironment; upregulation of ERK3 signaling then promotes lung tumor progression and metastasis. To test this hypothesis, the following specific aims are proposed. 1). To define the molecular regulation of ERK3 signaling: c-Jun-mediated gene expression and TAK-1-mediated kinase activation in response to TGFß/Wnt signals, in cultured lung cancer cell systems. 2). To test in vivo the idea that ERK3 signaling is upregulated upon the loss of LKB1 in tumor cells through c-Jun-mediated ERK3 gene upregulation and TAK-1-mediated activation of ERK3 signaling pathway in response to the stimulation of TGFßs and/or Wnts secreted by M2 type TAMs, utilizing a lung-specific KRasG12D/LKB1-deficient tumor model. 3). To determine the roles of ERK3 in lung tumor progression and metastasis by conditionally overexpressing ERK3 in KRasG12D lung tumor mouse model or conditionally knocking out ERK3 in lung tissue-specific KRasG12D/LKB1-null mouse model. The objective of this proposal is to elucidate ERK3 signaling pathway and to determine its role in lung tumor progression and metastasis. The proposed work is anticipated to define ERK3 as a novel diagnostic marker and/or a therapeutic drug target for the treatment of advanced lung cancer.

 描述（由申请人提供）：肿瘤抑制基因LKB1经常因肺癌突变而失活，这通常与伴随的激活KRas突变有关。 LKB1失活与晚期肿瘤进展和转移呈正相关。尽管有充分证据表明LKB1主要通过靶向AMPK/mTOR和p53信号通路来调节癌细胞生长，但LKB1调节肿瘤侵袭和转移的分子机制却知之甚少。有趣的是，在 LKB1 缺失后，ERK3（一种非典型 MAP 激酶）在 KRasG12D 诱导的肿瘤和人肺癌细胞中高度上调。最近发现ERK3在肺癌中过度表达，并通过上调基质金属蛋白酶（MMP）基因表达来促进肺癌细胞迁移和侵袭。与 ERK1/2 等经过充分研究的经典 MAPK 相比，人们对 ERK3 信号传导（基因表达和激酶激活）的分子调控知之甚少。重要的是，我们的初步研究中发现的 ERK3 相互作用蛋白的独创性通路分析表明，ERK3 与 TGFβ（或 Wnt）/TAK1 信号传导和 RhoGDI 信号传导高度相关。此外，体外共培养实验的初步数据表明，肺癌细胞中LKB1的耗竭有利于MФ向M2型的转化； M2 MФ 随后产生高水平的 TGFß1 和 Wnt2，进而作用于肿瘤，激活 TAK1 和 ERK3。基于这些发现，我们假设肺肿瘤微环境中 LKB1 缺失后 ERK3 信号传导上调； ERK3信号传导的上调促进肺肿瘤的进展和转移。为了检验这一假设，提出了以下具体目标。 1）。定义 ERK3 信号传导的分子调控：在培养的肺癌细胞系统中，c-Jun 介导的基因表达和 TAK-1 介导的激酶激活响应 TGFβ/Wnt 信号。 2）。利用肺特异性 KRasG12D/LKB1 缺陷肿瘤模型，通过 c-Jun 介导的 ERK3 基因上调和 TAK-1 介导的 ERK3 信号通路激活来响应 M2 型 TAM 分泌的 TGFβ 和/或 Wnt 的刺激，在体内测试 ERK3 信号在肿瘤细胞中 LKB1 丢失后上调的想法。 3）。通过在 KRasG12D 肺肿瘤小鼠模型中条件性过表达 ERK3 或在肺组织特异性 KRasG12D/LKB1 缺失小鼠模型中条件性敲除 ERK3，确定 ERK3 在肺肿瘤进展和转移中的作用。该提案的目的是阐明 ERK3 信号通路并确定其在肺肿瘤进展和转移中的作用。拟议的工作预计将 ERK3 定义为治疗晚期肺癌的新型诊断标记物和/或治疗药物靶点。