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ERK3 Kinase Signaling in Lung Cancer

肺癌中的 ERK3 激酶信号转导

基本信息

批准号：
9266383
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
项目类别：
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/9266383
关键词：
Cancer Cell Growth Cellular Morphology Coculture Techniques Data Drug Targeting FRAP1 gene Gene Expression Genes Genetic Transcription Goals Growth Guanosine Triphosphate Phosphohydrolases 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 Metastatic Neoplasm to the Liver Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Mus Mutation Neoplasm Metastasis Oncogenic Oncoproteins Pathologic Pathway Analysis Phosphorylation Phosphotransferases Pilot Projects Proteins Regulation Role STK11 gene Signal Pathway Signal Transduction Stimulus Structure of parenchyma of lung System Testing Therapeutic Transforming Growth Factor beta Treatment Efficacy Tumor Cell Invasion Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation WNT Signaling Pathway Work base cancer cell cell motility diagnostic biomarker experimental study extracellular signal-regulated kinase 3 in vivo knock-down macrophage mouse model neoplastic cell novel novel diagnostics overexpression p53 Signaling Pathway public health relevance response rho GTP-Binding Proteins rhoB p20 GDI targeted treatment tumor tumor growth tumor microenvironment tumor progression

项目摘要

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.