DCLK1 is a Novel Molecular Target in Hepatocellular Carcinoma

DCLK1 是肝细胞癌的新型分子靶点

• 批准号: 10046273
• 负责人: Courtney Wayne Houchen
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046273
• 关键词: Ablation; Alcoholic Liver Cirrhosis; Antineoplastic Agents; BAY 54-9085; Biological Assay; Biology; Cancer Burden; Cancer Etiology; Cause of Death; Cell Culture Techniques; Cell Cycle Progression; Cell Lineage; Cells; Cessation of life; Characteristics; Chronic Hepatitis; Chronic viral hepatitis; Cirrhosis; Colon; Data; Development; Diabetes Mellitus; Diagnosis; Drug usage; Epithelial; Epithelial Cells; Etiology; Excision; Exposure to; FDA approved; FUS-1 Protein; Fatty Liver; Goals; Growth; Health; Healthcare; Hepatic; Hepatitis C virus; Hepatocyte; Hepatotoxicity; Human; Immunodeficient Mouse; Incidence; Inflammation; Injury; Intestines; Investigation; Liver; Liver diseases; Liver neoplasms; Luciferases; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Medical; Mesenchymal; Metabolic Diseases; Microtubule Bundle; Molecular; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Nodule; Nude Mice; Obesity; Oncogenes; Oncogenic; Operative Surgical Procedures; Organ; Pancreas; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphotransferases; Prevalence; Primary carcinoma of the liver cells; Prognosis; Proteins; Protocols documentation; Public Health; RNA Interference; Radiation; Relapse; Reporter; Resistance; Risk; Risk Factors; Role; S100A9 gene; Series; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Solid Neoplasm; Survival Rate; TNF gene; Testing; Therapeutic Agents; Transforming Growth Factor beta; Transitional Cell Carcinoma; Transplantation; Tumor Stem Cells; Tumor Suppressor Genes; Tumor-Derived; Up-Regulation; Veterans; Virus Diseases; Xenograft Model; beta catenin; c-myc Genes; cancer initiation; cell motility; chemotherapy; disease diagnosis; efficacy evaluation; gamma secretase; genotoxicity; hepatoma cell; hepatotoxin; improved; inhibitor/antagonist; knock-down; liver injury; liver transplantation; migration; mortality; mouse model; neoplastic; new therapeutic target; non-alcoholic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; notch protein; novel; novel therapeutics; overexpression; patient derived xenograft model; prevent; programs; self-renewal; small hairpin RNA; stem cell population; therapeutically effective; trend; tumor; tumor growth; tumor initiation; tumor progression; tumor xenograft; tumorigenesis; tumorigenic

Hepatocellular carcinoma (HCC), a major form of liver cancer, is the second most common cause of cancer-related deaths worldwide. Its prognosis is poor, with a 5-year survival rate of less than 15%. The national prevalence and mortality due to cirrhosis and HCC in VA health care users have been increased by 2.5 to 3-fold during the last decade. The predicted increasing trend of HCC incidence and HCC-related deaths in the US veterans group remains alarming. Chronic hepatitis, alcoholic cirrhosis, fatty liver, and exposure to hepatotoxins are the major risk factors for HCC development. The risk of HCC increases strikingly in HCV carriers with diabetes and obesity. Thus, HCC is a major cause of deaths and veterans’ health issue. A single FDA-approved medical therapy for HCC, sorafenib only extends survival by approximately 3 months. Curative surgical options include hepatic resection and liver transplantation. However, very few patients are surgical candidates due to a late diagnosis of HCC. One of the major obstacles preventing the development of effective therapeutic agents is due to the potential existence of tumor stem cells (TSCs) in HCC. Most tumors contain a small percentage (1% to 2%) of TSC population that are believed to be responsible for resistance to chemotherapy, relapse, and metastasis. We have shown that a TSC-related protein, doublecortin- like kinase 1 (DCLK1) is induced in hepatotoxicity-induced liver injury, chronic hepatitis, cirrhosis, and HCC whereas a normal liver lacks DCLK1 expression. The elevated DCLK1 level promotes hepatoma cell migration, cell cycle progression, and HCC-like tumor growth. Our central hypothesis is that activation of DCLK1-expressing cells contributes to the development of hepatic neoplasia and, ultimately, HCC. Targeting the DCLK1-expressing subpopulation and DCLK1 regulated signaling will reduce the burden of cancer-related deaths. The proposed investigations rely on the use of primary human hepatocytes derived from normal and patient donors. We will determine the mechanism(s) which promote DCLK1-expressing human hepatocytes to acquire tumor characteristics. We will use cell culture and a unique mouse model with humanized/chimeric liver to test the hypothesis. We will also develop HCC patients-derived tumor xenografts to evaluate the impacts of targeting DCLK1 in HCC. Taken together, these studies will increase our understanding of the mechanism(s) that regulate hepatic neoplasia and will potentially validate DCLK1 as a new therapeutic target in HCC. These studies, if successful, will have a major impact on the field of cancer and veterans’ health because DCLK1 also contributes to the tumor growth in pancreas, intestine, and colon. !

肝细胞癌（HCC）是肝癌的一种主要形式，是肝癌的第二大常见原因