DCLK1 is a Novel Molecular Target in Hepatocellular Carcinoma

肝细胞癌是肝癌的一种主要形式，是第二大常见病因。 全球与癌症相关的死亡人数。预后较差，5年生存率不到15%。 退伍军人保健使用者中因肝硬化和肝癌而导致的全国患病率和死亡率一直是 在过去的十年里增长了2.5到3倍。预测的肝癌发病率上升趋势 美国退伍军人群体中与肝癌相关的死亡人数仍然令人担忧。慢性肝炎，酒精性 肝硬变、脂肪肝和接触肝毒素是肝细胞癌发生的主要危险因素。 在患有糖尿病和肥胖症的丙型肝炎病毒携带者中，患肝癌的风险显著增加。因此，肝癌是一种主要的 死亡原因和退伍军人健康问题。FDA批准的治疗肝癌的单一药物疗法， 索拉非尼只能将生存期延长约3个月。根治性手术选择包括肝脏 切除和肝移植。然而，由于手术时间较晚，很少有病人适合做手术。 肝细胞癌的诊断。阻碍有效治疗方法发展的主要障碍之一 药物是由于肝癌中潜在存在肿瘤干细胞(TSCs)。大多数肿瘤包含一种 TSC人群中的一小部分(1%到2%)，被认为是导致对 化疗、复发和转移。我们已经证明了一种与TSC相关的蛋白质，Doublecortin- 与激酶1(DCLK1)一样，DCLK1在肝毒性引起的肝损伤、慢性肝炎、肝硬化和 而正常肝组织缺乏DCLK1的表达。DCLK1水平升高促进肝癌 细胞迁移、细胞周期进展和肝细胞癌样肿瘤生长。我们的中心假设是 DCLK1表达细胞的激活有助于肝肿瘤的发生和发展， 最终，是肝细胞癌。靶向DCLK1表达亚群和DCLK1调控信号将 减轻癌症相关死亡的负担。拟议的调查依赖于使用初级 人肝细胞来源于正常和患者供者。我们将确定机制(S) 促进表达DCLK1的人肝细胞获得肿瘤特性。我们将使用 细胞培养和具有人源化/嵌合体肝脏的独特的小鼠模型来检验这一假设。我们会 也开发肝癌患者来源的肿瘤移植瘤，以评估靶向DCLK1在 肝细胞癌。综上所述，这些研究将增加我们对以下机制的理解(S) DCLK1可以调节肝肿瘤的发生，并有可能使DCLK1成为治疗肝癌的新靶点。 这些研究如果成功，将对癌症领域和退伍军人的健康产生重大影响 因为DCLK1还促进了胰腺、肠道和结肠的肿瘤生长。 好了！

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. !