Gut microbiota-derived signaling in liver carcinogenesis and cancer treatment

项目摘要 肝细胞癌是一种致命的疾病，治疗选择有限。因此，有一个 迫切需要开发肝癌的替代疗法，这是这项应用的主要目标 在现有研究计划(1R01 CA222490)下。有效的癌症治疗策略应以 首先是癌症发生的途径。新出现的证据还表明，肠道微生物区系- 衍生信号不仅与结肠癌有关，而且还影响肝脏炎症和肝脏 致癌。因此，为了开发有针对性的肝癌治疗策略，重要的是揭示 肝脏中肠源性信号的机制。研究专家(英虎博士)和单位主任(博士)。 Yvonne wan)在过去的8年里共同工作，从2011年开始，并产生了11个同行- 回顾了癌症研究方面的出版物。万博士的研究项目是由一个长期的， 持续资助的R01资助、NCI R01 CA053596(1991-2016)和合作U资助NCI U01 CA179582(2014-2019年，领衔PI)、NCI R01 CA222490(2018-2023年)和NIDDK R01 DK092100(2011-2017)。 胡博士参与了所有上述项目，并对胡博士如何 万的癌症研究项目得到了发展。胡博士在肠道-肝脏轴以及在 原位肝癌和结肠癌动物模型。她进行了广泛的研究，使用肝脏和 结肠癌细胞和小鼠模型来研究存在于结肠癌中的天然化合物控制的途径 肠道和肝脏，包括胆汁酸(BAS)、维甲酸(RA)和短链脂肪酸(SCFA)。我们的研究 项目(1R01 CA222490)关注的是这些由Gut直接或间接产生的天然化学品 细菌，并能够在肝脏和结肠中诱导肿瘤抑制基因miR-22。因此，miR-22及其 诱导剂不仅可以诱导癌细胞的凋亡和停滞，还可以提供一种预防性的停滞手段 癌症复发，导致有效的治疗策略。申请者英虎一直在密切合作 与万博士共同制定计划，以实现以下目标：Aim 1研究miR- 22通过研究miR-22的下游靶点具有抗癌作用。目标2研究miR-22的作用 用小鼠原位肝癌模型治疗肝癌。目标3分析miR-22的作用 肝癌治疗中的诱导剂。成功完成拟议的研究将产生新的战略 通过miR-22靶向通路治疗肝癌和结肠癌。因资金而腾出的资金 将使我们能够开发其他协作计划，从而导致提交 申请SBIR助学金，以推进胡博士的职业目标。万博士是主要的支持单位主任，他将 继续与胡博士合作，计划、指导和执行拟议的研究。

PROJECT ABSTRACT Hepatocellular carcinoma (HCC) is a deadly disease with limited treatment options. Therefore, there is an urgent need to develop alternative treatments for liver cancer, which is the primary goal of this application under the existing research program (1R01 CA222490). An effective cancer treatment strategy should target the pathways by which cancer arises in the first place. Emerging evidence also reveals that gut microbiota- derived signaling is not only implicated in colon cancer but also affects hepatic inflammation and liver carcinogenesis. Thus, to develop targeted strategies for liver cancer treatment, it is important to uncover the mechanism of gut-derived signaling in the liver. The Research Specialist (Dr. Ying Hu) and Unit Director (Dr. Yu-Jui Yvonne Wan) have worked together for the past 8 years, starting in 2011, and have generated 11 peer- reviewed publications in cancer research. Dr. Wan's research programs have been sponsored by a long-term, continuously funded R01 grant, NCI R01 CA053596 (1991-2016), and a cooperative U grant NCI U01 CA179582 (2014-2019, lead PI), NCI R01 CA222490 (2018-2023), and NIDDK R01 DK092100 (2011-2017). Dr. Hu has participated in all of these above-mentioned projects and has a thorough understanding of how Dr. Wan's cancer research program evolved. Dr. Hu has unique expertise in the gut-liver axis as well as in orthotopic liver and colon cancer animal models. She has conducted extensive research using both liver and colon cancer cells and mouse models to study the pathways controlled by natural compounds present in the gut and liver, including bile acids (BAs), retinoic acid (RA), and short-chain fatty acids (SCFAs). Our research program (1R01 CA222490) focuses on these natural chemicals, which are directly or indirectly produced by gut microbes and are able to induce the tumor suppressor miR-22 in the liver and colon. Thus, miR-22 and its inducers can not only induce cancer cell apoptosis and arrest, but also provide a preventive means to stop cancer reoccurrence, leading to an effective treatment strategy. The applicant, Ying Hu, has worked closely with Dr. Wan in developing plans to achieve the following goals: Aim 1 studies the mechanism by which miR- 22 has an anti-cancer effect by studying the downstream targets of miR-22. Aim 2 examines the role of miR-22 in liver cancer treatment using orthotopic liver cancer mouse models. Aim 3 analyzes the role of miR-22 inducers in liver cancer treatment. Successful completion of the proposed studies will lead to novel strategies to treat liver cancer as well as colon cancer via miR-22 targeted pathways. The funds freed-up due to funding of the current application will allow us to develop other collaborative programs that will lead to submission of an SBIR grant application to advance Dr. Hu's career goals. Dr. Wan is the primary support Unit Director who will continue to work with Dr. Hu to plan, direct, and execute the proposed research.