Beneficial effects of Honokiol against liver cancer

 描述（由申请人提供）：超重或肥胖的状况被认为是肝细胞癌的风险因素。男性中肝细胞癌（HCC）的风险为1.68，与所有研究的癌症（包括前列腺癌、肾癌、胆囊癌、结肠癌、直肠癌、食道癌、胃癌和胰腺癌）相比，HCC与肥胖导致的最高相对风险增加相关。考虑到肥胖症的流行性（大约三分之二的美国成年人超重或肥胖），相对肝癌风险增加1.68 - 4.52倍是一个非常重要的医学问题。有一个明确的和迫切的需要开发化学预防策略，以打击肝癌的肥胖人群。该提案的主要目标是开发有效的化学预防策略，以靶向肥胖状态下的HCC。我们将阐明和厚朴（一种来自木兰属物种的生物活性化合物）在肥胖高瘦素血症条件下预防HCC生长的分子机制。我们和其他人已经表明，与肥胖相关的高瘦素水平（高瘦素血症）是HCC进展和转移的主要驱动因素。因此，预防瘦素的肿瘤效应是迫在眉睫的重要研究领域。研究阻断瘦素信号传导的生物活性方法，我们最近发现和厚朴酚可以有效地减少瘦素诱导的肝癌细胞增殖和迁移。该项目包括两个高度创新的目标。目的1研究honoklatin是否阻断leptin诱导的上皮-间质转化，抑制leptin信号网络，并研究miR-122在honoklatin作用中的作用。这些研究的结果将建立honoklastine作为一种新的和有效的瘦素拮抗剂和解剖honoklastine和瘦素信号传导轴之间潜在的分子相互作用可能揭示新的串扰。目的二是研究和诺平是否能阻断瘦素的旁分泌作用并有效预防高瘦素血症肥胖状态下的肝癌。初步研究表明，瘦素的旁分泌效应在脂肪细胞-肝癌细胞的相互作用中起重要作用，从而导致肝癌细胞EMT增加、侵袭和迁移。这一目的的结果将揭示和诺平是否阻断瘦素的旁分泌作用，并防止脂肪细胞-肝癌细胞的串扰结果。我们的研究将推进honoklastin化学预防领域的一个新的方向，显示honoklastin在预防肝癌进展的肥胖高瘦素血症状态的有效性，并建立honoklastin作为一种新的瘦素拮抗剂。这些研究将提供临床前信息，以设计基于和厚朴酚的化学预防策略的临床试验，用于发展肝癌的高风险肥胖人群。值得注意的是，在美国，肥胖每年导致约10万例癌症相关死亡。此外，我们的研究将 也显示了honokaline在非肥胖条件下预防HCC的有效性，因此我们的发现将产生深远的影响。

 DESCRIPTION (provided by applicant): The condition of being overweight or obese has been implicated as a risk factor for hepatocellular carcinoma. Hepatocellular carcinoma (HCC) risk is 1.68 in men, HCC is associated with the highest relative-risk increase as a consequence of obesity compared to all the cancers studied including prostate, kidney, gallbladder, colon, rectum, esophagus, stomach and pancreas. Considering the pandemic nature of obesity (approximately two-thirds of US adults are overweight or obese), a 1.68 - 4.52 fold increase in relative liver cancer risk is a very significant medical problem. There is a clear and compelling need to develop chemopreventive strategies to combat HCC in obese population. The major goal of this proposal is to develop effective chemopreventive strategies to target HCC in obese state. We will elucidate the molecular mechanism(s) by which Honokiol, a bioactive compound derived from Magnolia species, prevents HCC growth in obese hyperleptinemic conditions. We and others have shown that high leptin levels (hyperleptinemia) associated with obesity is a major driver of HCC progression and metastasis. Thus, prevention of the neoplastic-effects of leptin is imminent and important area of research. Investigating bioactive approaches to block leptin signaling, we recently discovered that honokiol can effectively reduce leptin-induced proliferation and migration of HCC cells. The project consists of two highly innovative aims. Aim 1 will examine whether honokiol blocks leptin-induced epithelial-mesenchymal transition, inhibits leptin-signaling network and investigate the role of miR-122 in mediating honokiol actions. Results from these studies will establish honokiol as a novel and effective leptin-antagonist and dissect the underlying molecular interactions between honokiol and leptin signaling axes potentially revealing new crosstalk. Aim 2 will examine whether honokiol block paracrine actions of leptin and effectively prevents HCC in hyperleptinemic obese state. Preliminary data show that the paracrine effect of leptin plays an important role in adipocytes-HCC cells crosstalk which leads to increased EMT, invasion and migration of HCC cells. Results from this aim will reveal whether honokiol blocks the paracrine effects of leptin and prevent adipocytes-HCC cells crosstalk outcome. Our studies will advance the honokiol chemoprevention field in a new direction showing the effectiveness of honokiol in preventing HCC progression in obese-hyperleptinemic-state and establishing honokiol as a novel leptin-antagonist. These studies will provide pre-clinical information to design clinical trials of honokiol-based chemopreventive strategies for obese persons at high risk for developing HCC. It is important to note that obesity is attributed to ~100,000 cancer-related deaths per year in the USA. Additionally, our studies will also show the effectiveness of honokiol in preventing HCC in non-obese conditions therefore our findings will have far-reaching impact.