硫氧还蛋白-硫氧还蛋白还原酶在肝癌早期预警和化学预防中的作用及其机制研究

Chemoprevention is the one of the focues of cancer prevention research, and how to give proper chemopreventive drugs to proper target populations at proper timing is essential to the successful translation of chemoprevention studies into reality. Hepatocarcinoma is one of the most common high-incidence cancers in China. During the process of hepatocarcinogenesis, the thioredoxin (Trx)-thioredoxin reductase (TR ) system not only protects normal hepatocytes from oxidative damages, but also offers growth and survival advantages to mutated/initiated abnormal liver cells, and thus promote hepatocarcinogenesis at certain stages.In our preliminary studies we found that the plasma TR enzyme activity was positively associated with tumor burden. On the other hand, ethaselen, a novel organoseleno TR inhibitor designed and synthesized by our group, has finished all preclinical studies and entered clinical trials. We hypothesize that TR could serve as both a biomarker and a chemopreventive drug target for earlier precaution and chemoprevention of hepatocarcinogenesis, and integrated population study in high cancer incidence sites, chemical and knockout anmial models, and cellular and mollecular mechanistic studies into the present grant, to investigate the potential of plasma TR activity in hepatocarcingenesis precaution, and the chemopreventive effects and underlying mechanisms of ethaselen against hepatocarcinogenesis. The proposed research is distinguished by typical 4P (prediction, prevention, personalized and participatory) medicine and translational research characteristics, and will help in discovery of novel tumor early warning biomarker, chemopreventive drug and its target.

化学预防是癌症研究的热点，如何在合适的时机给予合适的目标人群以合适的化学预防药物则是化学预防研究实现临床转化的核心问题。肝癌是我国常见高发癌症之一，Trx-TR系统对正常肝细胞有抗氧化保护作用，但对异常肝细胞则可促进其存活和增殖，推动肝癌的发生发展。我们的前期人群研究显示血浆TR活性与肿瘤相关，而自主研发的TR抑制剂乙烷硒啉安全有效，已进入临床试验。本项目以TR作为生物标志物和药物靶标，整合早期预警、目标人群筛查和化学预防药物研究为一体，结合癌症高发现场人群、化学诱发和基因敲除动物模型和细胞与分子机制研究，以阐明血浆TR活性用于肝癌早期预警和TR抑制剂乙烷硒啉用于肝癌化学预防的可能性及其内在机制。本项目研究具有突出的"预测、预防、个体化和参与"的系统医学和转化研究特色，有助于发现新的肿瘤预警生物标志物、化学预防药物及其靶标，有助于建立癌症化学预防研究的新思路新模式。

化学预防是癌症研究的热点，在合适的时机给予合适的目标人群以合适的化学预防药物则是化学预防研究实现临床转化的核心问题。肝癌是我国常见高发癌症之一，Trx-TR系统对正常肝细胞有抗氧化保护作用，但对异常肝细胞则可促进其存活和增殖，推动肝癌的发生发展。我们的前期人群研究显示血浆TR活性与肿瘤相关，我们自主研发的TR抑制剂乙烷硒啉已进入临床试验，而我们新研发的抗肿瘤药物卟硒碄具有更优于乙烷硒啉的作用效果，可能在肿瘤治疗中发挥更好的作用。本项目以TR作为生物标志物和药物靶标，一方面研究了TR抑制剂卟硒啉对肝癌发生发展的化学预防作用，并初步阐明其分子机制，包括与氧化还原相关信号通路之间的crosstalk，以及卟硒啉通过调节免疫系统抑制肿瘤发生的分子机制；另一方面，研究了Trx-TR 水平和活性与肝癌发病风险、发展极端、疗效和相关肿瘤标志物的相关性，并初步阐明其内在机制，为发现新的肿瘤预警生物标志物、化学预防药物及其靶标、建立癌症化学预防提供了新思路。