ID1在黄芩黄酮类成分抑制尼古丁诱导的肺癌进展中的作用及机制

Nicotine is the main addictive component in tobacco, exerting its biological function by binding nicotinic acetylcholine receptors (nAChRs). In response to nAChRs, inhibitor of differentiation (ID1) facilitates the growth and metastasis of non-small cell lung cancer. Therefore, if there is a drug able to interfere the new target ID1, it is bound to make significance to the prevention of tobacco-induced lung cancer. In traditional Chinese medicine, Heat is the cause of tobacco-induced lung cancer. Scutellaria Baicalensis (SB) has long been considered as a drug to clear heat, and the flavones in it (baicalin, baicalein and wogonin) are the main components against heat and show anti-tumor effects. Flavones in SB inhibit proliferation, invasion, metastasis and inflammatory microenvironment in nicotine-induced lung cancer cells. More importantly, in previous studies we found that nicotine induced ID1 expression, while flavones in SB reversed this effect. In the present study, we explore the role of ID1 in inhibition of nicotine-induced lung cancer progression by flavones in SB in vitro and in vivo; in addition, we investigate the underlying mechanism from the already known pathways, such as nAChR, Src and PI3K/Akt, in order to provide more evidence to study the drugs against new target ID1.

尼古丁是烟草中的主要成瘾性组分，通过与烟碱乙酰胆碱受体（nAChR）结合发挥生物学功能。在nAChR介导下，分化抑制因子（ID）能促进尼古丁诱导的非小细胞肺癌的进展和转移。如果能针对ID1这个新靶点进行干预，必将对防治吸烟诱发的肺癌产生重大意义。中医学认为火热是烟致肺积的重要病机，黄芩是传统的清热药，其中黄酮类成分是其主要的清热组分，具有广泛的抗肿瘤活性。黄芩黄酮类成分对尼古丁诱导的肺癌细胞的增殖和侵袭转移均有明显的抑制作用。更为重要的是，申请者前期实验中发现，尼古丁诱导的肺癌细胞中ID1表达增加，而加入黄芩黄酮类成分干预后ID1表达下调。本研究拟从体内外实验观察ID1因子在黄芩黄酮类成分抑制尼古丁诱导的肺癌进展中的作用；并从ID1因子影响尼古丁诱导的肺癌进展的已知途径入手，如nAChR、Src激酶以及PI3K/Akt通路等，深入探讨其科学内涵，为发现防治肺癌进展的新靶点药物提供科学依据。

火热是导致肺积的重要病机，黄酮类成分是中药黄芩清热的主要有效成分，具有广泛的抗肿瘤活性。本研究证实黄芩黄酮类成分（黄芩苷、黄芩素、汉黄芩素）能抑制分化抑制因子（ID1）参与的肺癌进展，并从分子水平（ID1基因上下游）阐释其内在机制。.在体外研究中，采用基因沉默技术，研究黄芩黄酮类成分对ID1参与的肺癌细胞增殖转移的作用，结果表明黄芩黄酮类成分能明显抑制肺癌A549细胞和H1299细胞增殖、侵袭、迁移。对ID1上下游相关通路和分子检测发现，黄芩黄酮类成分能通过PI3K通路、Src通路抑制ID1及其下游通路中的关键分子。在动物实验中，黄芩黄酮类成分能抑制ID1参与的裸鼠皮下移植瘤和原位肺癌生长，并抑制ID1及其下游上皮间质转化（EMT）相关蛋白和VEGFA蛋白表达。.这些研究成果为清热药物在肺癌的进一步研究和临床应用提供了理论基础和应用依据，丰富了清热法作为肺癌的主要治则治法理论的科学内涵，并为抗肿瘤中药的筛选评价和机制研究新平台的建立提供了有益的实践。