STMN1调控微管在慢性萎缩性胃炎伴肠化生中的作用及铁皮枫斗颗粒干预的研究

Reversion of precancerous lesions is the key point to prevent the chronic atrophic gastritis (CAG) from deteriorating into gastric cancer. Our previous studies indicated that Granule Dendrobii (GD) can improve CAG, and promote the reversion of intestinal metaplasia (IM) and other precancerous lesions; through deep-sequencing and gene validation analysis, we found that candidate key genes were rich in functional classifications of microtubule, mitotic processes et al, and focused on microtubule depolymerization protein gene STMN1. Recent clinical studies confirmed that STMN1 plays an important role in the progression of gastric cancer, however, its role in IM has not been reported yet. Based on above, we intend to construct the IM model with human gastric epithelial cells GES-1, meanwhile, replicate the model of CAG precancerous lesion in rats, to study the regulation of CDX2/SOX2 mediated by STMN1 in IM, and to compare the effects of GD and its impact on pathological manifestations of IM in CAG when combinen with docetaxel. Through this study, we will preliminary confirm the role of microtubule regulation mediated by STMN1 in IM, and elucidate the mechanisms of GD in the treatment of IM, as well as explore the therapeutic potential of GD combined with paclitaxel on IM, which will provide us with a new clue and theoretical basis in CAG precancerous lesions.

癌前病变的逆转是预防慢性萎缩性胃炎（CAG）演化为胃癌的关键控点。我们前期研究表明，铁皮枫斗颗粒（GD）可显著改善CAG，促进肠化生等癌前病变逆转；通过高通量测序技术及基因验证分析，发现候选关键基因主要富集在微管、细胞有丝分裂等功能分类，聚焦于微管解聚蛋白基因STMN1。新近临床研究证实，STMN1在胃癌进展中扮演重要角色，但在肠化生中鲜有报道。基于此，我们拟采用GES-1人胃黏膜上皮细胞构建肠化生模型，同时复制大鼠CAG癌前病变模型，研究STMN1对肠化生基因CDX2/SOX2的表达调控，并比较GD及合用微管类药物紫杉醇对CAG肠化生病理表现的影响。本项目将初步明确STMN1调控微管在肠化生中的作用，阐明GD治疗CAG肠化生的机理，并探索GD及合用紫杉醇协同逆转肠化生的效应，为CAG癌前病变的防治提供新的思路和理论依据。

癌前病变的逆转是预防慢性萎缩性胃炎（CAG）演化为胃癌的关键控点。我们前期研究表明，铁皮枫斗颗粒（GD）可显著改善CAG，促进肠化生等癌前病变逆转；通过高通量测序技术及基因验证分析，发现候选关键基因主要富集在微管、细胞有丝分裂等功能分类，聚焦于微管解聚蛋白基因STMN1。新近临床研究证实，STMN1在胃癌进展中扮演重要角色，但在肠化生中鲜有报道。.在本项目中，我们采用GES-1人胃黏膜上皮细胞构建肠化生模型，同时复制大鼠CAG癌前病变模型，研究STMN1对肠化生基因CDX2/SOX2的表达调控，并比较GD及合用微管类药物紫杉醇对CAG肠化生病理表现的影响。.本项目的细胞实验明确了STMN1可在体外显著上调肠化生关键基因CDX2表达水平，GD可显著下调STMN1和CDX2的表达水平；动物实验明确了GD及其与紫杉醇联用，均显著改善了MNNG诱导的大鼠慢性萎缩性胃炎的炎症、萎缩、肠化生，值得关注的是，GD与紫杉醇联用可显著改善上皮内瘤变，而GD或紫杉醇单独用均无此药效，这体现了GD与紫杉醇联用在改善上皮内瘤变上的显著优势。GD及其与紫杉醇联用显著减低了STMN1的表达水平，并显著降低了STMN1的转录因子E2F1的表达水平。GD显著提高了miR-210-3p、miR-210-5p、miR-223-3p、miR-223-5p的表达水平。.这些研究结果再次验证了GD在显著改善慢性萎缩性胃炎伴癌前病变方面的药效，且可能是通过上调靶向微管解聚蛋白STMN1的miRNA,下调STMN1的转录因子，从而降低STMN1的表达水平实现的。GD与微管类药物紫杉醇联用，除显著改善肠化生外，还能显著改善上皮内瘤变，二者皆为胃癌的癌前病变，体现出GD与紫杉醇联用在治疗胃癌前病变方面的优势，具有临床应用前景。