胃癌和结直肠癌共性预后相关分子研究

Gastric cancer (GC) and colorectal carcinoma (CRC) are the main types of cancer in the Mainland China. The recurrence and metastasis are the leading causes of death in patients after surgery . However, there is currently a lack of effective prognostic makers. Applicants have discovered that gastric cancer and colorectal carcinoma share the same chemoresistance mechanism of NR4A2, which is also a prognositic maker in these two cancers. In addition, we've found that molecular signature can significantly improve the stability and consistency comparing with individual molecules. Therefore, in this project, we will explore the commonalities in GC and CRC, including prognostic value of the immunohistochemistry signature and the mechanisms of critical molecules. On the one hand, multicenter cohorts will be used to evaluate whether the prognositc immunohistochemistry signature we've found in CRC can be worked in GC. On the other hand, a series of in vitro experiments will be carried out to identify the mechanisms of two pivotal molecules POSTN and ITGB1 in GC and CRC. These two prognostic molecules might be associated with stemness and chemoresistance of tumor cells. At last, we will assess the commonalities of the prognostic value and mechanisms between GC and CRC. In this project, we will generate essential mechanistic information to the commonly prognostic molecules in gastric cancer and colorectal carcinoma. It will be useful for prognosis prediction, the development of targeted and personalized treatments of GC and CRC, even other inflammation related cancer.

胃癌和结直肠癌是中国大陆癌症发生和死亡的主要类型，复发转移是患者术后死亡的主要原因,但目前尚缺乏有效的预后预测指标。申请人前期研究发现预后相关分子NR4A2在胃癌和结直肠癌中具有相同的化疗耐药机制；此外还发现分子标志群对于结直肠癌术后患者预后预测的稳定性和一致性明显优于单个分子。因此，本项目旨在探索胃癌和结直肠癌的共性预后相关分子标志群及其作用机制。一方面利用已建立的多中心队列评估前期研究所得结直肠癌预后相关免疫组化分子标志群对于胃癌患者的预后预测能力；另一方面通过体外实验确定分子标志群中关键分子POSTN和ITGB1在胃癌和结直肠癌中的肿瘤细胞干性维持机制和化疗耐药机制，并分析其作用机制在胃癌和结直肠癌患者中是否具有共性。本项目的开展对于临床准确评价胃癌和结直肠癌等炎症相关癌症患者的预后，明确有效的治疗敏感/耐受靶点，开展有针对性的个体化治疗具有现实意义。

胃癌和结直肠癌是中国癌症发生和死亡的主要类型，复发和转移是患者术后死亡的主要原因，但目前尚缺乏有效的预后预测指标。本项目基于前期研究所得结肠癌免疫组化分子标志群，针对胃癌和结直肠癌的预后开展了一系列研究：1、POSTN高表达可增强胃癌肿瘤细胞以5-FU或（和）奥沙利铂为基础的化疗抵抗，进而与胃癌患者的不良预后密切相关，特别是对于实施根治术后接受化疗的患者；2、ITGB1低表达可影响结肠癌肿瘤细胞的生长，其高表达则预示结肠癌患者预后不良；3、利用公共数据库数据，整合后筛选得到差异表达mRNA和miRNA，构建调控模块得到了受miR-17调控的且具有预后指示功能的9个胃癌预后相关分子。研究中仍存在一些不足：1、POSTN稳定高表达细胞株和持续沉默细胞株已送至诺华生物技术公司进行深度测序，筛选差异表达基因和差异表达长链非编码RNA，了解作用通路后进一步详细阐明化疗耐药机制；2、ITGB1高表达细胞株建立不成功。针对ITGB1已构建新的表达质粒，待构建稳定高表达ITGB1的结肠癌细胞株以丰富实验结果；3、对之前由公共数据库筛选的胃癌相关分子进行实体样本验证。综上所述，本研究的实施为胃癌和结肠癌提供了新的预后标志物，可作为潜在的肿瘤靶向治疗靶标，有助于开展个体化治疗的应用。