干预胃癌微环境CAF外泌体中肿瘤抑制因子Sall2转运对胃癌进展的影响及机制研究

Cancer-associated fibroblasts (CAF) that locate in the stroma of cancer tissuess are important regulatory cells for cancer microenvironment. Previously, we have reported that metformin could inhibit the proliferation and invasion of gastric cancer cells. However, the effect of metformin on gastric environment remains elusive. In our preliminary study, we found that metformin did not kill gastric cancer CAF, but change the protein content of its exosomes by iTRAQ proteomic analysis. Among the dysregulated proteins, tumor suppressor Sall2 (Spalt-Like Transcription Factor 2) was highly enriched in the exosomes from metformin-treated CAF. Nevertheless, its regulatory role in the target gastric cancer still unknown. This project will use metformin to intervene cancer microenvironment and utilize mutiple molecular biological approaches to illustrate the following mechanisms: 1) The anti-cancer mechanism of CAF-derived exosomes through transportation of Sall2; 2) The effect of Sall2 delivered by exosomes on gastric cancer progression and its regulatory mechanism on its targets E2F1, GCH1 and MMP23b. This project will illustrate the anti-cancer mechanism of exosome-derived Sall2 from cancer microenvironment, which may provide new strategies for gastric cancer treatment.

肿瘤间质中大量存在的肿瘤相关成纤维细胞（CAF）是肿瘤微环境中的重要调节细胞。项目组前期对经典降糖药物二甲双胍（Metformin）抑制胃癌细胞生长及侵袭等作用进行了研究，发现低浓度二甲双胍作用于胃癌及CAF后并不直接杀死细胞，但蛋白质组学发现其能改变CAF分泌的外泌体中的多种蛋白质成分。其中肿瘤抑制因子Sall2在二甲双胍处理的胃癌CAF外泌体中含量升高，但其对受体胃癌细胞的影响及机制尚不明确。本项目拟以二甲双胍对胃癌细胞生长的微环境进行干预，分别从体内和体外水平进一步探索：1）胃癌CAF外泌体转运Sall2抑制胃癌生长和侵袭转移等的机制；2）转录因子Sall2对下游靶基因E2F1、GCH1及MMP23b的调控机制以及在抑制胃癌进展中的作用。本研究有望从干预胃癌CAF释放的外泌体中Sall2转运的角度揭示新的抗肿瘤机制，为胃癌的治疗提供新的靶点与策略。

肿瘤间质中大量存在的肿瘤相关成纤维细胞（CAF）是肿瘤微环境中的重要调节细胞。项目组前期对经典降糖药物二甲双胍（Metformin）抑制胃癌细胞生长及侵袭等作用进行了研究，发现低浓度二甲双胍作用于胃癌及CAF后并不直接杀死细胞，但能抑制与CAF共培养的胃癌细胞，提示二甲双胍影响了CAF微环境。我们通过蛋白质组学技术发现二甲双胍能改变CAF分泌的外泌体中的多种蛋白质成分。其中肿瘤抑制因子Sall2在二甲双胍处理的胃癌CAF外泌体中含量升高，能抑制胃癌进展。此外，二甲双胍通过刺激CAFs中Calml3的分泌来抑制胃癌，是二甲双胍的一种新的抗癌机制。本研究从干预胃癌CAF释放的外泌体及蛋白质成分的角度揭示新的抗肿瘤机制，为胃癌的治疗提供新的靶点与策略。本项目共发表论文9篇，其中SCI论文5篇；项目负责人以第一作者或通讯作者发表SCI论文3篇；获得1项国家发明专利和4项国家实用新型专利。