骨髓中间充质干细胞分泌的exosome中miR-221在胃癌卵巢转移中的作用及分子机制研究

Bone marrow mesenchymal stem cells (BM-MSCs) contribute to tumor microenvironment and promote tumorigenesis and metastasis. Gastric cancer (GC) is a main disease in China. Our presously found MSC-like cells could be extracted and isolated from primary tumor and metastasis tissues of ovarian metastasis of GC (Krukenberg tumor). Further researches showed that serum exosomal miR-221 is a novel diagnostic and prognostic biomarker for ovarian metastasis of GC. However, the precise role and mechanisms of is unclear on role and molecular mechanism of exosomal miR-221 from BM-MSCs in ovarian metastasis of GC. So, to define the role and its mechanisms, this study is to explore the BM-MSCs implantion in small mice, and observe the role of exosomal miR-221 from BM-MSCs in microenvironment to initinate cancer metastasis; The experiment is to study signal pathway regulation and metastatic relationship between exosomal miR-221 gene of BM-MSCs and cancer cell, and is to establish the cellular expression vector of exosomal miR-221 gene of BM-MSCs. Furthermore, this study includd verifying the effect of anti-cancer metastasis by suppressing exosomal miR-221 pathway of BM-MSCs in small mice.The aim of this study to provide theory new evidences and improve clinical effects of GC metastasis.

骨髓间充质干细胞(Bone marrow mesenchymal stem cells， BM-MSCs)有助于肿瘤微环境的形成和促进肿瘤发生发展和转移。胃癌是我国重大疾病，我们前期研究分离培育出了胃癌卵巢转移（库肯勃瘤）的原发灶及转移灶中间充质干细胞样细胞。进而发现血浆中外分泌体miR-221可作为其的诊断和预后的重要生物学指标。但BM-MSCs分泌的外分泌体含的miR-221在胃癌卵巢转移的作用及机制未明。为明确它。本研究拟建立BM-MSCs小鼠移植模型，观察其分泌的外分泌体中的miR-221在体内构建微环境对癌细胞转移的促进作用；研究BM-MSCs分泌的外分泌体中miR-221和癌细胞间信号途径的调节和转移的关系。构建BM-MSCs的外分泌体中的miR-221基因的细胞表达载体，在小鼠胃癌卵巢转移模型上验证其抑制外分泌体中的miR-221途径后抗癌转移效应。为胃癌转移治疗提供新理论。

骨髓间充质干细胞(Bone marrow mesenchymal stem cells， BM-MSCs)有助于肿瘤微环境的形成和促进肿瘤发生发展和转移。胃癌是我国重大疾病，我们前期研究分离培育出了胃癌卵巢转移（库肯勃瘤）的原发灶及转移灶中间充质干细胞样细胞。进而发现血浆中外分泌体miR-221可作为其的诊断和预后的重要生物学指标。我们从研究中发现，miR-221在外周血外泌体中的表达在GC中显著上调，miR-221的表达还可以通过体外转染得到有效的调控。我们还发现从BM-MSCs中提取的外泌体miR-221能加速GC细胞增殖、可以有效促进GC细胞迁移、侵袭和粘附到基质上。在外泌体中存在足够数量的miR-221模拟物和抑制剂，有效促进了GC细胞的致癌活性。及时检测外泌体miR-221可能对GC的早期诊断非常有价值。此外，外周血中的外泌体可以被开发为调节miR-221的体内表达的纳米载体。miR-221在外周血外泌体中的受控表达可能有助于将来缓解和治疗GC。