骨髓间充质干细胞源性外泌体通过miRNA141调控乳腺癌细胞休眠的机制研究

Recurrence is the leading cause of death in breast cancer. To elucidate the mechanisms of breast cancer cell dormancy maintenance and recovery and to develop novel drugs targeting dormant tumor cells are the key to improving the prognosis of breast cancer patients and also a difficult problem need to be solved as soon as possible. Mesenchymal stem cells in the bone marrow microenvironment are believed to be the major component of communication with breast cancer cells. Our previous study found that BM-MSCs-derived exosomes can affect the dormant state of metastatic breast cancer cells. miR-141 is highly expressed in bone marrow mesenchymal stem cell-derived exosomes and is involved in the regulation of cell cycle arrest. Based on this, we hypothesize that miR-141 delivered by BM-MSCs derived exosomes may induce breast cancer cell dormancy by regulating downstream gene expression. This study, from the three aspects of cell-animal-clinical samples, intends to explore in depth the relationship between miR-141 transport by BM-MSCs derived exosomes and dormancy of breast cancer and possible mechanisms through the expression of correlation experiments, functional recovery experiments and cancer tissue specimens. Cell proliferation, drug sensitivity, immunohistochemistry and other methods was used. In this study, miRNAs secreted from exosomes will provide a new idea for revealing the mechanism of dormancy in breast cancer cells for the prevention and treatment of breast cancer recurrence.

乳腺癌细胞休眠维持和复苏是乳腺癌复发的主要原因，研发针对休眠肿瘤细胞的新型药物，是改善乳腺癌患者预后的关键所在，也是临床上亟待解决的难题。骨髓间充质干细胞（BM-MSCs）被认为是骨髓微环境中与乳腺癌细胞发生交流的主要成分。我们的前期研究发现BM-MSCs源性外泌体能影响转移性乳腺癌细胞的休眠状态；miR-141高表达于骨髓间充质干细胞源性外泌体，同时参与调控了细胞周期阻滞。据此我们提出假说：BM-MSCs源性外泌体传递的miR-141可能通过调控下游基因表达诱导了乳腺癌细胞休眠。本研究拟从细胞-动物-临床样本三个层面，通过表达相关性实验，功能回复实验和癌组织标本，以细胞增殖，药物敏感性和免疫组化等方法，深入探索BM-MSCs源性外泌体转运的miR-141与乳腺癌休眠的关系以及可能的机制。本研究将从外泌体分泌的miRNA这个新视点为揭示乳腺癌细胞休眠发生机制，为乳腺癌复发的防治提供新思路。

骨是乳腺癌最常见的转移器官。阐明乳腺癌骨转移的分子机制对乳腺癌治疗有重要意义。肿瘤细胞源性外泌体被证明可促进癌症进展，但其在乳腺癌骨转移中的作用尚不清楚。我们研究发现miR-6739-5p在乳腺癌骨转移血清外泌体中下调并可调控肿瘤细胞功能；miR-6739-5p下游靶基因MAT2A是S-腺苷甲硫氨酸（SAM）合成限速酶；SAM循环通路可调节癌细胞的表观遗传状态并驱动肿瘤发生。据此我们提出假说：肿瘤细胞源性外泌体递送miR-6739-5p靶向MAT2A调控SAM合成介导乳腺癌骨转移。本研究拟从细胞、动物和临床样本三个层面，通过miRNA-seq分析、生信软件预测结合表达相关性、细胞功能、功能回复和分子互作等实验方法，探索肿瘤细胞源性外泌体miR-6739-5p在乳腺癌骨转移中的作用及机制。本研究将从外泌体转运的 miRNA 这个新视点为揭示乳腺癌骨转移发生机制为乳腺癌转移和复发的防治提供新思路。目前已进行的研究初步证实了以上假说。