多潜能因子Lin28在乳腺癌转移中的作用和机制研究

转移是乳腺癌最主要的死亡原因。上皮-间质转分化 (epithelial-mesenchymal transition, EMT)是肿瘤原位迁移和侵袭的重要机制，但是转移灶细胞多见上皮表型，提示EMT以外机制参与。新近研究表明，EMT的逆转(MET)是肿瘤远处定植(colonization)和生长的关键所在。Lin28是功能保守的RNA结合蛋白，在胚胎干细胞表达最为丰富，对干细胞生存和多潜能维持十分必要。临床资料显示，其在肿瘤转移期显著高表达。我们前期实验发现：Lin28的表达增强细胞上皮特征，抑制间质特征，反之亦然，推测其促MET作用。本实验拟通过3D基质胶和乳腺球等体外实验，在细胞水平阐明其促MET和促干性作用在乳腺癌侵袭转移中的协同作用关系和分子机制；进一步通过裸鼠脂肪垫原位移植和尾静脉注射方法，在体明确Lin28在肿瘤转移中的作用。预期为整体干预乳腺癌转移提供新的靶点。

Metastasis causes most deaths of breast carcinomas. Epithelial-mesenchymal transition (EMT) plays a crucial role in the migration and invasion of the primary tumors. However, distant metastases present an epithelial morphology, suggesting mechanism other than EMT is involved in metastasis. Recent studies revealed that reversible EMT (MET) is essential for disseminated tumor cells to colonize and proliferate and to form macrometastases. Lin28, which is an evolutionarily conserved RNA binding protein abundantly expressed in embryonic stem cells and is necessary for stem cell viability and pluripotency. Clinical data indicated that Lin28 overexpression is associated with advanced disease in multiple tumor types. Our results have showed that overexpression of Lin28 can strengthen the epithelial characteristic and restrain the mesenchymal feature for mammary epithelial cells and vice versa, suggesting Lin28 promotes MET. Here, we will confirm the roles of Lin28 in promoting MET and the acquisition of stem cell properties in breast tumor cells by means of 3D matrigel culture and mammosphere formation assay in vitro. Moreover, we will validate the effect of Lin28 for breast tumor distal metastasis in vivo via nude mammary fat pad graft and tail vein injection. These observations will bring valuable object for breast metastasis treatment.