IMPC极性倒转和集团性侵袭转移作用机制的深入研究

Invasive micropapillary carcinoma (IMPC) characterized by a special growth pattern of reversed polarity cell clusters and high propensity for lymphovascular invasion and lymph node metastasis, could occur in various organs. IMPC of breast is the histologic type that we’ve been studying for years continuously. We have proved that miR-30c/MTDH could mediates the polarity reversal and cluster of invasive and metastasis in IMPC through NF-κB signal pathway; and our recent study also indicated miR-30c/MTDH may also simultaneously regulate the Wnt/β-catenin signal pathway in IMPC. Hereby, we have our new hypothesis that miR-30c/MTDH could regulates the Wnt/β-catenin signal pathway as well as NF-κB signal pathway , and as the up-stream gene of miR-30c/MTDH, miR-27/GATA3 could be a potential driver gene for the polarity reversal and cluster of invasive and metastasis in IMPC. Base on above, we will focus on the miR-27/GATA3- miR-30c/MTDH - Wnt/β-catenin axis to verify our new discovery in IMPC of breast. Our results will provide comprehensive analysis the mechanism of the cluster invasive and metastasis of IMPC. Completion this project will identify the key molecular-drivers and provide theoretical and practical basis for the accurate diagnosis and treatment of IMPC.

浸润性微乳头状癌（Invasive micropapillary carcinoma, IMPC）是一种高淋巴管侵袭、高淋巴结转移的恶性肿瘤，可发生于身体多个器官。乳腺IMPC是我们多年来持续研究的肿瘤。我们在证明了miR-30c/MTDH介导NF-κB促使IMPC集团性、高侵袭转移的同时，新近发现miR-30c/MTDH还可能同时调控的另一条通路（Wnt/β-catenin）、及导致IMPC集团性侵袭转移的源头基因miR-27/GATA3。基于此，我们将继续以IMPC为对象，以miR-27/GATA3、Wnt/β-catenin信号通路为核心，研究验证我们的新发现。研究结果将为全面解析IMPC集团性侵袭转移的作用机制，为IMPC的精准诊治提供实验依据和靶点分子。

本课题通过对乳腺浸润性微乳头状癌（IMPC，Invasive micropapillary carcinoma）极性倒转和集团性侵袭、转移机制的深入机制研究，发现了β-catenin虽然在IMPC的细胞质中高表达、在胞膜低表达，但并不是激活Wnt信号通路促进IMPC极性倒转与集团性侵袭的主要原因。提示β-catenin在细胞质中的积累可能通过其他途径激活IMPC肿瘤细胞极性倒转和侵袭转移。进而，反向地证实了我们的研究设想——“IMPC中β-catenin可能不通过激活Wnt信号通路发挥作用”；继之，我们从基因组学角度研究揭示了乳腺IMPC肿瘤细胞团的基因组学特征及空间演化关系。发现纯型IMPC和混合型IMPC-IDC的基因组拷贝数变异存在显著差异。发现肿瘤转移种子基因IGSF9和PRDM16低表达或不表达/ALDH2高表达与IMPC及其他类型乳腺癌的淋巴结转移及不良预后密切相关。进一步地深入解析了IMPC“集团性生长侵袭转移”特殊形态学特征及生物学行为的分子基础，为IMPC的诊治提供了新的分子研究靶点，为后续深入研究提供了良好的支持。