miR-30c靶向MTDH调控乳腺浸润性微乳头状癌集团性侵袭转移机制的研究

Invasive micropapillary carcinoma (IMPC) is characterized by a high incidence of invasion and metastasis. Our previous study further confirmed the hypothesis of cluster invasive and metastasis in IMPC of the breast. Through the high-throughput sequencing and methylation chip, we find five miRNAs and 22 candidate genes were differentially expressed in IMPC and invasive ductal carcinoma-not otherwise specified (IDC–NOS).We also find the important matching molecules are miR-30c and MTDH. Through the bioinformatics, we found that miR-30c targeted metadherin (MTDH). Based on the above and the experimental results, we put forward the hypothesis that the lower expression of miR-30c makes the higher expression of MTDH in IMPC, and then influencing the NF-κB-STAT3-MUC1, EMA, SLeX pathways. This may be the cause of the cluster invasive and metastasis of IMPC. Through this research project, we will make miR-30c and MTDH as the basis, NF-κB-STAT3-MUC1, EMA, SLeX pathway as the core, revealing the mechanisms of the cluster invasive and metastasis of IMPC. We may find the key molecules for clinical diagnosis, prognostic markers and new target drugs.

浸润性微乳头状癌（IMPC）是一种高侵袭转移的恶性肿瘤。我们的前期研究进一步证实了“乳腺IMPC肿瘤细胞集团性的侵袭转移”，又通过高通量测序及甲基化芯片筛选出5个低表达的miRNA及22个候选基因，从中发现了与其调控相关的重要配对分子miR-30c和MTDH，并通过生物信息学方法预测证实了miR-30c的靶基因为MTDH。基于以上及预实验结果，我们提出“由于IMPC中miR-30c的低表达使得MTDH表达上调，进而通过影响NF-κB-STAT3-MUC1、EMA、SLeX等通路，导致或促进了IMPC集团性侵袭转移”的研究假说。本次申请立项研究，我们主要将以miR-30c和MTDH为基点，以NF-κB-STAT3-MUC1、EMA、SLeX通路为核心，研究揭示乳腺IMPC集团性侵袭转移的分子机制、发现关键分子，为临床诊断和预后预测提供标志物及治疗研究靶点。

乳腺浸润性微乳头状癌（Invasive micropapillary carcinoma，IMPC）是一种特殊的乳腺癌病理组织学类型，具有极性倒转的微乳头状簇细胞集团性生长模式、高侵袭/转移的生物学特性。课题组研究发现：在IMPC中miR-30c靶向调控MTDH，进而通过影响NF-κB-STAT3-MUC1、EMA、SLeX等通路，导致IMPC极性倒转和集团性侵袭转移。IMPC细胞在细胞膜（微乳头簇的面向间质侧表面）表达唾液酸化的Lewis X（sLex）和MUC1/EMA，且SLex在IMPC细胞膜的高表达还与不良预后密切相关，与MUC1/EMA联合检测可作为IMPC诊断及预后预测指标；发现IMPC的8q24区域PSCA基因扩增及过表达，并与IMPC复发和转移密切相关，检测PSCA蛋白和基因扩增可进一步预测IMPC患者的预后；从基因组学角度揭示了乳腺IMPC肿瘤细胞团的基因组学特征及空间演化关系。纯型IMPC和混合型IMPC-IDC的基因组拷贝数变异存在显著差异。鉴定出肿瘤转移种子基因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；并研究证实了术前新辅助化疗（neoadjuvant chemotherapy，NAC）对IMPC的治疗效果不明显，支持我们前期研究提出的对IMPC要尽快的手术的治疗原则。总之，我们在研究IMPC机制的同时鉴定出了多个与IMPC 肿瘤细胞生长、侵袭转移和极性倒转相关的候选基因，并与临床病理学特征相结合，研究其与IMPC发生、发展的关系，为IMPC的精准诊断和治疗提供理论和实践依据，为后续研究奠定了良好的基础。