Identification and characterisation of the expression, regulation and function as well as the clinical relevance of HLA-G regulatory microRNAs in solid tumors

非经典的人类白细胞抗原-G分子经常在不同来源的人类肿瘤中过度表达。人类白细胞抗原-G阳性细胞通过与不同免疫效应细胞受体的相互作用，逃避T细胞和NK细胞的免疫监视。人类白细胞抗原G的异常表达是由不同的分子机制介导的，如表观遗传、转录和转录后调控。最近，一些人类白细胞抗原G特异的microRNAs被发现，它们可以下调人类白细胞抗原G的表达，从而调节抗病毒和抗肿瘤的免疫反应。本项目的目的是(I)系统地鉴定调节肿瘤中构成和调控的人类microRNAs的全谱，(Ii)确定其表达模式，(Iii)调节，(Iv)这些特定于人的microRNAs的功能，以及(V)确定它们在不同组织学肿瘤中的临床相关性及其与免疫细胞浸润的关系。(Vi)此外，将在体外和体内使用人类白细胞抗原-G调节miRs/抗核抗体来操纵肿瘤的人类白细胞抗原-G的表达，并测试其抗肿瘤活性。该项目将有助于增加对人类白细胞抗原G调节microRNAs作为治疗人类白细胞抗原G表达肿瘤的新策略的认识。

The non-classical HLA-G molecule is frequently overexpressed in human tumors of distinct origin. By interaction with different receptors of immune effector cells HLA-G-positive cells escape immune surveillance by T and NK cells. This aberrant expression of HLA-G is mediated by distinct molecular mechanisms, such as epigenetic, transcriptional and post-transcriptional control. Recently, some HLA-G specific microRNAs have been identified, which downregulate the expression of HLA-G thereby modulating the anti-viral and anti-tumoral immune response. The aim of this project is to (i) systematically identify the whole spectrum of human microRNAs, which modulate the constitutive and regulated HLA-G expression in tumors, (ii) to characterize the expression pattern, (iii) the regulation, and (iv) the function of these HLA-G specific microRNAs as well as to (v) determine their clinical relevance in tumors of distinct histology and its correlation with the immune cell infiltration. (vi) In addition, the HLA-G expression of tumors will be manipulated in vitro and in vivo using HLA-G regulating miRs/antagomiRs and tested for their anti-tumoral activity. This project will contribute to an increased knowledge of HLA-G regulatory microRNAs as novel strategy for the treatment of HLA-G expressing tumors.