Meseure Didier, Vacher Sophie, Boudjemaa Sabah, Laé Marick, Nicolas André, Leclere Renaud, Chemlali Walid, Champenois Gabriel, Schnitzler Anne, Lesage Laetitia, Dubois Thierry, Bieche Ivan
Unit of Pharmacogenomics, Department of Genetics, Institut Curie, 75005 Paris, France.
Platform of Experimental Pathology PATHEX, Institut Curie, 75005 Paris, France.
Cancers (Basel). 2020 Sep 30;12(10):2833. doi: 10.3390/cancers12102833.
The PIWI proteins emerging in the development of human cancers, edify PIWI-piRNA ribonucleoproteic complexes acting as pivotal regulators of genome integrity, differentiation and homeostasis. The aim of this study is to analyze the four PIWILs gene expression in invasive breast carcinomas (IBCs): at RNA level using quantitative RT-PCR ( = 526) and protein level using immunohistochemistry ( = 150). In normal breast tissue, PIWILs 2 and 4 were solely expressed, whereas an abnormal emergence of PIWIL1 and 3 was observed in respectively 30% and 6% of IBCs. Conversely, PIWIL2 was underexpressed in 48.3% and PIWIL4 downregulated in 43.3% of IBCs. Significant positive associations were observed between PIWIL4 underexpression, HR+ status and HR+ ERBB2+ molecular subtype and PIWIL2 underexpression, PR- status, ERBB2- status and molecular subtype. Similar patterns of PIWIL deregulation were observed in a multitumoral panel, suggesting a generic mechanism in most cancers. PIWIL2-4 underexpression was mainly regulated at epigenetic or post-transcriptional levels. PIWIL2 underexpression was significantly associated with DNA methylation and strong cytotoxic immune response. PIWIL2-4 were mainly associated with genes implicated in cell proliferation. As a result of this study, characterization of the PIWIL-piRNA pathway in IBCs opens interesting therapeutic perspectives using piRNAs, hypomethylating drugs, checkpoints immunotherapies and anti-PIWIL 1-3 antibodies.
PIWI蛋白在人类癌症发展过程中出现，形成了PIWI-piRNA核糖核蛋白复合物，这些复合物是基因组完整性、分化和稳态的关键调节因子。本研究的目的是分析浸润性乳腺癌（IBC）中四种PIWIL基因的表达：在RNA水平上使用定量RT-PCR（n = 526），在蛋白质水平上使用免疫组织化学（n = 150）。在正常乳腺组织中，仅表达PIWIL2和4，而在30%的IBC中分别观察到PIWIL1异常出现，在6%的IBC中观察到PIWIL3异常出现。相反，48.3%的IBC中PIWIL2表达不足，43.3%的IBC中PIWIL4下调。PIWIL4表达不足、HR+状态和HR+ ERBB2+分子亚型之间以及PIWIL2表达不足、PR-状态、ERBB2-状态和分子亚型之间观察到显著的正相关。在多肿瘤组中观察到类似的PIWIL失调模式，表明在大多数癌症中存在一种普遍机制。PIWIL2-4表达不足主要在表观遗传或转录后水平受到调节。PIWIL2表达不足与DNA甲基化和强烈的细胞毒性免疫反应显著相关。PIWIL2-4主要与参与细胞增殖的基因相关。这项研究的结果表明，IBC中PIWIL-piRNA途径的特征为使用piRNA、去甲基化药物、检查点免疫疗法和抗PIWIL 1-3抗体开辟了有趣的治疗前景。
