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The Concomitant Expression of Human Endogenous Retroviruses and Embryonic Genes in Cancer Cells under Microenvironmental Changes is a Potential Target for Antiretroviral Drugs
Cancer Microenvironment Pub Date : 2019-11-05 , DOI: 10.1007/s12307-019-00231-3
Alessandro Giovinazzo 1 , Emanuela Balestrieri 1 , Vita Petrone 1 , Ayele Argaw-Denboba 2 , Chiara Cipriani 1, 3 , Martino Tony Miele 1 , Sandro Grelli 1 , Paola Sinibaldi-Vallebona 1, 4 , Claudia Matteucci 1
Affiliation  

In our genomes there are thousands of copies of human endogenous retroviruses (HERVs) originated from the integration of exogenous retroviruses that infected germ line cells millions of years ago, and currently an altered expression of this elements has been associated to the onset, progression and acquisition of aggressiveness features of many cancers. The transcriptional reactivation of HERVs is mainly an effect of their responsiveness to some factors in cell microenvironment, such as nutrients, hormones and cytokines. We have already demonstrated that, under pressure of microenvironmental changes, HERV-K (HML-2) activation is required to maintain human melanoma cell plasticity and CD133+ cancer stem cells survival. In the present study, the transcriptional activity of HERV-K (HML-2), HERV-H, CD133 and the embryonic transcription factors OCT4, NANOG and SOX2 was evaluated during the in vitro treatment with antiretroviral drugs in cells from melanoma, liver and lung cancers exposed to microenvironmental changes. The exposure to stem cell medium induced a phenotype switching with the generation of sphere-like aggregates, characterized by the concomitant increase of HERV-K (HML-2) and HERV-H, CD133 and embryonic genes transcriptional activity. Although with heterogenic response among the different cell lines, the in vitro treatment with antiretroviral drugs affected HERVs transcriptional activity in parallel with the reduction of CD133 and embryonic genes expression, clonogenic activity and cell growth, accompanied by the induction of apoptosis. The responsiveness to antiretroviral drugs treatment of cancer cells with stemness features and expressing HERVs suggests the use of these drugs as innovative approach to treat aggressive tumours in combination with chemotherapeutic/radiotherapy regimens.



中文翻译:

微环境变化下人内源性逆转录病毒和胚胎基因在癌细胞中的伴随表达是抗逆转录病毒药物的潜在靶点

在我们的基因组中,有数千个人类内源性逆转录病毒(HERV)拷贝,这些拷贝源自数百万年前感染生殖系细胞的外源逆转录病毒的整合,目前该元件的表达改变与发病、进展和获得有关。许多癌症的侵袭性特征。 HERV的转录再激活主要是其对细胞微环境中的一些因素,如营养物质、激素和细胞因子的反应的影响。我们已经证明,在微环境变化的压力下,HERV-K (HML-2) 激活是维持人类黑色素瘤细胞可塑性和 CD133+ 癌症干细胞存活所必需的。在本研究中,在体外用抗逆转录病毒药物治疗黑色素瘤、肝脏和肝癌细胞期间,评估了 HERV-K (HML-2)、HERV-H、CD133 以及胚胎转录因子 OCT4、NANOG 和 SOX2 的转录活性。肺癌暴露于微环境变化。暴露于干细胞培养基诱导表型转换,产生球状聚集体,其特征是 HERV-K (HML-2) 和 HERV-H、CD133 和胚胎基因转录活性随之增加。尽管不同细胞系之间存在异质反应,但体外抗逆转录病毒药物治疗会影响 HERV 转录活性,同时降低 CD133 和胚胎基因表达、克隆形成活性和细胞生长,并诱导细胞凋亡。具有干细胞特征和表达 HERV 的癌细胞对抗逆转录病毒药物治疗的反应表明,使用这些药物作为创新方法,与化疗/放疗方案相结合,治疗侵袭性肿瘤。

更新日期:2019-11-05
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