Curty Gislaine, Beckerle Greta A, Iñiguez Luis P, Furler Robert L, de Carvalho Pedro S, Marston Jez L, Champiat Stephane, Heymann Jonas J, Ormsby Christopher E, Reyes-Terán Gustavo, Soares Marcelo A, Nixon Douglas F, Bendall Matthew L, Leal Fabio E, de Mulder Rougvie Miguel
Oncovirology Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, United States.
Front Oncol. 2020 Oct 22;10:553983. doi: 10.3389/fonc.2020.553983. eCollection 2020.
In people living with HIV (PLWH), chronic inflammation can lead to cancer initiation and progression, besides driving a dysregulated and diminished immune responsiveness. HIV infection also leads to increased transcription of Human Endogenous Retroviruses (HERVs), which could increase an inflammatory environment and create a tumor growth suppressive environment with high expression of pro-inflammatory cytokines. In order to determine the impact of HIV infection to HERV expression on the breast cancer microenvironment, we sequenced total RNA from formalin-fixed paraffin-embedded (FFPE) breast cancer samples of women HIV-negative and HIV-positive for transcriptome and retrotranscriptome analyses. We performed RNA extraction from FFPE samples, library preparation and total RNA sequencing (RNA-seq). The RNA-seq analysis shows 185 differentially expressed genes: 181 host genes (178 upregulated and three downregulated) and four upregulated HERV transcripts in HIV-positive samples. We also explored the impact of HERV expression in its neighboring breast cancer development genes (//) and in long non-coding RNA expression (AC060780.1, also known as RP11-242D8.1). We found a significant positive association of HERV expression with and with AC060780.1, which suggest a possible role of HERV in regulating breast cancer genes from PLWH with breast cancer. In addition, we found immune system, extracellular matrix organization and metabolic signaling genes upregulated in HIV-positive breast cancer. In conclusion, our findings provide evidence of transcriptional and retrotranscriptional changes in breast cancer from PLWH compared to non-HIV breast cancer, including dysregulation of HERVs, suggesting an indirect effect of the virus on the breast cancer microenvironment.
在感染人类免疫缺陷病毒（HIV）的人群（PLWH）中，慢性炎症除了会导致免疫反应失调和减弱外，还会引发癌症的起始和进展。HIV感染还会导致人类内源性逆转录病毒（HERV）转录增加，这可能会加剧炎症环境，并通过促炎细胞因子的高表达营造出肿瘤生长抑制环境。为了确定HIV感染对HERV在乳腺癌微环境中表达的影响，我们对HIV阴性和HIV阳性女性的福尔马林固定石蜡包埋（FFPE）乳腺癌样本的总RNA进行了测序，以进行转录组和逆转录组分析。我们从FFPE样本中提取RNA，进行文库制备和总RNA测序（RNA-seq）。RNA-seq分析显示有185个差异表达基因：181个宿主基因（178个上调，3个下调）以及HIV阳性样本中4个上调的HERV转录本。我们还探究了HERV表达对其邻近的乳腺癌发育基因（//）以及长链非编码RNA表达（AC060780.1，也称为RP11 - 242D8.1）的影响。我们发现HERV表达与 和AC060780.1之间存在显著正相关，这表明HERV在调节患有乳腺癌的PLWH的乳腺癌基因方面可能发挥作用。此外，我们发现HIV阳性乳腺癌中免疫系统、细胞外基质组织和代谢信号基因上调。总之，我们的研究结果提供了证据，表明与非HIV乳腺癌相比，PLWH的乳腺癌存在转录和逆转录变化，包括HERV失调，这表明病毒对乳腺癌微环境有间接影响。
