Ovine pulmonary adenocarcinoma (OPA) is a chronic respiratory disease of sheep caused by jaagsiekte sheep retrovirus (JSRV). JSRV infects respiratory epithelial cells and initiates tumor growth. OPA is an important economic and welfare issue for sheep farmers but is also considered to be a valuable animal model for human lung adenocarcinoma. In this study, whole transcriptome profiling was performed on lung samples derived from JSRV-infected and uninfected lambs using RNA-seq.. Transcriptional Response of Ovine Lung to Infection with Jaagsiekte Sheep Retrovirus

Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of ovine pulmonary adenocarcinoma (OPA), a neoplastic lung disease of sheep. OPA is an important economic and welfare issue for sheep farmers and a valuable naturally occurring animal model for human lung adenocarcinoma. Here, we used RNA sequencing to study the transcriptional response of ovine lung tissue to infection by JSRV. We identified 1,971 ovine genes differentially expressed in JSRV-infected lung compared to noninfected lung, including many genes with roles in carcinogenesis and immunomodulation. The differential expression of selected genes was confirmed using immunohistochemistry and reverse transcription-quantitative PCR. A key finding was the activation of anterior gradient 2, yes-associated protein 1, and amphiregulin in OPA tumor cells, indicating a role for this oncogenic pathway in OPA. In addition, there was differential expression of genes related to innate immunity, including genes encoding cytokines, chemokines, and complement system proteins. In contrast, there was little evidence for the upregulation of genes involved in T-cell immunity. Many genes related to macrophage function were also differentially expressed, reflecting the increased abundance of these cells in OPA-affected lung tissue. Comparison of the genes differentially regulated in OPA with the transcriptional changes occurring in human lung cancer revealed important similarities and differences between OPA and human lung adenocarcinoma. This study provides valuable new information on the pathogenesis of OPA and strengthens the use of this naturally occurring animal model for human lung adenocarcinoma.

绵羊肺腺瘤病毒（Jaagsiekte sheep retrovirus, JSRV）是绵羊肺腺瘤病（ovine pulmonary adenocarcinoma, OPA）的致病因子，该病是一类发生于绵羊的肿瘤性肺部疾病。绵羊肺腺瘤病不仅是养羊产业中亟待解决的重要经济与福利问题，同时也是人类肺腺癌研究的珍贵天然动物模型。本研究采用RNA测序（RNA sequencing）技术，分析绵羊肺组织感染JSRV后的转录应答特征。结果显示，与未感染的肺组织相比，JSRV感染的肺组织中共计1971个绵羊基因呈现差异表达，其中诸多基因参与肿瘤发生与免疫调控过程。研究团队通过免疫组化（immunohistochemistry）与逆转录定量PCR（reverse transcription-quantitative PCR）验证了部分筛选基因的差异表达情况。一项核心发现为：前部梯度蛋白2、Yes相关蛋白1及双调蛋白在OPA肿瘤细胞中被激活，提示该致癌通路在OPA发病机制中发挥关键作用。此外，固有免疫相关基因的表达亦存在显著差异，包括编码细胞因子、趋化因子及补体系统蛋白的基因。与之形成对比的是，几乎未观测到T细胞免疫相关基因的上调现象。诸多与巨噬细胞功能相关的基因同样呈现差异表达，这反映出OPA受累肺组织中巨噬细胞的丰度显著升高。将OPA中差异调控的基因与人类肺癌的转录变化进行比对后，研究团队发现OPA与人类肺腺癌之间存在诸多重要的相似性与差异。本研究为OPA的发病机制提供了全新的宝贵研究数据，同时进一步强化了该天然动物模型在人类肺腺癌研究中的应用价值。