A Cell Type-Specific Cryptic Promoter Drives ERVK-7 Overexpression in Lung Cancer

Human endogenous retroviruses have been implicated to play important roles in health and disease, with recent evidence linking ERVK-7 envelope glycoprotein to immune checkpoint blockade response and prognosis in lung adenocarcinoma (LUAD) patients. However, the mechanisms underlying ERVK-7 regulation remain unclear. We show that the 5' long terminal repeat (LTR) of ERVK-7 is methylated and non-functional, requiring alternative upstream promoters to drive its expression via two novel transcripts, ERVK-7.long and ERVK-7.short. ERVK-7.long is the primary driver of ERVK-7 overexpression in LUAD, with the transcript predominantly active in malignant cells. Epigenetic and single-cell RNA analyses reveal that ERVK-7.long activation is predetermined by cellular origin, with tumor necrosis factor-alpha (TNF-alpha) contributing to its upregulation. Higher levels of ERVK-7 observed in LUAD compared with lung squamous cell carcinoma (LUSC) can be further explained by increased interferon signaling, the key regulator of ERVK-7.short, in LUAD. Our findings uncover the mechanistic basis of ERVK-7 upregulation in LUAD and potential avenues for its use as a therapeutic or diagnostic target in non-small cell lung cancer.

人类内源性逆转录病毒（Human endogenous retroviruses）已被证实于机体健康与疾病进程中发挥重要作用。近期研究证据表明，ERVK-7包膜糖蛋白（ERVK-7 envelope glycoprotein）与肺腺癌（lung adenocarcinoma, LUAD）患者的免疫检查点阻断治疗应答及预后密切相关。然而，ERVK-7的调控机制目前仍不明确。本研究发现，ERVK-7的5'长末端重复序列（5' long terminal repeat, LTR）存在甲基化修饰且丧失功能，因此需要借助其他上游启动子，通过两种新型转录本ERVK-7.long与ERVK-7.short来驱动其表达。ERVK-7.long是肺腺癌中ERVK-7过表达的主要驱动因素，该转录本主要在恶性肿瘤细胞中活跃表达。表观遗传学与单细胞RNA分析结果显示，ERVK-7.long的激活由细胞起源预先决定，而肿瘤坏死因子-α（tumor necrosis factor-alpha, TNF-α）可促进其表达上调。相较于肺鳞状细胞癌（lung squamous cell carcinoma, LUSC），肺腺癌中ERVK-7的表达水平更高，这一现象可进一步由肺腺癌中增强的、作为ERVK-7.short关键调控因子的干扰素信号通路得到解释。本研究揭示了肺腺癌中ERVK-7表达上调的分子机制，同时为其作为非小细胞肺癌治疗或诊断靶点的应用提供了潜在方向。