PVRL4 (or nectin‑4) is a promising therapeutic target since its upregulated expression is found in a wide range of human cancer types. Enfortumab vedotin, an antibody‑drug conjugate targeting PVRL4, is clinically used for the treatment of urothelial bladder cancer. In addition, rMV‑SLAMblind, a genetically engineered oncolytic measles virus, can infect cancer cells and induce apoptosis through interaction with PVRL4. Although PVRL4 transcript levels are elevated in breast, lung and ovarian cancer, the mechanisms of its upregulation have not yet been uncovered. To clarify the regulatory mechanisms of elevated PVRL4 expression in breast cancer cells, Assay for Transposase‑Accessible Chromatin‑sequencing and chromatin immunoprecipitation‑sequencing (ChIP‑seq) data were used to search for its regulatory regions. Using breast cancer cells, an enhancer region was ultimately identified. Additional analyses, including ChIP and reporter assays, demonstrated that FOS interacted with the PVRL4 enhancer region, and that alterations of the FOS‑binding motifs in the enhancer region decreased reporter activity. Consistent with these data, exogenous expression of FOS enhanced the reporter activity and PVRL4 expression in breast cancer cells. Furthermore, RNA‑seq analysis using breast cancer cells treated with PVRL4 small interfering RNA revealed its possible involvement in the cytokine response and immune system. These data suggested that FOS was involved, at least partly, in the regulation of PVRL4 expression in breast cancer cells, and that elevated PVRL4 expression may regulate the response of cancer cells to cytokines and the immune system.

中文翻译：

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PVRL4 是癌症治疗的分子靶标，其表达受 FOS 转录调节。

PVRL4（或 nectin-4）是一个有前途的治疗靶点，因为它在多种人类癌症类型中表达上调。Enfortumab vedotin 是一种靶向 PVRL4 的抗体药物偶联物，临床上用于治疗膀胱尿路上皮癌。此外，rMV-SLAMblind是一种基因工程溶瘤麻疹病毒，可以通过与PVRL4相互作用来感染癌细胞并诱导细胞凋亡。尽管PVRL4转录水平在乳腺癌、肺癌和卵巢癌中升高，但其上调的机制尚未被揭示。为了阐明乳腺癌细胞中PVRL4表达升高的调控机制，使用转座酶可及染色质测序和染色质免疫沉淀测序 (ChIP-seq) 数据来寻找其调控区域。使用乳腺癌细胞，最终确定了增强子区域。其他分析，包括 ChIP 和报告基因检测，证明 FOS 与PVRL4增强子区域相互作用，并且增强子区域中 FOS 结合基序的改变降低了报告基因活性。与这些数据一致，FOS的外源表达增强了乳腺癌细胞中的报告基因活性和PVRL4表达。此外，使用PVRL4小干扰RNA处理的乳腺癌细胞进行的RNA-seq分析揭示了它可能参与细胞因子反应和免疫系统。这些数据表明，FOS 至少部分参与了乳腺癌细胞中PVRL4表达的调节，并且PVRL4表达升高可能调节癌细胞对细胞因子和免疫系统的反应。