Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, 9 Dublin, Ireland.
Data Science Centre, Royal College of Surgeons in Ireland, 2 Dublin, Ireland.
Cells. 2022 Feb 19;11(4):735. doi: 10.3390/cells11040735.
Overexpression of the human epidermal growth factor receptor-2 (HER2) is associated with aggressive disease in breast and certain other cancers. At a cellular level, the adhesion protein Junctional Adhesion Molecule-A (JAM-A) has been reported to regulate the expression of HER3 via a transcriptional pathway involving FOXA1. Since FOXA1 is also a suggested transcription factor for HER2, this study set out to determine if JAM-A regulates HER2 expression via a similar mechanism. An integrated tripartite approach was taken, involving cellular expression studies after targeted disruption of individual players in the putative pathway, in silico identification of relevant HER2 promoter regions and, finally, interrogation of cancer patient survival databases to deconstruct functionally important links between HER2, JAM-A and FOXA1 gene expression. The outcome of these investigations revealed a unidirectional pathway in which JAM-A expression transcriptionally regulates that of HER2 by influencing the binding of FOXA1 to a specific site in the HER2 gene promoter. Moreover, a correlation between JAM-A and HER2 gene expression was identified in 75% of a sample of 40 cancer types from The Cancer Genome Atlas, and coincident high mean mRNA expression of JAM-A, HER2 and FOXA1 was associated with poorer survival outcomes in HER2-positive (but not HER2-negative) patients with either breast or gastric tumors. These investigations provide the first evidence of a transcriptional pathway linking JAM-A, HER2 and FOXA1 in cancer settings, and support potential future pharmacological targeting of JAM-A as an upstream regulator of HER2.
人表皮生长因子受体 2（HER2）的过度表达与乳腺癌和某些其他癌症的侵袭性疾病有关。在细胞水平上，黏附蛋白连接黏附分子-A（JAM-A）已被报道通过涉及 FOXA1 的转录途径调节 HER3 的表达。由于 FOXA1 也是 HER2 的一个建议转录因子，因此本研究旨在确定 JAM-A 是否通过类似的机制调节 HER2 表达。采用了一种综合的三方方法，涉及在假定途径中靶向破坏单个参与者后的细胞表达研究、HER2 启动子区域的计算机识别，以及最后对癌症患者生存数据库的询问，以解构 HER2、JAM-A 和 FOXA1 基因表达之间的功能重要联系。这些研究的结果揭示了一个单向途径，其中 JAM-A 表达通过影响 FOXA1 与 HER2 基因启动子中特定位点的结合来转录调节 HER2 的表达。此外，在癌症基因组图谱中 40 种癌症类型的样本中，有 75%的样本中鉴定出 JAM-A 和 HER2 基因表达之间存在相关性，而在 HER2 阳性（但不是 HER2 阴性）的乳腺癌或胃癌患者中，JAM-A、HER2 和 FOXA1 的平均 mRNA 表达水平较高，且生存结果较差。这些研究首次提供了在癌症环境中连接 JAM-A、HER2 和 FOXA1 的转录途径的证据，并支持未来针对 JAM-A 的潜在药理学靶向作为 HER2 的上游调节剂。
