Esophageal squamous cell carcinoma (ESCC) is an aggressive epithelial malignancy with poor prognosis. Interestingly, ESCC is strongly characterized by a male-predominant propensity. Our previous study showed that androgen receptor (AR) orchestrated a transcriptional repression program to promote ESCC growth, but it remains unclear whether AR can also activate oncogenic signaling during ESCC progression. In this study, by analyzing our previous AR cistromes and androgen-regulated transcriptomes, we identified uridine diphosphate glucuronosyltransferase family 2 member B15 (UGT2B15) as a bona fide target gene of AR. Mechanistically, AP-1 cofactors played important and collaborative roles in AR-mediatedUGT2B15upregulation. Functional studies have revealed that UGT2B15 promoted invasiveness in vitro and lymph node metastasis in vivo. UGT2B15 was partially responsible for the AR-induced invasive phenotype in ESCC cells. Importantly, simultaneous blocking of AP-1 and AR resulted in stronger inhibition of cell invasiveness compared to inhibiting AP-1 or AR alone. In conclusion, our study reveals the molecular mechanisms underlying the AR-driven ESCC invasion and suggests that the AR/AP1/UGT2B15 transcriptional axis can be potentially targeted in suppressing metastasis in male ESCC patients.
食管鳞状细胞癌（ESCC）是一种侵袭性上皮恶性肿瘤，预后较差。值得注意的是，该疾病具有显著的男性高发倾向。我们先前的研究表明，雄激素受体（AR）通过调控转录抑制程序促进ESCC生长，但AR是否在ESCC进展过程中也能激活致癌信号尚不明确。本研究通过分析既往AR顺式作用组及雄激素调控转录组数据，发现尿苷二磷酸葡萄糖醛酸转移酶家族2成员B15（UGT2B15）是AR的直接靶基因。机制研究表明，AP-1辅助因子在AR介导的UGT2B15上调过程中发挥重要协同作用。功能实验证实，UGT2B15在体外能促进细胞侵袭能力，在体内可加速淋巴结转移。UGT2B15部分介导了AR诱导的ESCC细胞侵袭表型。值得注意的是，同时阻断AP-1与AR对细胞侵袭能力的抑制作用显著强于单独抑制AP-1或AR。本研究揭示了AR驱动ESCC侵袭的分子机制，提示AR/AP1/UGT2B15转录轴可能成为抑制男性ESCC患者转移的潜在治疗靶点。
肿瘤(癌症)患者之家