Liaoning Provincial Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang City, China.
Department of Medical Bioscience, Building 6M, Umeå University, Umeå, Sweden.
Int J Cancer. 2024 May 15;154(10):1814-1827. doi: 10.1002/ijc.34856. Epub 2024 Jan 28.
Adenoid cystic carcinoma (ACC) and basal cell adenoma (BCA) share many histological characteristics and often need a differential diagnosis in clinical pathology. Recently, we found homeobox protein engrailed-1 (EN1) was a potential diagnostic marker for ACC in an organoids library of salivary gland tumors (SGTs). Here we aim to confirm EN1 as a differential diagnostic marker for ACC, and further investigate the regulatory mechanism and biological function of EN1 in tumor progression. The transcriptional analysis, quantitative polymerase chain reaction, Western blot and immunohistochemistry staining were performed and revealed that EN1 was specifically and highly expressed in ACC, and accurately differentiated ACC from BCA. Furthermore, TGFβ signaling pathway was found associated with ACC, and the regulation of EN1 through TGFβ was detected in the human ACC cell lines and patient-derived organoids (PDOs). TGFβ-induced EN1 was important in promoting tumor budding in the PDOs model. Interestingly, a high level of EN1 and TGFβ1 in the budding tips was observed in ACC clinical samples, and the expression of EN1 and TGFβ1 in ACC was significantly associated with the clinical stage. In summary, our study verified EN1 is a good diagnostic marker to differentiate ACC from BCA. TGFβ-induced EN1 facilitates the tumor budding of ACC, which might be an important mechanism related to the malignant phenotype of ACC.
腺样囊性癌 (ACC) 和基底细胞腺瘤 (BCA) 在组织学上具有许多相似特征，临床病理中常需要进行鉴别诊断。最近，我们在唾液腺肿瘤 (SGT) 的类器官文库中发现同源盒蛋白 engrailed-1 (EN1) 是 ACC 的潜在诊断标志物。在此，我们旨在证实 EN1 是 ACC 的鉴别诊断标志物，并进一步研究 EN1 在肿瘤进展中的调控机制和生物学功能。进行了转录分析、定量聚合酶链反应、Western blot 和免疫组织化学染色，结果表明 EN1 在 ACC 中特异性且高度表达，并能准确地区分 ACC 与 BCA。此外，发现 TGFβ 信号通路与 ACC 相关，并在人 ACC 细胞系和患者来源的类器官 (PDO) 中检测到 EN1 通过 TGFβ 的调节。TGFβ 诱导的 EN1 对 PDO 模型中的肿瘤芽生具有重要作用。有趣的是，在 ACC 临床样本中观察到芽生尖端的 EN1 和 TGFβ1 水平较高，并且在 ACC 中 EN1 和 TGFβ1 的表达与临床分期显著相关。总之，本研究验证了 EN1 是区分 ACC 和 BCA 的良好诊断标志物。TGFβ 诱导的 EN1 促进了 ACC 的肿瘤芽生，这可能是与 ACC 恶性表型相关的重要机制。
