醛脱氢酶 1A3 (ALDH1A3) 是一种促进转移的癌症干细胞标志物。三阴性乳腺癌 (TNBC) 的进展与 ALDH1A3 诱导的基因表达变化有关。为了研究 ALDH1A3 介导的乳腺癌转移机制，我们评估了 ALDH1A3 对蛋白酶表达和降解细胞外基质的蛋白酶调节剂的影响，这是侵袭和转移所必需的过程。这表明 ALDH1A3 调节纤溶酶原激活途径；它增加了组织纤溶酶原激活剂（tPA）和尿激酶纤溶酶原激活剂（uPA）的水平和活性。这导致丝氨酸蛋白酶纤溶酶（tPA 和 uPA 的酶促产物）的活性相应增加。 ALDH1A3 产物全反式视黄酸同样增加了 tPA 和纤溶酶活性。 ALDH1A3 对 TNBC 细胞侵袭的增加是纤溶酶原依赖性的。在患者肿瘤中，ALDH1A3 和 tPA 共表达，它们的联合表达与 TNBC 亚型、高肿瘤级别和复发转移性疾病相关。 TNBC 细胞中 tPA 的敲低抑制了纤溶酶的产生和淋巴结转移。这些结果确定 ALDH1A3-tPA-纤溶酶轴是乳腺癌进展的关键因素。© 2023 作者。约翰·威利出版的《分子肿瘤学》

Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell marker that promotes metastasis. Triple-negative breast cancer (TNBC) progression has been linked to ALDH1A3-induced gene expression changes. To investigate the mechanism of ALDH1A3-mediated breast cancer metastasis, we assessed the effect of ALDH1A3 on the expression of proteases and the regulators of proteases that degrade the extracellular matrix, a process that is essential for invasion and metastasis. This revealed that ALDH1A3 regulates the plasminogen activation pathway; it increased the levels and activity of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). This resulted in a corresponding increase in the activity of serine protease plasmin, the enzymatic product of tPA and uPA. The ALDH1A3 product all-trans-retinoic acid similarly increased tPA and plasmin activity. The increased invasion of TNBC cells by ALDH1A3 was plasminogen-dependent. In patient tumours, ALDH1A3 and tPA are co-expressed and their combined expression correlated with the TNBC subtype, high tumour grade and recurrent metastatic disease. Knockdown of tPA in TNBC cells inhibited plasmin generation and lymph node metastasis. These results identify the ALDH1A3-tPA-plasmin axis as a key contributor to breast cancer progression.© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.