Biernacka K M, Barker R, Sewell A, Bahl A, Perks C M
Cancer Endocrinology Group, Translational Health Sciences, University of Bristol Southmead Hospital, BS10 5NB, Bristol, UK.
Department of Cellular Pathology, North Bristol NHS Trust, Southmead Hospital, Bristol, UK.
Transl Oncol. 2023 Aug;34:101698. doi: 10.1016/j.tranon.2023.101698. Epub 2023 Jun 10.
Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Localised PCa can be treated effectively, but most patients relapse/progress to more aggressive disease. One possible mechanism underlying this progression is alternative splicing of the androgen receptor, with AR variant 7(ARV7) considered to play a major role. Using viability assays, we confirmed that ARV7-positive PCa cells were less sensitive to treatment with cabazitaxel and an anti-androgen-enzalutamide. Also, using live-holographic imaging, we showed that PCa cells with ARV7 exhibited an increased rate of cell division, proliferation, and motility, which could potentially contribute to a more aggressive phenotype. Furthermore, protein analysis demonstrated that ARV7 knock-down was associated with a decrease in insulin-like growth factor-2 (IGFBP-2) and forkhead box protein A1(FOXA1). This correlation was confirmed in-vivo using PCa tissue samples. Spearman rank correlation analysis showed significant positive associations between ARV7 and IGFBP-2 or FOXA1 in tissue from patients with PCa. This association was not present with the AR. These data suggest an interplay of FOXA1 and IGFBP-2 with ARV7-mediated acquisition of an aggressive prostate cancer phenotype.
前列腺癌（PCa）是男性癌症相关死亡的主要原因之一。局限性PCa可以得到有效治疗，但大多数患者会复发/进展为更具侵袭性的疾病。这种进展的一种可能机制是雄激素受体的可变剪接，其中AR变体7（ARV7）被认为起主要作用。通过活力测定，我们证实ARV7阳性的PCa细胞对卡巴他赛和抗雄激素恩杂鲁胺治疗的敏感性较低。此外，使用实时全息成像，我们发现具有ARV7的PCa细胞表现出更高的细胞分裂、增殖和运动速率，这可能导致更具侵袭性的表型。此外，蛋白质分析表明，ARV7敲低与胰岛素样生长因子-2（IGFBP-2）和叉头框蛋白A1（FOXA1）的减少有关。使用PCa组织样本在体内证实了这种相关性。Spearman等级相关分析显示，在PCa患者的组织中，ARV7与IGFBP-2或FOXA1之间存在显著正相关。AR不存在这种关联。这些数据表明FOXA1和IGFBP-2与ARV7介导的侵袭性前列腺癌表型的获得之间存在相互作用。
