Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Matrix Biol. 2020 Nov;93:10-24. doi: 10.1016/j.matbio.2020.03.009. Epub 2020 May 15.
The growth factor progranulin plays a critical role in bladder cancer by modulating tumor cell motility and invasion. Progranulin regulates remodeling of the actin cytoskeleton by interacting with drebrin, an actin binding protein that regulates tumor growth. We previously discovered that progranulin depletion inhibits epithelial-to-mesenchymal transition and markedly reduces in vivo tumor growth. Moreover, progranulin depletion sensitizes urothelial cancer cells to cisplatin treatment, further substantiating a pro-survival function of progranulin. Until recently, the progranulin signaling receptor remained unidentified, precluding a full understanding of progranulin action in tumor cell biology. We recently identified EphA2, a member of a large family of receptor tyrosine-kinases, as the functional receptor for progranulin. However, it is not established whether EphA2 plays an oncogenic role in bladder cancer. Here we demonstrate that progranulin, and not ephrin-A1, the canonical ligand for EphA2, is the predominant EphA2 ligand in bladder cancer. Progranulin evoked Akt- and Erk1/2-mediated EphA2 phosphorylation at Ser897, which could drive bladder tumorigenesis. We discovered that EphA2 depletion severely blunted progranulin-dependent motility and anchorage-independent growth, and sensitized bladder cancer cells to cisplatin treatment. We further defined the mechanisms of progranulin/EphA2-dependent motility by identifying liprin-α1 as a novel progranulin-dependent EphA2 interacting protein and establishing its critical role in cell motility. The discovery of EphA2 as the functional signaling receptor for progranulin and the identification of novel downstream effectors offer a new avenue for understanding the underlying mechanism of progranulin action and may constitute novel clinical and therapeutic targets in bladder cancer.
生长因子颗粒蛋白聚糖通过调节肿瘤细胞的运动和侵袭在膀胱癌中发挥关键作用。颗粒蛋白聚糖通过与 drebrin 相互作用调节肌动蛋白细胞骨架的重塑，drebrin 是一种调节肿瘤生长的肌动蛋白结合蛋白。我们之前发现颗粒蛋白聚糖耗竭抑制上皮间质转化，并显著减少体内肿瘤生长。此外，颗粒蛋白聚糖耗竭使尿路上皮癌细胞对顺铂治疗敏感，进一步证实颗粒蛋白聚糖具有促生存功能。直到最近，颗粒蛋白聚糖信号受体仍然未知，这妨碍了对颗粒蛋白聚糖在肿瘤细胞生物学中的作用的全面理解。我们最近确定 EphA2 是受体酪氨酸激酶大家族的一个成员，是颗粒蛋白聚糖的功能受体。然而，EphA2 是否在膀胱癌中发挥致癌作用尚不清楚。在这里，我们证明颗粒蛋白聚糖，而不是 EphA2 的经典配体 Ephrin-A1，是膀胱癌中 EphA2 的主要配体。颗粒蛋白聚糖引发 Akt 和 Erk1/2 介导的 EphA2 在 Ser897 处磷酸化，这可能驱动膀胱癌发生。我们发现 EphA2 耗竭严重削弱了颗粒蛋白聚糖依赖性运动和锚定非依赖性生长，并使膀胱癌细胞对顺铂治疗敏感。我们进一步通过鉴定 liprin-α1 作为一种新型颗粒蛋白聚糖依赖性 EphA2 相互作用蛋白，并确定其在细胞运动中的关键作用，从而确定了颗粒蛋白聚糖/EphA2 依赖性运动的机制。EphA2 作为颗粒蛋白聚糖的功能信号受体的发现和新型下游效应物的鉴定为理解颗粒蛋白聚糖作用的潜在机制提供了新途径，并可能构成膀胱癌的新临床和治疗靶点。
