Santibanez Juan F, Krstic Jelena
Group for Molecular Oncology, Institute for Medical Research, University of Belgrade Dr Subotica 4, POB 102, 11129 Belgrade, Serbia.
Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, General Gana 1780, Santiago 8370854, Chile.
Curr Protein Pept Sci. 2018;19(12):1155-1163. doi: 10.2174/1389203718666171030103801.
Transforming growth factor-beta (TGF-β) is well recognized as playing a double role in tumor progression. Its antitumor role takes place in the early stages of cancer development, when TGF-β acts as a repressor of epithelial tumor growth. In advanced stages of cancer development, TGF-β has a tumor stimulating role, acting concomitantly with the increase of cancer cell migration and metastasis. One of the critical features of cancer cells is their ability to migrate and invade the surrounding tissues leading to metastases in different organs. Cancer cells that leave the tumor to infiltrate neighboring tissues and ultimately overtake a distant organ, need a complex and fine-regulated mechanism to move through the barrier imposed by the extracellular matrix (ECM). Therefore, cancer cells express a set of proteinases which are involved in the degradation and turnover of ECM. In particular, the urokinase type plasminogen activator (uPA) and the uPA cell surface receptor play key cellular roles in the enhancement of cell malignance during tumor progression. In normal cells uPA system is finely regulated, while in tumor cells its expression and activity are dysregulated in a way to enhance cells' invasion capacity during tumor progression. TGF-β strongly regulates uPA in cancer from transcriptional expression to enzyme activity. In turn, uPA participates in the activation of secreted latent TGF-β, thus producing a malicious loop which contributes to tumor progression and metastasis. In this review we will analyze the main molecular mechanisms implicated in uPA regulation by TGF-β. Moreover, the specific roles and interaction between TGF-β and uPA system in cancer cells and their impact on tumorigenesis will be portrayed.
转化生长因子-β（TGF-β）在肿瘤进展中发挥双重作用已得到广泛认可。其抗肿瘤作用发生在癌症发展的早期阶段，此时TGF-β作为上皮肿瘤生长的抑制因子。在癌症发展的晚期阶段，TGF-β具有肿瘤刺激作用，与癌细胞迁移和转移的增加同时发生。癌细胞的一个关键特征是它们具有迁移和侵袭周围组织并导致不同器官转移的能力。离开肿瘤浸润邻近组织并最终占据远处器官的癌细胞，需要一种复杂且精细调节的机制来穿过细胞外基质（ECM）所形成的屏障。因此，癌细胞表达一组参与ECM降解和周转的蛋白酶。特别是，尿激酶型纤溶酶原激活剂（uPA）及其细胞表面受体在肿瘤进展过程中增强细胞恶性程度方面发挥关键的细胞作用。在正常细胞中，uPA系统受到精细调节，而在肿瘤细胞中，其表达和活性失调，以增强肿瘤进展过程中细胞的侵袭能力。TGF-β从转录表达到酶活性对癌症中的uPA有强烈调节作用。反过来，uPA参与分泌型潜伏TGF-β的激活，从而形成一个恶性循环，促进肿瘤进展和转移。在本综述中，我们将分析TGF-β调节uPA的主要分子机制。此外，还将描述TGF-β与uPA系统在癌细胞中的具体作用和相互作用及其对肿瘤发生的影响。
