Nuclear Localization of PTTG1 Promotes Migration and Invasion of Seminoma Tumor through Activation of MMP-2

SIMPLE SUMMARY: Seminoma is the most common subtype of testicular germ cell tumors (TGCTs) and its molecular patterns have not been clarified. The pituitary tumor-transforming gene 1 (PTTG1) is a securin and its overexpression is reported in many cancers. We previously demonstrated that PTTG1 is mainly localized at the neoplasm periphery and infiltration area of seminoma. Therefore, we aim to investigate in vitro the role of PTTG1 on the invasive properties of seminoma. Our results elucidate the role of nuclear PTTG1 in promoting invasiveness and the metastatic process of these cells through its transcriptional target matrix-metalloproteinase-2 (MMP-2). Analysis of human testicular tumors from the Atlas database revealed an exclusive PTTG1 nuclear localization and a concomitant increase of MMP-2 levels in seminoma compared to non-seminoma tumors. Our data provide insights into the molecular characterization of seminoma, promoting PTTG1 as a prognostic marker useful in human seminoma clinical management. ABSTRACT: (1) Background: PTTG1 sustains the invasiveness of several cancer types. We previously reported that in seminomas, PTTG1 was detected in the peripheral area of the tumor and in the leading infiltrative edge. Here, we investigate the PTTG1 role on the invasive properties of seminoma. (2) Methods: three seminoma cell lines were used as in vitro model. PTTG1 levels and localization were investigated by biochemical and immunofluorescence analyses. Wound-healing, Matrigel invasion assays, and zymography were applied to study migratory and invasive capability of the cell lines. RNA interference and overexpression experiments were performed to address the PTTG1 role in seminoma invasiveness. PTTG1 and its target MMP-2 were analyzed in human testicular tumors using the Atlas database. (3) Results: PTTG1 was highly and differentially expressed in the seminoma cell lines. Nuclear PTTG1 was positively correlated to the aggressive phenotype. Its modulation confirms these results. Atlas database analysis revealed that PTTG1 was localized in the nucleus in seminoma compared with non-seminoma tumors, and that MMP-2 levels were significantly higher in seminomas. (4) Conclusions: nuclear PTTG1 promotes invasiveness of seminoma cell lines. Atlas database supported these results. These data lead to the hypothesis that nuclear PTTG1 is an eligible prognostic factor in seminomas.