Silencing Of Peptidyl-Prolyl Isomerase 1 (Pin1) By RNA Interference Suppresses Tumorigenicity In Cervical Cancer

Background and Objective: Phosphorylation of proteins on serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is a central signaling mechanism in cell proliferation and transformation. Recent studies indicate that certain pSer/Thr-Pro motifs in native proteins exist in two completely distinct conformations, cis and trans, whose conversion is markedly slowed down upon phosphorylation, but specifically catalyzed by the peptidyl-prolyl cis/trans isomerase Pin1. Importantly, such Pin1-catalyzed conformational changes can have profound effects on the function of many phosphorylation signaling pathways, thereby playing an important role in various cellular processes. Moreover, increasing evidence indicates that aberrant Pin1 function plays an important role in the pathogenesis of some human diseases and suggests that Pin1-mediated postphosphorylation regulation may provide a unique opportunity for disrupting oncogenic pathways. Our preceding studies have found that Pin1 is overexpressed in cervical cancer, and whether silence Pin in could suppresse the development of cervical cancer? In this study, we sought to determine whether small interfering (si)RNA-mediated down-regulation of Pin1 inhibit cellular growth and oncogenesis in cervical cancer and provided a novel valuable supplement for potential therapeutic development in cervical cancer treatment. Methods:. The specific Pin1 siRNA expression vectors were constructed and transfected into SiHa cell. The expression of Pin1 after transfection was detected, and then cell growth, cell apoptosis, sensitivity to the chemotherapy, cell adhension test, cell migration test and cell invasion test were investigated. In addition, the expression of VEGF and MMP-2 were analyzed by western blot. In animal experiments, cervical cancer cells SiHa were injected into the right flank subcutaneously of 4-6 week old female nude athymic BALB/c mice and then the mice were treated by Pin1-si, Con-si or PBS. VEGF and MMP-2 expression were dectected by western blot and immunohistochemical analysis.Results: Pin1 was over-expressed in the cervical lesions tissues and its expression levels are correlated with the tumor stage. After transfection, Pin1 expression in SiHa cell was down-regulated, and significantly suppressed cellular proliferation, adhesion, and invasion, strongly induced the apoptotic response and increased sensitivity to the chemotherapy. In addition, Pin1-siRNA significantly suppressed tumor growth, decreased tumor angiogenesis and metastasis in athymic mice.Conclusions: Our results strongly suggest that Pin1 plays an important role in cervical cancer development. Inhibition of Pin1 may thus provide a unique way of disrupting oncogenic pathways and therefore Pin1 could be an attractive new anti-cancer target.