Downregulation of ASPP2 in choriocarcinoma contributes to increased migratory potential through Src signaling pathway activation

Abstract

Gestational choriocarcinoma is a malignant tumor derived from placental trophoblast and the most aggressive member of gestational trophoblastic disease (GTD). Apoptosis-stimulating protein of p53-2 (ASPP2) is a member of ASPP family that transactivates p53 and thereby functions as a tumor suppressor. In this study, the expression profile of ASPP2 in choriocarcinoma was examined in comparison with normal placentas and hydatidiform moles, the latter being a type of GTD that carries malignant potential. Downregulation of ASPP2 messenger RNA and protein was demonstrated in choriocarcinoma by quantitative PCR and immunohistochemistry. ASPP2-transfected choriocarcinoma cells (JEG-3 and JAR) showed an increase in apoptosis and a decrease in cell migration as detected by TdT-mediated dUTP nick end labeling and wound healing assays, respectively, illustrating the complex action of ASPP2 on cell functions other than programmed cell death. Activated Src is known to be important in tumor progression. Transfection of ASPP2 but not ASPP1, another tumor-suppressive ASPP, was found to be related to subsequent decreased Src-pY416 phosphorylation, suggesting an inactivating effect of ASPP2 on Src. Moreover, this ASPP2-mediated inactivation of Src could be abolished by RNA interference with C-terminal Src kinase (Csk), a kinase that can inhibit Src activation. Our findings suggested that the ability of ASPP2 to attenuate Src activation was specific to ASPP2 in a Csk-dependent manner. Taken together, we demonstrated a loss of tumor-suppressive ASPP2 in choriocarcinoma with effects on cell migration and apoptosis. We also unveiled a possible mechanistic link between ASPP2 and Csk/Src signaling pathway, implicating the multiple cellular functions of ASPP2.

Prognostic values of apoptosis-stimulating P53-binding protein 1 and 2 and their relationships with clinical characteristics of esophageal squamous cell carcinoma patients: a retrospective study

“…ASPP2 is commonly considered a tumor suppressor, and its expression is often reduced in malignant tumors [14, 24, 25]. However, inconsistent with previous reports, our results indicated that ASPP2 expression was significantly increased in ESCCs as compared with noncancerous tissues, suggesting that ASPP2 might be involved in ESCC tumorigenesis.…”

“…Iwabuchi et al [43] suggested that ASPP1 and ASPP2 exerted their function of inhibiting tumorigenesis only in the presence of wild-type P53. However, later studies showed that ASPP2 played tumor-suppressing roles independent of P53, such as enhancing colorectal cancer cell apoptosis through autophagy inhibition [18], inhibiting cell migration through Src inactivation [14], and stimulating Ras-induced senescence through direct interactions with Ras-GTP [44]. Additionally, we did not find any correlation among ASPP1, ASPP2, and P53, indicating that they may all function independently.…”

“…Sgroi et al [13] found that invasive and metastatic breast cancer tissue exhibited reduced ASPP2 expression compared with normal breast tissue, suggesting a possible role of ASPP2 in breast cancer progression and metastasis. Mak et al [14] reported the down-regulation of ASPP2 in choriocarcinoma, which contributed to the increased migratory potential of the tumor cells. High ASPP2 expression has been reported to predict good prognosis in some tumors, including breast cancer [15], non-small cell lung cancer [16], diffuse large B cell lymphoma, and follicular center lymphoma [17].…”

FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling

“…For example, we have previously demonstrated that proapoptotic apoptosisstimulating protein of p53 2 is down-regulated in highly metastatic CCA and contributes to increased migratory potential through the activation of the Src signaling pathway. 11 Interestingly, our qPCR analysis of apoptotic genes in FBI1etransfected CCA cells revealed an unreported downregulation of a broad range of proapoptotic genes in both intrinsic and extrinsic pathways, including death receptor FAS, apoptosis-initiating BAK, initiator caspases (CASP8, CASP9, and CASP10), as well as apoptosis-executing polyeADP ribose polymerases ( Figure 5). FBI-1einduced down-regulation of these proapoptotic gene transcripts implicates the ability of FBI-1 to manipulate apoptosis cassette/machineries and to hence protect cells from apoptosis in GTD.…”

“…15 In GTD, p53-related genes or regulators play crucial roles in modulating apoptosis during disease progression. 9,11 Also, the involvement of these regulators in crosstalk between apoptosis and the cell signaling pathway in GTD may result in an adverse clinical outcome. For example, we have previously demonstrated that proapoptotic apoptosisstimulating protein of p53 2 is down-regulated in highly metastatic CCA and contributes to increased migratory potential through the activation of the Src signaling pathway.…”