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EIF5A2 controls ovarian tumor growth and metastasis by promoting epithelial to mesenchymal transition via the TGFβ pathway.

ABSTRACT:

Background

Epithelial to mesenchymal transition (EMT) contributes to tumor metastasis and chemoresistance. Eukaryotic initiation factor 5A2 (EIF5A2) is highly expressed in a variety of human cancers but rarely expressed in normal tissues. While EIF5A2 has oncogenic activity in several cancers and contributes to tumor metastasis, its role in ovarian cancer is unknown. In this study, we investigate whether EIF5A2 contributes to ovarian tumor metastasis by promoting EMT.

Methods

To investigate the role of EIF5A2, we knocked out (KO) EIF5A2 using lentiviral CRISPR/Cas9 nickase in high invasive SKOV3 and OVCAR8 cells and overexpressed EIF5A2 in low invasive OVCAR3 cells using lentiviral vector. Cell proliferation, migration and invasion was examined in vitro ovarian cancer cells and tumor metastasis was evaluated in vivo using orthotopic ovarian cancer mouse models.

Results

Here we report that EIF5A2 is highly expressed in ovarian cancers and associated with patient poor survival. Lentiviral CRISPR/Cas9 nickase vector mediated knockout (KO) of EIF5A2 inhibits epithelial to mesenchymal transition (EMT) in SKOV3 and OVCAR8 ovarian cancer cells that express high levels of EIF5A2. In contrast, overexpression of EIF5A2 promotes EMT in OVCAR3 epithelial adenocarcinoma cells that express relatively low EIF5A2 levels. KO of EIF5A2 in SKOV3 and OVCAR8 cells inhibits ovarian cancer cell migration and invasion, while its overexpression promotes cell migration and invasion in OVCAR3 adenocarcinoma cells. We further demonstrate that EIF5A2 promotes EMT by activating the TGFβ pathway and KO of EIF5A2 inhibits ovarian tumor growth and metastasis in orthotopic ovarian cancer mouse models.

Conclusion

Our results indicate that EIF5A2 is an important controller of ovarian tumor growth and metastasis by promoting EMT and activating the TGFβ pathway.

SUBMITTER: Zhao G

PROVIDER: S-EPMC8025533 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMetastasis accounts for the most lethal reason for the death of ovarian cancer patients, but remains largely untreated. Epithelial-mesenchymal transition (EMT) is critical for the conversion of early-stage ovarian tumours into metastatic malignancies. Thus the exploration of the signalling pathways promoting EMT would open potential opportunities for the treatment of metastatic ovarian cancer. Herein, the putative role of MDM2 in regulating EMT and metastasis of ovarian cancer SKOV3 cells was investigated.MethodsThe regulatory effects by MDM2 on cell motility was emulated by wound-healing and transwell assays. The effects on EMT transition and Smad pathway were studied by depicting the expression levels of epithelial marker E-cadherin as well as key components of Smad pathway. To evaluate the clinical relevance of our findings, the correlation of MDM2 expression levels with the stages of 104 ovarian cancer patients was investigated by immunohistochemistry assay.ResultsWe demonstrate that MDM2 functions as a key factor to drive EMT and motility of ovarian SKOV3 cells, by facilitating the activation of TGF-β-Smad pathway, which results in the increased transcription of snail/slug and the subsequent loss of E-cadherin levels. Such induction of EMT is sustained in either E3 ligase-depleted MDM2 or E3 ligase inhibitor HLI-373-treated cells, while being impaired by the N-terminal deletion of MDM2, which is also reflected by the inhibitory effects against EMT by Nutlin-3a, the N-terminal targeting agent. The expression levels of MDM2 is highly correlated with the stages of the ovarian cancer patients, and the higher expression of MDM2 together with TGFB are closely correlated with poor prognosis and predict a high risk of ovarian cancer patients.ConclusionsThis study suggests that MDM2 activates Smad pathway to promote EMT in ovarian cancer metastasis, and targeting the N-terminal of MDM2 can reprogram EMT and impede the mobility of cancer cells.