miR-29c-3p acts as a tumor promoter by regulating ß-catenin signaling through suppressing DNMT3A, TET1 and HBP1 in ovarian carcinoma.

Ovarian Carcinoma (OvCa) is characterized by rapid and sustained growth, activated invasion and metastasis. Studies have shown that microRNAs recruit and alter the expression of key regulators to modulate carcinogenesis. Here, we find that miR-29c-3p is increased in benign OvCa and malignant OvCa compared to normal ovary. Univariate and multivariate analyses report that miR-29c-3p overexpression is associated with poor prognosis in OvCa. Furthermore, we investigate that expression of miR-29c-3p is inversely correlated to DNA methyltransferase (DNMT) 3 A and Ten-Eleven-Translocation enzyme TET1. The high-throughput mRNA sequencing, bioinformatics analysis and pharmacological studies confirm that aberrant miR-29c-3p modulates tumorigenesis in OvCa cells, including epithelial-mesenchymal transition (EMT), proliferation, migration, and invasion. This modulation occurs through the regulation of ß-catenin signaling by directly targeting 3'UTR of DNMT3A, TET1 and the HMG box transcription factor HBP1 and suppressing their expression. The further 3D spheres assay clearly shows the regulatory effects of miR-29c-3p on OvCa tumorigenesis. Additionally, the receiver operating characteristic (ROC) curve analysis of miR-29c-3p and the clinical detection/diagnostic biomarker CA125 suggests that miR-29c-3p may be conducive for clinical diagnosis or co-diagnosis of OvCa. These findings support miR-29c-3p functions as a tumor promoter by targeting its functional targets, providing new potential biomarker (s) for precision medicine strategies in OvCa.

Lysophosphatidic acid suppresses apoptosis of high-grade serous ovarian cancer cells by inducing autophagy activity and promotes cell-cycle progression via EGFR-PI3K/Aurora-AThr288-geminin dual signaling pathways.

Lysophosphatidic acid (LPA) and geminin are overexpressed in ovarian cancer, and increasing evidence supports their contribution to ovarian tumor development. Here, we reveal that geminin depletion induces autophagy suppression and enhances reactive oxygen species (ROS) production and apoptosis of high-grade serous ovarian cancer (HGSOC) cells. Bioinformatics analysis and pharmacological inhibition studies confirm that LPA activates geminin expression in the early S phase in HGSOC cells via the LPAR1/3/MMPs/EGFR/PI3K/mTOR pathway. Furthermore, LPA phosphorylates Aurora-A kinase on Thr288 through EGFR transactivation, and this event potentiates additional geminin stabilization. In turn, overexpressed and stabilized geminin regulates DNA replication, cell-cycle progression, and cell proliferation of HGSOC cells. Our data provide potential targets for enhancing the clinical benefit of HGSOC precision medicine.