Am J Cancer Res. 2021 Apr 15;11(4):1480-1502. eCollection 2021.
ABSTRACT
Our previous study introduced the oncogenic role of the long non-coding RNA plasmacytoma variant translocation 1 (PVT1) in endometrial cancer (EC). In this study, we aimed to construct a PVT1-centered competing endogenous RNA (ceRNA) network to outline a regulatory axis that might promote the malignant progression of advanced EC. Raw Uterine Corpus Endometrial Carcinoma (UCEC) datasets were collected from The Cancer Genome Atlas (TCGA) database and used for construction of the PVT1-centered ceRNA network. The ceRNA binding sites were established using dual-luciferase assays. FISH assays displayed the co-location of PVT1 and miR-612 in EC cells. Immunohistochemistry, in situ hybridization, qRT-PCR, and western blots were used to assess the expression of miR-612 and CENP-H in EC tissues, and their functions on biological behaviours were examined by a series of in vitro and in vivo assays. Molecule interactions were illustrated by co-transfection assays. The bioinformatics analysis showed that PVT1/miR-612/CENP-H/CDK1 axis played a vital role in the malignant progression of advanced EC. MiR-612 was downregulated in EC tissues and acted as a tumour suppressor to inhibit cell proliferation, migration, invasion, and promote cell apoptosis. CENP-H was found overexpressed in EC tissues, and the expression level was correlated to diagnosis and prognosis of EC. Hyperactivated CENP-H promoted cell proliferation, migration, invasion, and inhibited cell apoptosis. Overexpressed CENP-H prevented the anti-tumour effects observed with upregulated miR-612; knockdown of miR-612 also suppressed the anti-tumour effects of downregulated PVT1. Knockdown of PVT1 together with upregulated miR-612 exerted the strongest anti-tumour effects in nude mice. These effects were mediated by CDK1 through modulation of the Akt/mTOR signaling pathway. In conclusi on, the PVT1/miR-612/CENP-H/CDK1 axis promoted the malignant progression of advanced EC and could serve as a promising target for potential treatments.
PMID:33948369 | PMC:PMC8085881
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