Medical College of Wisconsin
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CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer. Mol Cancer 2019 10 17;18(1):144

Date

10/19/2019

Pubmed ID

31623606

Pubmed Central ID

PMC6796346

DOI

10.1186/s12943-019-1080-5

Scopus ID

2-s2.0-85073621877   17 Citations

Abstract

BACKGROUND: Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive.

METHODS: RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings.

RESULTS: CircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial-mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells.

CONCLUSIONS: Our findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.

Author List

Zhang L, Zhou Q, Qiu Q, Hou L, Wu M, Li J, Li X, Lu B, Cheng X, Liu P, Lu W, Lu Y

Author

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

3' Untranslated Regions
Animals
BRCA1 Protein
Cell Line, Tumor
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genes, Tumor Suppressor
HSP40 Heat-Shock Proteins
Humans
Immunohistochemistry
Lipid-Linked Proteins
Mice
MicroRNAs
Models, Biological
Molecular Chaperones
Nerve Tissue Proteins
Ovarian Neoplasms
Prognosis
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
RNA Interference
Wnt Signaling Pathway
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d