MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways

• Published in: Oncogene 2019-08, Vol.38 (32), p.6035-6050
• Main Authors: Majem, Blanca, Parrilla, Alfonso, Jiménez, Carlos, Suárez-Cabrera, Leticia, Barber, Marta, Marín, Andrea, Castellví, Josep, Tamayo, Gabriel, Moreno-Bueno, Gema, Ponce, Jordi, Matias-Guiu, Xavier, Alameda, Francesc, Romero, Ignacio, Sánchez, José Luis, Pérez-Benavente, Asunción, Moran, Sebastián, Esteller, Manel, Reventós, Jaume, Rigau, Marina, Gil-Moreno, Antonio, Segura, Miguel F., Santamaría, Anna
• Format: Article
• Language: English
• Subjects: 13/109; 13/2; 38/89; 45/29; 45/47; 631/337/176; 631/337/384; 631/67/1517/1709; 631/80/82/23; 64/60; 96/1; 96/106; AKT protein; Animals; Antigens, Neoplasm - genetics; Apoptosis; Cancer cells; Carcinogenesis - genetics; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - pathology; Cell Adhesion Molecules - genetics; Cell Biology; Cell Line, Tumor; Cell viability; Chromosome 5; Development and progression; DNA-Binding Proteins - genetics; Down-Regulation - genetics; Drug resistance; Female; Gene Expression Regulation, Neoplastic; Genetic aspects; HEK293 Cells; Human Genetics; Humans; Internal Medicine; Malignancy; Medicine; Medicine & Public Health; Mice; Mice, Nude; MicroRNA; MicroRNAs; MicroRNAs - physiology; miRNA; Myc protein; Oncology; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA-Binding Proteins - genetics; Therapeutic applications; Transcription Factors - genetics; Tumor suppressor genes; Tumorigenesis; Wnt protein; Wnt Signaling Pathway - genetics; Wnt1 Protein - genetics; Wnt1 Protein - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0860-0

Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.