TY - JOUR
T1 - Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer
AU - Rodriguez-Aguayo, Cristian
AU - Monroig, Paloma del C.
AU - Redis, Roxana S.
AU - Bayraktar, Emine
AU - Almeida, Maria Inês
AU - Ivan, Cristina
AU - Fuentes-Mattei, Enrique
AU - Rashed, Mohammed H.
AU - Chavez-Reyes, Arturo
AU - Ozpolat, Bulent
AU - Mitra, Rahul
AU - Sood, Anil K.
AU - Calin, George A.
AU - Lopez-Berestein, Gabriel
N1 - Funding Information:
We thank Kathryn Hale for critical reading of the manuscript and Dr Chang-Gong Liu, Center for Targeted Therapy, NGS Sequencing and ncRNA Service for the microarray profiling. This work was supported in part by grants from the National Institutes of Health/National Cancer Institute (R44GM086937, P50 CA093459, U54 CA151668, P50 CA083639, P50 CA098258, R21 CA180145, UH2TR000943 and U54CA96300) and from the Cancer Prevention Research Institute of Texas (RP120214).
Publisher Copyright:
© The Author(s) 2017
PY - 2017
Y1 - 2017
N2 - The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a-3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a-5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS, through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor.
AB - The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a-3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a-5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS, through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor.
KW - Chemotherapy resistance
KW - HnRNPA1
KW - K-RAS
KW - MicroRNAs
KW - Ovarian cancer
KW - RNA-binding proteins
UR - http://www.scopus.com/inward/record.url?scp=85041004698&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041004698&partnerID=8YFLogxK
U2 - 10.1038/celldisc.2017.29
DO - 10.1038/celldisc.2017.29
M3 - Article
AN - SCOPUS:85041004698
SN - 2056-5968
VL - 3
JO - Cell Discovery
JF - Cell Discovery
M1 - 17029
ER -