MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy.
OBJECTIVE
Few successful therapeutic options exist for patients with recurrent ovarian cancer (OVCA). This is due in part to an incomplete understanding of the molecular determinants of chemotherapy-response. Recently, it has been shown that microRNAs (miRNAs) influence messenger-RNA (mRNA) post-transcriptional control and can contribute to human carcinogenesis. The objective of the current study was to explore the role of miRNAs, and their predicted mRNA targets, in OVCA in-vitro response to chemotherapy.


METHODS
The expression of 335 unique miRNAs was measured in 16 OVCA cell lines. In parallel, the sensitivity of these cell lines to 6 commonly used chemotherapeutic agents (cisplatin, doxorubicin, topotecan, paclitaxel, docetaxel, and gemcitabine) was evaluated by in-vitro cell proliferation assay. MiRNAs associated with cell line drug response were identified by linear regression analysis, and their predicted mRNA targets subject to functional biologic pathway analyses.


RESULTS
Twenty-seven miRNAs were found to be associated with response to the one or more of the 6 salvage chemotherapies tested (p<0.05). Predicted targets of these miRNAs included 52 mRNAs, previously reported to be associated with chemo-responsiveness, and which are also involved in functional biologic pathways that influence cancer cell cytotoxicity, carcinogenesis, cell mitosis, p53 signaling, and tumor cell growth and invasion.


CONCLUSIONS
We have identified miRNAs and their predicted target mRNAs associated with ovarian cancer cell response to chemotherapeutic agents. Our strategy of integrating miRNA and mRNA data may aid in the characterization of important molecular pathways associated with OVCA chemo-response.
Boren
Todd
T
H Lee Moffitt Cancer Center and Research Institute, Department of Women's Oncology, Tampa, FL, USA.
Xiong
Yin
Y
Hakam
Ardeshir
A
Wenham
Robert
R
Apte
Sachin
S
Chan
Gina
G
Kamath
Siddharth G
SG
Chen
Dung-Tsa
DT
Dressman
Holly
H
Lancaster
Johnathan M
JM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D016014:Linear Models; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*; D043823:Taxoids / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D019772:Topotecan; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine