Restoration of miR-200c to ovarian cancer reduces tumor burden and increases sensitivity to paclitaxel.
A therapeutic intervention that could decrease tumor burden and increase sensitivity to chemotherapy would have a significant impact on the high morbidity rate associated with ovarian cancer. miRNAs have emerged as potential therapeutic candidates due to their ability to downregulate multiple targets involved in tumor progression and chemoresistance. miRNA-200c (miR-200c) is downregulated in ovarian cancer cell lines and stage III ovarian tumors, and low miR-200c correlates with poor prognosis. miR-200c increases sensitivity to taxanes in vitro by targeting class III β-tubulin gene (TUBB3), a tubulin known to mediate chemoresistance. Indeed, we find that patients with tumors having low TUBB3 had significantly prolonged survival (average survival 52.73 ± 4.08 months) as compared with those having high TUBB3 (average survival 42.56 ± 3.19 months). miR-200c also targets TrkB, a mediator of resistance to anoikis. We show that restoration of miR-200c to ovarian cancer cells results in increased anoikis sensitivity and reduced adherence to biologic substrates in vitro. Because both chemo- and anoikis-resistance are critical steps in the progression of ovarian cancer, we sought to determine how restoration of miR-200c affects tumor burden and chemosensitivity in an in vivo preclinical model of ovarian cancer. Restoration of miR-200c in an intraperitoneal xenograft model of human ovarian cancer results in decreased tumor formation and tumor burden. Furthermore, even in established tumors, restoration of miR-200c, alone or in combination with paclitaxel, results in significantly decreased tumor burden. Our study suggests that restoration of miR-200c immediately before cytotoxic chemotherapy may allow for a better response or lower effective dose.
Departments of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Diana M
DM
Cittelly
Irina
I
Dimitrova
Erin N
EN
Howe
Dawn R
DR
Cochrane
Annie
A
Jean
Nicole S
NS
Spoelstra
Miriam D
MD
Post
Xian
X
Lu
Russell R
RR
Broaddus
Monique A
MA
Spillman
Jennifer K
JK
Richer
D000818:Animals; D023102:Anoikis / Q000187:drug effects / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D017239:Paclitaxel / Q000494:pharmacology*; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection; D014404:Tubulin / Q000096:biosynthesis; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C498585:TUBB3 protein, human; D014404:Tubulin; D017239:Paclitaxel