title: miR-221/222 Are Involved in Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma.
abstract: Sunitinib is a multitargeting tyrosine kinase inhibitor used for metastatic renal cancer. There are no biomarkers that can predict sunitinib response. Such markers are needed to avoid administration of costly medication with side effects to patients who would not benefit from it. We compared global miRNA expression between patients with a short (≤12 months) versus prolonged (>12 months) progression-free survival (PFS) under sunitinib as first-line therapy for metastatic renal cell carcinoma. We identified a number of differentially expressed miRNAs and developed miRNA statistical models that can accurately distinguish between the two groups. We validated our models in the discovery set and an independent set of 57 patients. Target prediction and pathway analysis showed that these miRNAs are involved in vascular endothelial growth factor (VEGF), TGFβ, and mammalian target of rapamycin (mTOR)-mediated signaling and cell-cell communication. We tested the effect of these miRNAs on cellular proliferation and angiogenesis. We validated the negative correlation between miR-221 and its target, VEGFR2.miR-221 overexpression was associated with a poor PFS while its target, VEGFR2 was associated with longer survival. Gain of function experiments showed that miR-221 and miR-222 decreased angiogenesis and cellular proliferation in human umbilical vein endothelial cells (HUVEC) while increasing cellular proliferation in ACHN cells. miRNAs represent potential predictive markers for sunitinib response.
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Heba W Z
authors.initials: HWZ
authors.lastname: Khella
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Henriett
authors.initials: H
authors.lastname: Butz
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rotondo
authors.affiliation: Ontario Cancer Biomarker Network, MaRS Centre, Toronto, Ontario, Canada.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Evans
authors.affiliation: Ontario Cancer Biomarker Network, MaRS Centre, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Kupchak
authors.affiliation: Ontario Cancer Biomarker Network, MaRS Centre, Toronto, Ontario, Canada.
authors.forename: Moyez
authors.initials: M
authors.lastname: Dharsee
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Latif
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Pasic
authors.affiliation: Department of Chemistry, University of Athens, Athens, Greece.
authors.forename: Evi
authors.initials: E
authors.lastname: Lianidou
authors.affiliation: Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada. Electronic address: bjarnason@sri.utoronto.ca.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: yousefg@smh.ca.
authors.forename: George M
authors.initials: GM
authors.lastname: Yousef
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D015233:Models, Statistical; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011379:Prognosis; D011758:Pyrroles / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D054316:Biomarkers, Pharmacological; D007211:Indoles; D035683:MicroRNAs; D011758:Pyrroles; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C525709:MIR221, human; C525710:MIR222, human; C546842:MTOR protein, human