title: High expression of microRNA-625-3p is associated with poor response to first-line oxaliplatin based treatment of metastatic colorectal cancer.
abstract: The backbone of current cytotoxic treatment of metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine together with either oxaliplatin (XELOX/FOLFOX) or irinotecan (XELIRI/FOLFIRI). With an overall objective response rate of approximately 50% for either treatment combination, a major unsolved problem is that no predictors of response to these treatments are available. To address this issue, we profiled 742 microRNAs in laser-capture microdissected cancer cells from responding and non-responding patients receiving XELOX/FOLFOX as first-line treatment for mCRC, and identified, among others, high expression of miR-625-3p, miR-181b and miR-27b to be associated with poor clinical response. In a validation cohort of 94 mCRC patients treated first-line with XELOX, high expression of miR-625-3p was confirmed to be associated with poor response (OR = 6.25, 95%CI [1.8; 21.0]). Independent analyses showed that miR-625-3p was not dysregulated between normal and cancer samples, nor was its expression associated with recurrence of stage II or III disease, indicating that miR-625-3p solely is a response marker. Finally, we also found that these miRNAs were up-regulated in oxaliplatin resistant HCT116/oxPt (miR-625-3p, miR-181b and miR-27b) and LoVo/oxPt (miR-181b) colon cancer cell lines as compared with their isogenic parental cells. Altogether, our results suggest an association between miR-625-3p and response to first-line oxaliplatin based chemotherapy of mCRC.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgårdsvej 100, DK-8200 Aarhus N, Denmark.
authors.forename: Mads H
authors.initials: MH
authors.lastname: Rasmussen
authors.forename: Niels F
authors.initials: NF
authors.lastname: Jensen
authors.forename: Line S
authors.initials: LS
authors.lastname: Tarpgaard
authors.forename: Camilla
authors.initials: C
authors.lastname: Qvortrup
authors.forename: Maria U
authors.initials: MU
authors.lastname: Rømer
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.forename: Tine P
authors.initials: TP
authors.lastname: Hansen
authors.forename: Lise L
authors.initials: LL
authors.lastname: Christensen
authors.forename: Jan
authors.initials: J
authors.lastname: Lindebjerg
authors.forename: Flemming
authors.initials: F
authors.lastname: Hansen
authors.forename: Benny V
authors.initials: BV
authors.lastname: Jensen
authors.forename: Torben F
authors.initials: TF
authors.lastname: Hansen
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: Claus L
authors.initials: CL
authors.lastname: Andersen
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D000069287:Capecitabine; D045744:Cell Line, Tumor; D015331:Cohort Studies; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000077150:Oxaliplatin; D010071:Oxaloacetates; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C575476:MIRN625 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D010071:Oxaloacetates; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil