title: MicroRNA-218 is a prognostic indicator in colorectal cancer and enhances 5-fluorouracil-induced apoptosis by targeting BIRC5.
abstract: One major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to fluoropyrimidine (FU)-based chemotherapy. Various reports showed that ectopic expression and function of microRNAs (miRNAs) played key roles to mediate apoptosis at the post-transcriptional level. To further explore the possible mechanisms, we evaluated the prognostic effect of miR-218 in patients with CRC receiving 5-FU-based treatment and investigated the proapoptotic role of miR-218 in vitro. Primary tumour specimens and adjacent non-tumour sites were used to determine miR-218 expression distribution and explore its potential prognostic value in response to 5-FU-based treatment in patients with CRC. HCT116 and HT29 cells were transfected with precursor miR-218 or negative control, followed by assays to investigate its influence on apoptosis, cell proliferation and pathways involved in molecular mechanisms of chemoresistance to 5-FU. Results showed that high miR-218 expression was associated with positive response to firstline 5-FU treatment in CRC patients. MiR-218 promoted apoptosis, inhibited cell proliferation and caused cell cycle arrest in CRC cells by suppressing BIRC5 expression. Furthermore, miR-218 enhanced 5-FU cytotoxicity in CRC cells by suppressing the 5-FU targeted enzyme, thymidylate synthase (TS). In conclusion, we demonstrated that high miR-218 expression had a positive prognostic value in 5-FU-based treatments for CRC patients and discovered a novel mechanism mediated by miR-218 to promote apoptosis and to function synergistically with 5-FU to promote chemosensitivity by suppressing BIRC5 and TS in CRC. These suggest the unique potential of miR-218 as a novel candidate for developing miR-218-based therapeutic strategies in CRC.
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, Shandong province, China.
authors.forename: Pei-Long
authors.initials: PL
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, Shandong province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, Shandong province, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, Shandong province, China.
authors.forename: Lu-Tao
authors.initials: LT
authors.lastname: Du
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, Shandong province, China.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, Shandong province, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, Shandong province, China cxwang@sdu.edu.cn.
authors.forename: Chuan-Xin
authors.initials: CX
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000502:physiology*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D011379:Prognosis; D034622:RNA Interference; D000077022:Survivin
chemical_list: D000964:Antimetabolites, Antineoplastic; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D000077022:Survivin; D005472:Fluorouracil