title: Restoration of microRNA‑218 increases cellular chemosensitivity to cervical cancer by inhibiting cell‑cycle progression.
abstract: We previously reported frequent loss of microRNA‑218 (miR‑218) in human cervical cancer, which was associated with tumor progression and poor prognosis. In this study, we investigated whether restoration of the miR‑218 level is a valid strategy for the treatment of cervical cancer. The expression of miR‑218 in cervical cancer samples and cell lines was quantified by reverse transcription TaqMan quantitative (RT‑q)PCR. Overexpression of miR‑218 was achieved by both transient and stable transfection, using a miR‑218 mimic and a miR‑218‑expressing plasmid, respectively. Alterations in cellular proliferation and cell‑cycle progression were measured by the MTT assay and flow cytometry analysis. Nude mice bearing SiHa xenografts were used to investigate the functions of miR‑218 and carboplatin on tumor growth and weight. The expression of cycle‑related proteins was detected by western blotting and immunohistochemical staining. In vitro, miR‑218 significantly inhibited cellular growth in all four cell lines tested (P=0.021 for CaSki, P=0.009 for HeLa, P=0.016 for SiHa, and P=0.029 for C33A). Overexpression of miR‑218 induced G1 phase arrest and reduced expression of cyclin D1 and CDK4. In vivo, restoration of miR‑218 notably inhibited tumor growth and decreased tumor weight. In primary cultured samples, tumors with high levels of miR‑218 were more sensitive to carboplatin (R2=0.3319, P=0.0026); consistently, miR‑218 overexpression suppressed tumor growth, induced cell‑cycle arrest, and reduced the cyclin D1 level. Based on these and previous results, we conclude that restoration of the miR‑218 level inhibits the growth of cervical cancer cells both in vitro and in vivo; furthermore, overexpression of miR‑218 sensitizes cervical cancer cells to carboplatin. Our findings suggest a novel therapy for cervical cancer based on miR‑218, especially in patients with reduced levels of miR‑218.
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Ruofan
authors.initials: R
authors.lastname: Dong
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital of the China Welfare Institute Affiliated to Shanghai Jiaotong University, Shanghai 200030, P.R. China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200080, P.R. China.
authors.forename: Guiqiang
authors.initials: G
authors.lastname: Du
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Jiangnan University and the Fourth People's Hospital of Wuxi, Wuxi, Jiangsu 214062, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Jiangnan University and the Fourth People's Hospital of Wuxi, Wuxi, Jiangsu 214062, P.R. China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Caiping
authors.initials: C
authors.lastname: Mao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D014162:Transfection / Q000379:methods; D002583:Uterine Cervical Neoplasms / Q000235:genetics*
chemical_list: C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4