title: Deregulation of the miR-222-ABCG2 regulatory module in tongue squamous cell carcinoma contributes to chemoresistance and enhanced migratory/invasive potential.
abstract: Chemoresistance is often associated with other clinical characteristics such as enhanced migratory/invasive potential. However, the correlation and underlying molecular mechanisms remain unclear. The aim of this study was to elucidate the function of the miR-222-ABCG2 pathway in the correlation between cisplatin (DDP) resistance and enhanced cell migration/invasion in tongue squamous cell carcinoma (TSCC). Using TSCC cell lines and primary cultures from TSCC cases, we first confirmed the correlation among DDP resistance (measured by IC50 values and ABCG2/ERCC1 expression), migratory/invasive potential (assessed by migration/invasion assays) and miR-222 expression. In TSCC cells, siRNA-mediated ABCG2 knockdown led to enhanced DDP responsiveness and reduced migratory/invasive potential, whereas ABCG2 overexpression induced DDP resistance and enhanced cell migration/invasion. Luciferase assays revealed that ABCG2 is a direct target of miR-222. In addition to reducing cell migration/invasion, functional analyses in TSCC cells indicated that miR-222 can reduce expression of the ABCG2 gene and enhance DDP responsiveness. However, co-transfection with ABCG2 cDNA restored both DDP resistance and migration/invasion. Moreover, miR-222 mimics and ABCG2 siRNA inhibited tumor growth and lung metastasis in vivo. Thus, our results verified that DDP resistance is correlated with enhanced migratory/invasive potential in TSCC. ABCG2 is a direct target of miR-222,and deregulation of the miR-222-ABCG2 regulatory module in TSCC contributes to both DDP resistance and enhanced migratory/invasive potential.
authors.affiliation: Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Luodan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Haikuo
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qianting
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Anxun
authors.initials: A
authors.lastname: Wang
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002945:Cisplatin; D035683:MicroRNAs; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human; C525710:MIR222, human
keywords: ABCG2; chemoresistance; cisplatin; metastasis; tongue squamous cell carcinoma