Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer.
Lung cancer is the most common cancer that is caused by perturbation of regulatory pathways rather than dysfunction of a single gene. Cisplatin (CDDP; cis-diamminedichloroplatinum II) is the first member of a class of platinum-containing anti-cancer medication, which binds to DNA and triggers apoptosis. CDDP-based chemotherapy is used to treat various types of cancers. However, the efficacy of CDDP in the treatment of non-small-cell lung cancer (NSCLC) is limited by acquired drug resistance. MicroRNAs have recently emerged as key regulators of cancers, and miR-26a is one of down-regulated miRNAs in A549/CDDPres cell line. This study aimed to investigate the role of miR-26a in CDDP resistance in NSCLC as well as the underlying mechanisms.



In this study, we analyzed expressional profiles of CDDP resistance-related mRNA, miRNA, and transcription factors (TF) that regulate miRNA expression in NSCLC. A549 cells were treated with CDDP, miR-26a mimic, or miR-26a inhibitor, and followed by biological analysis including drug sensitivity assay, colony formation assay, terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay, and cell cycle analysis. Luciferase assay was used to determine the target of miR-26a. The regulation of miR-26a in Akt pathway was measured by western blot.



High mobility group A (HMGA) 2 was identified as the target of miR-26a. Overexpression of miR-26a in A549 cells inhibited G1-S transition, increased cell death in response to CDDP treatment, and decreased the colony formation of A549 cells. MiR-26a significantly decreased the expression of E2F1, diminished Akt phosphorylation, and downregulated Bcl2 expression. Cell growth was suppressed by inhibiting HMGA2-mediated E2F1-Akt pathway.



MiR-26a is responsible for A549 cell sensitivity in the treatment of CDDP through regulating HMGA2-mediated E2F1-Akt pathway.
a Department of Thoracic Surgery , Shanghai Pulmonary Hospital, Tongji University School of Medicine , Shanghai , China.
Yong
Y
Yang
a Department of Thoracic Surgery , Shanghai Pulmonary Hospital, Tongji University School of Medicine , Shanghai , China.
Peng
P
Zhang
a Department of Thoracic Surgery , Shanghai Pulmonary Hospital, Tongji University School of Medicine , Shanghai , China.
Yanfeng
Y
Zhao
a Department of Thoracic Surgery , Shanghai Pulmonary Hospital, Tongji University School of Medicine , Shanghai , China.
Jie
J
Yang
a Department of Thoracic Surgery , Shanghai Pulmonary Hospital, Tongji University School of Medicine , Shanghai , China.
Gening
G
Jiang
a Department of Thoracic Surgery , Shanghai Pulmonary Hospital, Tongji University School of Medicine , Shanghai , China.|b Department of Surgery , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.
Jie
J
Fan
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000970:Antineoplastic Agents; D035683:MicroRNAs; D002945:Cisplatin
Cisplatin resistance; E2F1; HMGA2; miR-26a; non-small-cell lung cancer