RT Journal Article
SR Electronic
T1 Chemotherapy-Regulated microRNA-125–HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 1414
OP 1423
DO 10.1158/1535-7163.MCT-14-0625
VO 14
IS 6
A1 Yagishita, Shigehiro
A1 Fujita, Yu
A1 Kitazono, Satoru
A1 Ko, Ryo
A1 Nakadate, Yusuke
A1 Sawada, Takeshi
A1 Kitamura, Yuka
A1 Shimoyama, Tatsu
A1 Maeda, Yoshiharu
A1 Takahashi, Fumiyuki
A1 Takahashi, Kazuhisa
A1 Tamura, Tomohide
A1 Koizumi, Fumiaki
YR 2015
UL http://mct.aacrjournals.org/content/14/6/1414.abstract
AB Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. For the last several decades, the standard treatment for SCLC has been deadlocked, and new therapeutic strategies are urgently needed. HER2 is a member of the HER family and has been reported to be overexpressed in 30% of SCLC cases with poor prognosis. However, the clinical relevance of HER2-targeted therapy for SCLC remains unclear. Here, we first identify that cytotoxic drugs induce significant HER2 overexpression through microRNA-125a (miR-125a) and miR-125b downregulation, which in turn act as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in SCLC. In this study, we showed that treatment of the HER2-positive SCLC cells, SBC-3 and SBC-5, with cytotoxic drugs induced a significant upregulation of HER2. Cisplatin (CDDP) treatment of SCLC cells resulted in a significant downregulation of miR-125a and miR-125b. We confirmed that miR-125a and miR-125b bound to the 3′-untranslated regions of HER2 mRNA, and that downregulation of miR-125a and miR-125b resulted in upregulation of HER2 in SCLC cells, suggesting a relationship between cytotoxic drug exposure and miR-125/HER2 dysregulation. Furthermore, using a calcein assay, we demonstrated a significantly enhanced cytotoxic effect of CDDP and trastuzumab that was mediated via antibody-dependent cellular cytotoxicity. Finally, we clearly demonstrated the enhanced antitumor effect of these agents in an orthotopic lung cancer model in vivo. Our results offer a novel therapeutic strategy for HER2-positive SCLCs by using trastuzumab combined with cytotoxic drugs. Mol Cancer Ther; 14(6); 1414–23. ©2015 AACR.