miR-217 and CAGE form feedback loop and regulates the response to anti-cancer drugs through EGFR and HER2
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Youngmi Kim1,*, Hyuna Kim1,*, Deokbum Park1,*, Minho Han1, Hansoo Lee2, Yun Sil Lee3, Jongseon Choe4, Young Myeong Kim4, Dooil Jeoung1
1Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200–701, Korea
2Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon 200–701, Korea
3College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
4Graduate School of Medicine, Kangwon National University, Chunchon 200–701, Korea
*These authors contributed equally to this work
Dooil Jeoung, e-mail: [email protected]
Keywords: anti-cancer drug-resistance, CAGE, EGFR, HER2, miR-217
Received: October 05, 2015 Accepted: January 23, 2016 Published: February 04, 2016
MicroRNA array analysis revealed that miR-217 expression was decreased in anti-cancer drug-resistant Malme3MR cancer cells. CAGE, a cancer/testis antigen, was predicted as a target of miR-217. Luciferase activity and ChIP assays revealed a negative feedback relationship between CAGE and miR-217. miR-217 and CAGE oppositely regulated the response to anti-cancer drugs such as taxol, gefitinib and trastuzumab, an inhibitor of HER2. miR-217 negatively regulated the tumorigenic, metastatic, angiogenic, migration and invasion potential of cancer cells. The xenograft of Malme3MR cells showed an increased expression of pEGFRY845. CAGE and miR-217 inhibitor regulated the expression of pEGFRY845. CAGE showed interactions with EGFR and HER2 and regulated the in vivo sensitivity to trastuzumab. The down-regulation of EGFR or HER2 enhanced the sensitivity to anti-cancer drugs. CAGE showed direct regulation of HER2 and was necessary for the interaction between EGFR and HER2 in Malme3MR cells. miR-217 inhibitor induced interactions of CAGE with EGFR and HER2 in Malme3M cells. The inhibition of EGFR by CAGE-binding GTGKT peptide enhanced the sensitivity to gefitinib and trastuzumab and prevented interactions of EGFR with CAGE and HER2. Our results show that miR-217-CAGE feedback loop serves as a target for overcoming resistance to various anti-cancer drugs, including EGFR and HER2 inhibitors.
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