MiR-217 and CAGE form feedback loop and regulates the response to anti-cancer drugs through EGFR and HER2

Youngmi Kim, Hyuna Kim, Deokbum Park, Minho Han, Hansoo Lee, Yun Sil Lee, Jongseon Choe, Young Myeong Kim, Dooil Jeoung

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish
Pages (from-to)10297-10321
Number of pages25
Issue number9
StatePublished - 2016

Bibliographical note

Funding Information:
This work was supported by National Research Foundation Grants (2014R1A2A2A01002448, 2015R1A1A3A04001339 and 2015R1A2A1A15051678), a grant from the BK21 plus Program, and by National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea Grant 1320160. This work was also supported by a grant from ther Kangwon National University.


  • Anti-cancer drug-resistance
  • CAGE
  • EGFR
  • HER2
  • MiR-217


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