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

doi:10.18632/oncotarget.7185

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

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

MicroRNA array analysis revealed that miR-217 expression was decreased in anti-cancer drug-resistant Malme3M^R 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 Malme3M^R cells showed an increased expression of pEGFR^Y845. CAGE and miR-217 inhibitor regulated the expression of pEGFR^Y845. 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 Malme3M^R 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 language	English
Pages (from-to)	10297-10321
Number of pages	25
Journal	Oncotarget
Volume	7
Issue number	9
DOIs	https://doi.org/10.18632/oncotarget.7185
State	Published - 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.

Keywords

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

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

abstract = "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.",

keywords = "Anti-cancer drug-resistance, CAGE, EGFR, HER2, MiR-217",

author = "Youngmi Kim and Hyuna Kim and Deokbum Park and Minho Han and Hansoo Lee and Lee, {Yun Sil} and Jongseon Choe and Kim, {Young Myeong} and Dooil Jeoung",

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.",

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AU - Kim, Youngmi

AU - Kim, Hyuna

AU - Park, Deokbum

AU - Han, Minho

AU - Lee, Hansoo

AU - Lee, Yun Sil

AU - Choe, Jongseon

AU - Kim, Young Myeong

AU - Jeoung, Dooil

N1 - 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.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Anti-cancer drug-resistance

KW - CAGE

KW - EGFR

KW - HER2

KW - MiR-217

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SN - 1949-2553

VL - 7

SP - 10297

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JO - Oncotarget

JF - Oncotarget

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

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