MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET

Jian-Ya Zhou; Xi Chen; Jing Zhao; Zhang Bao; Xing Chen; Pei Zhang; Zhen-Feng Liu; Jian-Ying Zhou

doi:10.1016/j.canlet.2014.06.010

MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET

Cancer Lett. 2014 Sep 1;351(2):265-71. doi: 10.1016/j.canlet.2014.06.010. Epub 2014 Jun 28.

Authors

Jian-Ya Zhou¹, Xi Chen¹, Jing Zhao², Zhang Bao¹, Xing Chen¹, Pei Zhang¹, Zhen-Feng Liu³, Jian-Ying Zhou⁴

Affiliations

¹ Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
³ PET Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁴ Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: zjyhz@zju.edu.cn.

PMID: 24983493
DOI: 10.1016/j.canlet.2014.06.010

Abstract

In non-small-cell lung cancer (NSCLC) that harbours an activating epidermal growth factor receptor (EGFR) mutation, over-expression of hepatocyte growth factor (HGF) is an important mechanism involved in the acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) by restoring activity of the PI3K/Akt pathway via phosphorylation of MET. In our study, we found that the forced expression of miR-34a inhibited cell growth and induced apoptosis partly by targeting MET in HGF-induced gefitinib-resistant HCC827 and PC-9 cells. Furthermore, dramatic tumour regression was observed in the miR-34a plus gefitinib group in HGF-induced gefitinib resistant mouse xenograft models. This study demonstrates for the first time that miR-34a rescues HGF-induced gefitinib resistance in EGFR mutant NSCLC cells.

Keywords: Gefitinib resistance; HGF; Lung cancer; MET; miR-34a.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Carcinoma, Non-Small-Cell Lung / therapy*
Cell Growth Processes / drug effects
Cell Line, Tumor
Down-Regulation
Drug Resistance, Neoplasm
ErbB Receptors / genetics*
ErbB Receptors / metabolism
Female
Gefitinib
Hepatocyte Growth Factor / genetics*
Hepatocyte Growth Factor / metabolism
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Lung Neoplasms / therapy*
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics*
MicroRNAs / metabolism
Proto-Oncogene Proteins c-met / antagonists & inhibitors
Proto-Oncogene Proteins c-met / biosynthesis
Proto-Oncogene Proteins c-met / genetics*
Proto-Oncogene Proteins c-met / metabolism
Quinazolines / pharmacology*
Random Allocation
Transfection
Xenograft Model Antitumor Assays

Substances

3' Untranslated Regions
Antineoplastic Agents
HGF protein, human
MIRN34 microRNA, human
MicroRNAs
Quinazolines
Hepatocyte Growth Factor
EGFR protein, human
ErbB Receptors
MET protein, human
Proto-Oncogene Proteins c-met
Gefitinib