Hepatocyte growth factor and HER2/neu downregulate expression of apoptosis-inducing factor in non-small cell lung cancer

Yung-Yen Chiang; Kuan-Chih Chow; Tze-Yi Lin; I-Ping Chiang; Hsing-Yuan Fang

doi:10.3892/or.2013.2867

Hepatocyte growth factor and HER2/neu downregulate expression of apoptosis-inducing factor in non-small cell lung cancer

Oncol Rep. 2014 Feb;31(2):597-604. doi: 10.3892/or.2013.2867. Epub 2013 Nov 25.

Authors

Yung-Yen Chiang¹, Kuan-Chih Chow², Tze-Yi Lin³, I-Ping Chiang³, Hsing-Yuan Fang⁴

Affiliations

¹ Department of Dental Laboratory Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C.
² Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan, R.O.C.
³ Department of Pathology, China Medical University Hospital, Taichung, Taiwan, R.O.C.
⁴ Department of Surgery, China Medical University Hospital, Taichung, Taiwan, R.O.C.

PMID: 24276579
DOI: 10.3892/or.2013.2867

Abstract

Our previous study showed that patients with advanced stages of non-small cell lung cancer (NSCLC) were frequently detected with upregulation of hepatocyte growth factor (HGF). In vitro, HGF reduced expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in NSCLC cells. The effect of HGF was via HGF receptor (c-MET) and the downstream effector, focal adhesion kinase (FAK). In this study, we determined the prognostic value of AIF in NSCLC patients. AIF expression was determined by immunohistochemistry and immunoblotting. Our data show that AIF expression was associated with better prognosis. Expression of AIF inversely correlated with that of positive NSCLC markers, e.g., dihydrodiol dehydrogenase (DDH), c-MET, short oncostatin M receptor (OSMRs), matrix metalloproteinase (MMP)-1, and HER2/neu, which were closely associated with drug resistance, tumor recurrence, metastasis and poor prognosis. Noteworthy, silence of HER2/neu gene expression increases AIF level and drug sensitivity. Addition of HGF inhibits AIF expression in HER2/neu-silenced cells. These results suggested that both HGF and HER2/neu affect drug resistance by regulating AIF expression in NSCLC.

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / mortality
Adenocarcinoma of Lung
Animals
Antineoplastic Agents / pharmacology
Apoptosis / genetics*
Apoptosis Inducing Factor / biosynthesis*
Apoptosis Inducing Factor / genetics
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / mortality
Cell Cycle Proteins / biosynthesis
Checkpoint Kinase 1
Cisplatin / pharmacology
Disease-Free Survival
Down-Regulation
Drug Resistance, Neoplasm / genetics
Focal Adhesion Kinase 1 / metabolism
Gene Expression Regulation, Neoplastic
Hepatocyte Growth Factor / genetics*
Humans
Lung Neoplasms / genetics
Lung Neoplasms / mortality
Male
Matrix Metalloproteinase 1 / biosynthesis
Mice
Mice, Inbred BALB C
Neoplasm Metastasis / genetics
Neoplasm Recurrence, Local / genetics
Nuclear Proteins / biosynthesis
Oncostatin M Receptor beta Subunit / biosynthesis
Oxidoreductases / biosynthesis
Protein Kinases / biosynthesis
Proto-Oncogene Proteins c-met / biosynthesis
RNA Interference
RNA, Small Interfering
Receptor, ErbB-2 / biosynthesis
Receptor, ErbB-2 / genetics*
Receptor, ErbB-2 / immunology
Smoking
Survival
Treatment Outcome

Substances

Antineoplastic Agents
Apoptosis Inducing Factor
Cell Cycle Proteins
NBN protein, human
Nuclear Proteins
OSMR protein, human
Oncostatin M Receptor beta Subunit
RNA, Small Interfering
Hepatocyte Growth Factor
Oxidoreductases
trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
Protein Kinases
ERBB2 protein, human
MET protein, human
Proto-Oncogene Proteins c-met
Receptor, ErbB-2
Focal Adhesion Kinase 1
PTK2 protein, human
Checkpoint Kinase 1
MMP1 protein, human
Matrix Metalloproteinase 1
Cisplatin