Nuclear Y-box binding protein-1, a predictive marker of prognosis, is correlated with expression of HER2/ErbB2 and HER3/ErbB3 in non-small cell lung cancer.
BACKGROUND
Nuclear expression of Y-box binding protein-1 (YB-1) is closely associated not only with global drug resistance and expression of several growth factor receptors in various human malignancies but also with overall patient survival.


METHODS
The effect of YB-1 knockdown on expression of epidermal growth factor receptor (EGFR) family proteins was examined by Western blot using human lung cancer cell lines. Immunohistochemistry was used to evaluate the expression of nuclear YB-1 and EGFR family proteins in patients with non-small cell lung cancer (NSCLC) (n = 104).


RESULTS
In the five NSCLC cell lines, expressions of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and hepatocyte growth factor receptor (c-Met) in PC-9 cells; of HER2 and c-Met in EBC-1 cells; and of HER3 in QG56 cells were down-regulated by YB-1 knockdown. By immunohistochemical analysis, we observed that HER3 expression was significantly negatively correlated with nuclear YB-1 expression in squamous cell carcinoma (p = 0.038). HER2 expression was positively correlated with nuclear YB-1 expression in adenocarcinoma (p = 0.052). Nuclear expression of YB-1 correlated with overall survival of all patients (p = 0.028) and of patients with adenocarcinoma (p = 0.007). Furthermore, there was a significant difference in therapeutic efficacies of gefitinib between patients with nuclear YB-1 expression and those with non-nuclear YB-1 expression in patients with NSCLC (p = 0.004, n = 26) but not between those with high and those with low expression of EGFR, HER2, HER3, and c-Met.


CONCLUSIONS
Nuclear YB-1 expression might be essential for the malignant phenotype in lung cancer patients and might be an important biomarker for the development of therapeutic strategy against NSCLC.
Kashihara
Masaki
M
Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Azuma
Koichi
K
Kawahara
Akihiko
A
Basaki
Yuji
Y
Hattori
Satoshi
S
Yanagawa
Takashi
T
Terazaki
Yasuhiro
Y
Takamori
Shinzo
S
Shirouzu
Kazuo
K
Aizawa
Hisamichi
H
Nakano
Kenji
K
Kage
Masayoshi
M
Kuwano
Michihiko
M
Ono
Mayumi
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000502:physiology; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis* / Q000502:physiology; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D020893:Receptor, ErbB-3 / Q000032:analysis*; D051840:Y-Box-Binding Protein 1
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D000077156:Gefitinib; D009687:Nuclear Proteins; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C508053:ERBB2 protein, human