期刊
MOLECULAR CANCER THERAPEUTICS
卷 12, 期 5, 页码 737-746出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-12-1125
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资金
- Ministry of Health, Labour, and Welfare, Japan
- Japan Society for the Promotion of Science (JSPS), KAKENHI Grant [24650646]
- Grants-in-Aid for Scientific Research [24650646] Funding Source: KAKEN
Gene amplification of HER2/ErbB2 occurs in gastric cancer and the therapeutic efficacy of the HER2-targeted antibody, trastuzumab, has recently been improved against HER2-positive advanced stomach cancer. Here, we examined whether Y-box-binding protein-1 (YB-1) could selectively control HER2 gene expression and cellular sensitivity to EGF receptor (EGFR) family protein-targeted drugs in human gastric cancer cells. HER2 expression was specifically downregulated by YB-1 silencing using its cognate siRNA, whereas there was less change in the expression of EGFR and HER3. Achromatin immunoprecipitation assay revealed the specific binding of YB-1 to its consensus sequence on the 50-regulatory region of HER2. YB-1 knockdown induced drug resistance to lapatinib, a dual EGFR and HER2 kinase inhibitor, and also to erlotinib, an EGFR kinase inhibitor. Moreover, phosphorylation of protein kinase B (Akt) was not markedly affected by lapatinib or erlotinib when YB-1 was silenced. Nuclear YB-1 expression was significantly (P = 0.026) associated with HER2 expression, but not with EGFR or HER3, in patients with gastric cancer (n = 111). The YB-1-HER2 axis may therefore be useful for the further development of personalized therapeutics against gastric cancer by HER2-targeted drugs. (c) 2013 AACR.
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