Publications (280) View all
-
Article: Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma.
[show abstract] [hide abstract]
ABSTRACT: Molecular targeted therapy is expected to be a promising therapeutic approach for the treatment of esophageal squamous cell carcinoma (ESCC); however, the gene amplification status of molecular targeted genes in ESCC remains largely unclear. The gene amplification of EGFR, HER2, FGFR2 and MET was examined using a real-time PCR-based copy number assay of 245 ESCC surgical specimens of formalin-fixed, paraffin-embedded samples. Fluorescence in situ hybridization (FISH) and comparative genomic hybridization analyses verified the results of the copy number assay. EGFR mutation was detected using the Scorpions-ARMS method. The EGFR status and drug sensitivity to an EGFR tyrosine kinase inhibitor was then evaluated in vitro. Gene amplification of EGFR and HER2 was observed in 7% (16/244) and 11% (27/245) of the ESCC specimens. A multivariate analysis revealed that HER2 amplification was a significant predictor of a poor prognosis in patients with stage III post-operative ESCC. The L861Q type of EGFR mutation with hypersensitivity to EGFR tyrosine kinase inhibitor was found in one of the eight ESCC cell lines and one del745 type of EGFR mutation was identified in 107 clinical samples. In addition, we demonstrated for the first time that FGFR2 amplification was observed in 4% (8/196) of the ESCC specimens. MET amplification was observed in 1% (2/196). In conclusion, the frequent gene amplification of EGFR, HER2 and FGFR2 and the presence of active EGFR mutations were observed in ESCC specimens. Our results strongly encourage the development of molecular targeted therapy for ESCC.International Journal of Oncology 04/2013; 42(4):1151-8. · 2.40 Impact Factor -
Article: Slug increases sensitivity to tubulin-binding agents via the downregulation of βIII and βIVa-tubulin in lung cancer cells.
[show abstract] [hide abstract]
ABSTRACT: Transcription factor Slug/SNAI2 (snail homolog 2) plays a key role in the induction of the epithelial mesenchymal transition in cancer cells; however, whether the overexpression of Slug mediates the malignant phenotype and alters drug sensitivity in lung cancer cells remains largely unclear. We investigated Slug focusing on its biological function and involvement in drug sensitivity in lung cancer cells. Stable Slug transfectants showed typical morphological changes compared with control cells. Slug overexpression did not change the cellular proliferations; however, migration activity and anchorage-independent growth activity with an antiapoptotic effect were increased. Interestingly, stable Slug overexpression increased drug sensitivity to tubulin-binding agents including vinorelbine, vincristine, and paclitaxel (5.8- to 8.9-fold increase) in several lung cancer cell lines but did not increase sensitivity to agents other than tubulin-binding agents. Real-time RT-PCR (polymerase chain reaction) and western blotting revealed that Slug overexpression downregulated the expression of βIII and βIVa-tubulin, which is considered to be a major factor determining sensitivity to tubulin-binding agents. A luciferase reporter assay confirmed that Slug suppressed the promoter activity of βIVa-tubulin at a transcriptional level. Slug overexpression enhanced tumor growth, whereas Slug overexpression increased drug sensitivity to vinorelbine with the downregulation of βIII and βIV-tubulin in vivo. Immunohistochemistry of Slug with clinical lung cancer samples showed that Slug overexpression tended to be involved in response to tubulin-binding agents. In conclusion, our data indicate that Slug mediates an aggressive phenotype including enhanced migration activity, anoikis suppression, and tumor growth, but increases sensitivity to tubulin-binding agents via the downregulation of βIII and βIVa-tubulin in lung cancer cells.Cancer medicine. 04/2013; 2(2):144-54. -
Article: SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma.
[show abstract] [hide abstract]
ABSTRACT: Key points SOX4 is consistently expressed in ATL, is involved in ATL cell growth, and induces genes such as GCRK, NAP1 and HDAC8 in ATL.FRA-2/JUND and SOX4 form an important oncogenic cascade in ATL, leading to up-regulation of genes such as HDAC8.Blood 03/2013; · 9.90 Impact Factor -
Article: Gene amplification of ribosomal protein s6 kinase-1 and -2 in gastric cancer.
[show abstract] [hide abstract]
ABSTRACT: The gene amplification of ribosomal protein S6 kinase 1 and 2 (S6K1 and S6K2) and its clinical relevance in gastric cancer remain unclear. A comparative genomic hybridization analysis and DNA copy number assay were performed for nine cancer cell lines. The gene amplification of S6K1 and S6K2 were determined using a DNA copy number assay of 213 gastric cancer tissues. S6K1 and S6K2 amplifications were observed in one and three cancer cell lines, respectively. No amplification of S6K1 was detected in the gastric cancer tissues, while S6K2 amplification was observed in 4.7% of the gastric carcinoma tissues. Patients with stage IV gastric cancer whose tumors exhibited amplification had a significantly shorter overall survival. S6K2 amplification was frequently observed in gastric cancer and was related to a poor prognosis. Our findings may provide novel insight into the dysregulation of mammalian target of rapamycin signaling by S6K2 amplification in gastric cancer.Anticancer research 02/2013; 33(2):469-75. · 1.73 Impact Factor -
Article: MET amplification as a potential therapeutic target in gastric cancer.
[show abstract] [hide abstract]
ABSTRACT: Our aim was to investigate both the prevalence of MET amplification in gastric cancer as well as the potential of this genetic alteration to serve as a therapeutic target in gastric cancer. MET amplification was assessed by initial screening with a PCR-based copy number assay followed by confirmatory FISH analysis in formalin-fixed, paraffin-embedded specimens of gastric cancer obtained at surgery. The effects of MET tyrosine kinase inhibitors (MET-TKIs) in gastric cancer cells with or without MET amplification were also examined. The median MET copy number in 266 cases of gastric cancer was 1.7, with a range of 0.41 to 21.3. We performed FISH analysis for the 15 cases with the highest MET copy numbers. MET amplification was confirmed in the four assessable cases with a MET copy number of at least 4, whereas MET amplification was not detected in those with a gene copy number of less than 4. The prevalence of MET amplification was thus 1.5% (4 out of 266 cases). Inhibition of MET by MET-TKIs resulted in the induction of apoptosis accompanied by attenuation of downstream MET signaling in gastric cancer cell lines with MET amplification but not in those without this genetic change. MET amplification identifies a small but clinically important subgroup of gastric cancer patients who are likely to respond to MET-TKIs. Furthermore, screening with a PCR-based copy number assay is an efficient way to reduce the number of patients requiring confirmation of MET amplification by FISH analysis.Oncotarget 11/2012; · 4.78 Impact Factor
