title: Alteration of gene expression and DNA methylation in drug-resistant gastric cancer.
abstract: The mechanisms of drug resistance in cancer are not fully elucidated. To study the drug resistance of gastric cancer, we analyzed gene expression and DNA methylation profiles of 5-fluorouracil (5-FU)- and cisplatin (CDDP)-resistant gastric cancer cells and biopsy specimens. Drug-resistant gastric cancer cells were established with culture for >10 months in a medium containing 5-FU or CDDP. Endoscopic biopsy specimens were obtained from gastric cancer patients who underwent chemotherapy with oral fluoropyrimidine S-1 and CDDP. Gene expression and DNA methylation analyses were performed using microarray, and validated using real-time PCR and pyrosequencing, respectively. Out of 17,933 genes, 541 genes commonly increased and 569 genes decreased in both 5-FU- and CDDP-resistant AGS cells. Genes with expression changed by drugs were related to GO term 'extracellular region' and 'p53 signaling pathway' in both 5-FU- and CDDP-treated cells. Expression of 15 genes including KLK13 increased and 12 genes including ETV7 decreased, in both drug-resistant cells and biopsy specimens of two patients after chemotherapy. Out of 10,365 genes evaluated with both expression microarray and methylation microarray, 74 genes were hypermethylated and downregulated, or hypomethylated and upregulated in either 5-FU-resistant or CDDP-resistant cells. Of these genes, expression of 21 genes including FSCN1, CPT1C and NOTCH3, increased from treatment with a demethylating agent. There are alterations of gene expression and DNA methylation in drug-resistant gastric cancer; they may be related to mechanisms of drug resistance and may be useful as biomarkers of gastric cancer drug sensitivity.
authors: Department of Advanced Research of Gastroenterology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors: Osamu
authors: O
authors: Maeda
authors: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors: Takafumi
authors: T
authors: Ando
authors: Department of Gastroenterology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
authors: Naoki
authors: N
authors: Ohmiya
authors: Department of Advanced Research of Gastroenterology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors: Kazuhiro
authors: K
authors: Ishiguro
authors: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors: Osamu
authors: O
authors: Watanabe
authors: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors: Ryoji
authors: R
authors: Miyahara
authors: Department of Hospital Pharmacy, Nagoya University Hospital, Nagoya, Japan.
authors: Yoko
authors: Y
authors: Hibi
authors: Department of Hospital Pharmacy, Nagoya University Hospital, Nagoya, Japan.
authors: Taku
authors: T
authors: Nagai
authors: Department of Hospital Pharmacy, Nagoya University Hospital, Nagoya, Japan.
authors: Kiyofumi
authors: K
authors: Yamada
authors: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors: Hidemi
authors: H
authors: Goto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019175:DNA Methylation / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics*; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents