Alteration of gene expression and DNA methylation in drug-resistant gastric cancer

Osamu Maeda, Takafumi Ando, Naoki Omiya, Kazuhiro Ishiguro, Osamu Watanabe, Ryoji Miyahara, Yoko Hibi, Taku Nagai, Kiyofumi Yamada, Hidemi Goto

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1883-1890
Number of pages8
JournalOncology Reports
Volume31
Issue number4
DOIs
Publication statusPublished - 01-01-2014

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DNA Methylation
Stomach Neoplasms
Fluorouracil
Gene Expression
Pharmaceutical Preparations
Genes
Drug Resistance
Biopsy
Gastrointestinal Agents
Drug Therapy
Neoplasm Genes
Methylation
Cisplatin
Real-Time Polymerase Chain Reaction
Down-Regulation
Biomarkers
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Maeda, O., Ando, T., Omiya, N., Ishiguro, K., Watanabe, O., Miyahara, R., ... Goto, H. (2014). Alteration of gene expression and DNA methylation in drug-resistant gastric cancer. Oncology Reports, 31(4), 1883-1890. https://doi.org/10.3892/or.2014.3014
Maeda, Osamu ; Ando, Takafumi ; Omiya, Naoki ; Ishiguro, Kazuhiro ; Watanabe, Osamu ; Miyahara, Ryoji ; Hibi, Yoko ; Nagai, Taku ; Yamada, Kiyofumi ; Goto, Hidemi. / Alteration of gene expression and DNA methylation in drug-resistant gastric cancer. In: Oncology Reports. 2014 ; Vol. 31, No. 4. pp. 1883-1890.
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Maeda, O, Ando, T, Omiya, N, Ishiguro, K, Watanabe, O, Miyahara, R, Hibi, Y, Nagai, T, Yamada, K & Goto, H 2014, 'Alteration of gene expression and DNA methylation in drug-resistant gastric cancer', Oncology Reports, vol. 31, no. 4, pp. 1883-1890. https://doi.org/10.3892/or.2014.3014

Alteration of gene expression and DNA methylation in drug-resistant gastric cancer. / Maeda, Osamu; Ando, Takafumi; Omiya, Naoki; Ishiguro, Kazuhiro; Watanabe, Osamu; Miyahara, Ryoji; Hibi, Yoko; Nagai, Taku; Yamada, Kiyofumi; Goto, Hidemi.

In: Oncology Reports, Vol. 31, No. 4, 01.01.2014, p. 1883-1890.

Research output: Contribution to journalArticle

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T1 - Alteration of gene expression and DNA methylation in drug-resistant gastric cancer

AU - Maeda, Osamu

AU - Ando, Takafumi

AU - Omiya, Naoki

AU - Ishiguro, Kazuhiro

AU - Watanabe, Osamu

AU - Miyahara, Ryoji

AU - Hibi, Yoko

AU - Nagai, Taku

AU - Yamada, Kiyofumi

AU - Goto, Hidemi

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N2 - 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.

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