Identification of Genes with Differential Expression in Acquired Drug-Resistant Gastric Cancer Cells Using High-Density Oligonucleotide Microarrays

Purpose: A major obstacle in chemotherapy is treatment failure due to anticancer drug resistance. The emergence of acquired resistance results from host factors and genetic or epigenetic changes in the cancer cells. The purpose of this study was to identify differentially expressed genes associated with acquisition of resistance in human gastric cancer cells. Experimental Design: We performed global gene expression analysis in the acquired drug-resistant gastric cancer cell lines to the commonly used drugs 5-fluorouracil, doxorubicin, and cisplatin using Affymetrix HG-U133A microarray. The gene expression patterns of 10 chemoresistant gastric cancer cell lines were compared with those of four parent cell lines using fold-change and Wilcoxon’s test for data analysis. Results: We identified over 250 genes differentially expressed in 5-fluorouracil-, cisplatin-, or doxorubicin-resistant gastric cancer cell lines. Our expression analysis also identified eight multidrug resistance candidate genes that were associated with resistance to two or more of the tested chemotherapeutic agents. Among these, midkine (MDK), a heparin-binding growth factor, was overexpressed in all drug-resistant cell lines, strongly suggesting that MDK might contribute to multidrug resistance in gastric cancer cells. Conclusions: Our investigation provides comprehensive gene information associated with acquired resistance to anticancer drugs in gastric cancer cells and a basis for additional functional studies.

[1]  S. Y. Park,et al.  Development and applications of a beta-catenin oligonucleotide microarray: beta-catenin mutations are dominantly found in the proximal colon cancers with microsatellite instability. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  Hironobu Nakayama,et al.  Possible chemoresistance‐related genes for gastric cancer detected by cDNA microarray , 2003, Cancer science.

[3]  J. R. Kelley,et al.  Gastric cancer epidemiology and risk factors. , 2003, Journal of clinical epidemiology.

[4]  Myriam Rochdi,et al.  Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper. , 2002, Cancer research.

[5]  Jan Mollenhauer,et al.  Candidate genes for cross-resistance against DNA-damaging drugs. , 2002, Cancer research.

[6]  Y. Hayashizaki,et al.  Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites , 2002, British Journal of Cancer.

[7]  K. Ogawa,et al.  Copper‐transporting P‐type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: Comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP , 2002, International journal of cancer.

[8]  Rui Li,et al.  Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines , 2002, Oncogene.

[9]  C. Kwak,et al.  Suppression of clusterin expression enhanced cisplatin-induced cytotoxicity on renal cell carcinoma cells. , 2002, Urology.

[10]  W. Sessa,et al.  Inhibitor of apoptosis protein survivin regulates vascular injury , 2002, Nature Medicine.

[11]  Debabrata Banerjee,et al.  Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. , 2002, Biochimica et biophysica acta.

[12]  S. Kubota,et al.  5′-,3′-Inverted Thymidine-modified Antisense Oligodeoxynucleotide Targeting Midkine , 2002, The Journal of Biological Chemistry.

[13]  Dena Leshkowitz,et al.  Identification of a Novel Hypoxia-Inducible Factor 1-Responsive Gene, RTP801, Involved in Apoptosis , 2002, Molecular and Cellular Biology.

[14]  S. Houser,et al.  Overexpression of sorcin, a calcium-binding protein, induces a low level of paclitaxel resistance in human ovarian and breast cancer cells. , 2002, Biochemical pharmacology.

[15]  Yusuke Nakamura,et al.  An integrated database of chemosensitivity to 55 anticancer drugs and gene expression profiles of 39 human cancer cell lines. , 2002, Cancer research.

[16]  Jae-Hyun Park,et al.  RET oligonucleotide microarray for the detection of RET mutations in multiple endocrine neoplasia type 2 syndromes. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  M. Gottesman.  Mechanisms of cancer drug resistance. , 2002, Annual review of medicine.

[18]  Shuichi Tsutsumi,et al.  Global gene expression analysis of gastric cancer by oligonucleotide microarrays. , 2002, Cancer research.

[19]  Y. Yen,et al.  Characterization of the human ribonucleotide reductase M2 subunit gene; genomic structure and promoter analyses , 2001, Cytogenetic and Genome Research.

[20]  H. Miyake,et al.  Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  S. Kubota,et al.  Antisense oligodeoxynucleotide targeted to Midkine, a heparin-binding growth factor, suppresses tumorigenicity of mouse rectal carcinoma cells. , 2001, Cancer research.

[22]  J. G. Park,et al.  Annual Report of the Central Cancer Registry in Korea-1999: Based on Registered Data from 128 Hospitals. , 2001, Cancer research and treatment : official journal of Korean Cancer Association.

[23]  J. Mesirov,et al.  Chemosensitivity prediction by transcriptional profiling , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Essigmann,et al.  Mechanisms of resistance to cisplatin. , 2001, Mutation research.

[25]  M. Bittner,et al.  Monitoring the expression profiles of doxorubicin-induced and doxorubicin-resistant cancer cells by cDNA microarray. , 2000, Cancer research.

[26]  A. Escargueil,et al.  Resistance mechanisms associated with altered intracellular distribution of anticancer agents. , 2000, Pharmacology & therapeutics.

[27]  D. Botstein,et al.  A gene expression database for the molecular pharmacology of cancer , 2000, Nature Genetics.

[28]  T. Muramatsu,et al.  Midkine rescues Wilms' tumor cells from cisplatin-induced apoptosis: regulation of Bcl-2 expression by Midkine. , 2000, Journal of biochemistry.

[29]  崎谷 博征.  Overexpression of midkine in lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine in rats and its increase with progression , 2000 .

[30]  W. Hiddemann,et al.  Suppressive subtractive hybridisation reveals differential expression of serglycin, sorcin, bone marrow proteoglycan and prostate-tumour-inducing gene I (PTI-1) in drug-resistant and sensitive tumour cell lines of haematopoetic origin. , 1999, European journal of cancer.

[31]  J. Robert,et al.  Drug resistance to topoisomerase II inhibitors. , 1998, Biochimie.

[32]  R. Kavlock,et al.  Nucleoside-mediated mitigation of 5-fluorouracil-induced toxicity in synchronized murine erythroleukemic cells. , 1997, Toxicology and applied pharmacology.

[33]  H. S. Kim,et al.  Characteristics of human gastric carcinoma cell lines with induced multidrug resistance. , 1997, Anticancer research.

[34]  Y. Bang,et al.  Establishment and characterization of human gastric carcinoma cell lines , 1997, International journal of cancer.

[35]  T. Muramatsu,et al.  Midkine induces the transformation of NIH3T3 cells. , 1997, British Journal of Cancer.

[36]  B. Kramer,et al.  Chemosensitivity patterns and expression of human multidrug resistance-associated MDR1 gene by human gastric and colorectal carcinoma cell lines. , 1990, Journal of the National Cancer Institute.

[37]  A. Fornace,et al.  Induction of fos RNA by DNA-damaging agents. , 1989, Cancer research.

[38]  S. Steinberg,et al.  Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based colorimetric assay. , 1987, Cancer research.