Biomedical subjects

Yan C Wang

Publications and source records attributed to Yan C Wang.

3 recordsLinked to original sources

PubMed2006

Regional activation of chromosomal arm 7q with and without gene amplification in taxane-selected human ovarian cancer cell lines.

Taxanes are important drugs in the treatment of ovarian and other cancers, but their efficacy is limited by intrinsic and acquired drug resistance. Expression of the multidrug transporter P-glycoprotein, encoded by the MDR1 (ABCB1) gene, is one of the causes of clinical drug resistance to taxanes. To study the mechanisms of MDR1 activation related to taxanes, we established 11 multidrug-resistant variants from six ovarian cancer cell lines by continuous exposure to either paclitaxel or docetaxel. We profiled gene expression and gene copy number alterations in these cell lines using cDNA microarrays and identified a cluster of genes coactivated with MDR1 in 7q21.11-13. Regional activation was evident in nine resistant variants displaying a coexpression pattern of up to 22 genes over an 8-Mb area, including SRI, MGC4175, CLDN12, CROT, and CDK6. In six of these variants, regional activation was driven by gene copy number alterations, with low-level gains or high-level amplifications spanning the involved region. However, three variants displayed regional increases in gene expression even without concomitant gene copy number changes. These results suggest that regional gene activation may be a fundamental mechanism for acquired drug resistance, with or without changes in gene dosage. In addition to numerical and structural chromosomal changes driven by genome instability in cancer cells, other mechanisms might be involved in MDR1 regional activation, such as chromatin remodeling and DNA or histone modifications of the 7q21 region.

Cell Line, Tumor↗

PubMed2005

Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line.

The origin of drug-resistant cells in human cancers has been a fundamental problem of cancer pharmacology. Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions through investigation of the genetic and epigenetic pathways that control the origin of ABCB1 (MDR1) gene activation with acquired multidrug resistance in drug-sensitive human sarcoma (MES-SA cells). The genetic and epigenetic bases of this selected activation involve the initiation of transcription at a site 112 kb upstream of the ABCB1 proximal promoter (P1) in the drug-resistant cells. This activation was associated with a chromatin-remodeling process characterized by an increase in acetylated histone H3 within a 968-bp region 5' of the ABCB1 upstream promoter. These alterations provide both genetic and epigenetic susceptibility for ABCB1 expression in drug-resistant cells. Complete activation of the ABCB1 gene through the coding region was proposed by interactions of selected trans-alterations or epigenetic changes on the ABCB1 proximal promoter, which occurred during initial drug exposure. Thus, our data provide evidence for a major genomic alteration that changes the chromatin structure of the ABCB1 upstream promoter via acetylation of histone H3 initiating ABCB1 activation, further elucidating the genetic and epigenetic bases that determine chemotherapeutic response in drug-resistant derivatives of MES-SA cells.

Acetylation↗

PubMed2003

Gene expression patterns in ovarian carcinomas.

We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly serous papillary) based on their gene expression patterns. The differences may yield insights into the worse prognosis and therapeutic resistance associated with clear cell carcinomas. A comparison of the gene expression patterns in the ovarian cancers to published data of gene expression in breast cancers revealed a large number of differentially expressed genes. We identified a group of 62 genes that correctly classified all 125 breast and ovarian cancer specimens. Among the best discriminators more highly expressed in the ovarian carcinomas were PAX8 (paired box gene 8), mesothelin, and ephrin-B1 (EFNB1). Although estrogen receptor was expressed in both the ovarian and breast cancers, genes that are coregulated with the estrogen receptor in breast cancers, including GATA-3, LIV-1, and X-box binding protein 1, did not show a similar pattern of coexpression in the ovarian cancers.

Adenocarcinoma↗