Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy... More
Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. Less
The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cance... More
The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSESV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models. Less
Background Serous epithelial ovarian cancer (SEOC) is a highly metastatic disease and its progression has been implicated with microRNAs. This study aimed to identify the... More
Background Serous epithelial ovarian cancer (SEOC) is a highly metastatic disease and its progression has been implicated with microRNAs. This study aimed to identify the differentially expressed microRNAs in Malaysian patients with SEOC and examine the microRNAs functional roles in SEOC cells. Methods Twenty-two SEOC and twenty-two normal samples were subjected to miRNA expression profiling using the locked nucleic acid (LNA) quantitative real-time PCR (qPCR). The localization of miR-200c was... Less
Resveratrol (trans-3,4,5’ –trihydroxystilbene) is an active compound in food, such as red grapes, peanuts, and berries. Resveratrol exhibits an anticancer effect on v... More
Resveratrol (trans-3,4,5’ –trihydroxystilbene) is an active compound in food, such as red grapes, peanuts, and berries. Resveratrol exhibits an anticancer effect on various human cancer cells. However, the mechanism of resveratrol-induced anti-cancer effect at the molecular level remains to be elucidated. In this study, the mechanism underlying the anti-cancer effect of resveratrol in human ovarian cancer cells (OVCAR-3 and Caov-3) was investigated using various molecular biology technique... Less
Mirk/dyrk1B kinase is expressed in about 75% of resected human ovarian cancers and in most ovarian cancer cell lines with amplification in the OVCAR3 line. Mirk (minibrai... More
Mirk/dyrk1B kinase is expressed in about 75% of resected human ovarian cancers and in most ovarian cancer cell lines with amplification in the OVCAR3 line. Mirk (minibrain-related kinase) is a member of the Minibrain/dyrk family of related serine/threonine kinases. Mirk maintains cells in a quiescent state by stabilizing the CDK inhibitor p27 and by inducing the breakdown of cyclin D isoforms. Mirk also stabilizes the DREAM complex, which maintains G0 quiescence by sequestering transcription factors needed to enter cycle. By entering a quiescent state, tumor cells can resist the nutrient deficiencies, hypoxic and acidic conditions within the tumor mass. Mirk maintains the viability of quiescent ovarian cancer cells by reducing intracellular levels of reactive oxygen species. CDKN2A-negative ovarian cancer cells treated with a Mirk kinase inhibitor escaped G0/G1 quiescence, entered cycle with high ROS levels and underwent apoptosis. The ROS scavenger N-acetyl cysteine reduced the extent of cancer cell loss. In contrast, the Mirk kinase inhibitor slightly reduced the fraction of G0 quiescent diploid epithelial cells and fibroblasts, and the majority of the cells pushed into cycle accumulated in G2 + M. Apoptotic sub-G0/G1 cells were not detected. Thus, normal cells were spared because of their expression of CDK inhibitors that blocked unregulated cycling and Mirk kinase inhibitor-treated normal diploid cells were about as viable as untreated controls. Less
