Upregulation of HOXA10 in gastric cancer with the intestinal mucin phenotype: reduction during tumor progression and favorable prognosis

Gastric cancer (GC) is one of the most common malignancies worldwide. Better knowledge of the changes in gene expression that occur during gastric carcinogenesis may lead to improvements in diagnosis, treatment and prevention. In this study, we screened for genes upregulated in GC by comparing gene expression profiles from microarray and serial analysis of gene expression and identified the HOXA10 gene. The aim of the present study was to investigate the significance of HOXA10 in GC. Immunohistochemical analysis demonstrated that 221 (30%) of 749 GC cases were positive for HOXA10, whereas HOXA10 was scarcely expressed in non-neoplastic gastric mucosa except in the case of intestinal metaplasia. Next, we analyzed the relationship between HOXA10 expression and clinicopathological characteristics. HOXA10 expression showed a significant inverse correlation with the depth of invasion and was observed more frequently in the differentiated type of GC than in the undifferentiated type of GC. HOXA10 expression was associated with GC with the intestinal mucin phenotype and correlated with CDX2 expression. Furthermore, the prognosis of patients with positive HOXA10 expression was significantly better than in the negative expression cases. 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and wound healing assay revealed that knockdown of HOXA10 in GC cells by short interfering RNA transfection significantly increased viability and motility relative to the negative control, indicating that HOXA10 expression inhibits cell growth and motility. These results suggest that expression of HOXA10 may be a key regulator for GC with the intestinal mucin phenotype

Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis

Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute to the development of ovarian cancer