G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression. Cancer Res; 70(20); 7830-40. ©2010 AACR.

Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5′-ESR1/GREB1 and 3′-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, α-inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.

Background Vaccine is supposed to be the most effective means to prevent COVID-19 as it may not only save lives but also reduce productivity loss due to resuming pre-pandemic activities. Providing the results of economic evaluation for mass vaccination is paramount important for all stakeholders worldwide. Methods We developed a Markov decision tree for the economic evaluation of mass vaccination against COVID-19. The effectiveness of reducing outcomes after the administration of three COVID-19 vaccines (BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and AZD1222 (Oxford-AstraZeneca)) were modelled with empirical parameters obtained from literatures. The direct cost of vaccine and COVID-19 related medical cost, the indirect cost of productivity loss due to vaccine jabs and hospitalization, and the productivity loss were accumulated given different vaccination scenarios. We reported the incremental cost-utility ratio and benefit/cost (B/C) ratio of three vaccines compared to no vaccination with a probabilistic approach. Results Moderna and Pfizer vaccines won the greatest effectiveness among the three vaccines under consideration. After taking both direct and indirect costs into account, all of the three vaccines dominated no vaccination strategy. The results of B/C ratio show that one dollar invested in vaccine would have USD $13, USD $23, and USD $28 in return for Moderna, Pfizer, and AstraZeneca, respectively when health and education loss are considered. The corresponding figures taking value of the statistical life into account were USD $176, USD $300, and USD $443. Conclusion Mass vaccination against COVID-19 with three current available vaccines is cost-saving for gaining more lives and less cost incurred.