Journal of Bacteriology & Parasitology

Dysfunction of polycomb repressive complex2 (PRC2) promotes the tumorigenesis of human endometrial stromal sarcoma (ESS) through activation of WNT11 signaling pathway

9^th Biotechnology Congress

August 31-September 02, 2015 Orlando,Florida, USA

Xianyong Ma, Jinan Wang, Jianhui Wang, Xiaobin Gao and Jeffrey Sklar

Yale University School of Medicine, USA

Scientific Tracks Abstracts: J Biotechnol Biomater

Abstract:

Human Endometrial Stromal Sarcoma (ESS) represents a very rare gynecological malignant tumor that originates from endometrial stromal cells. Tumorigenesis of ESS can originate from abnormal hormone estrogen level/bleeding, and possible from the chemical insult, radiation and viral infection, as well as genetic predispositions. Recently findings indicate that this type of tumor is highly associated with chromosomal translocation including t (6; 10) (p21; p11) (very rare), t (6; 7) (p21; p15) (>25%) and t (7; 17) (p15; q21) (>50%). These translocations result in production of the fusion proteins of EPC-PHF1, JAZF1-PHF1 and JAZF1-SUZ12 respectively. Very interestingly both of PHF1 and SUZ12 are the poly-comb proteins that involve in poly-comb repressive complex 2/3 (PRC2/3), which is one of the most critical complexes for chromatin compaction and gene inactivation. In this study, we established the HESC cell lines that stably express fusion protein JAZF1-SUZ12, wild type JAZF1 and SUZ12 respectively, carried out the proliferation assay for these cells. The cell line with over expression of fusion protein has significant higher proliferation rate in comparison with the cell line over expressed SUZ12 (P=0.01<0.05), and shows the features of de-differentiation. Next, we globally detected the gene expression patterns for these cell lines together with ESS samples from Yale New-Haven hospital by using micro-array technique. We identified there were 12,817 genes (in total 47323 genes) with same expression behavior among HESC/JAZF1-SUZ12, ESS tumor 1# and ESS tumor 2#. 156 genes with known function are significantly up-regulated (>2 fold) and 15 genes are significantly down-regulated (>2 fold) only in these three samples. These data were further confirmed by qRT-PCR. Analysis of the 156 up-regulated gene indicates there are 9 signaling pathways which are activated and 8 are significant; both P and Benjamini values <0.05 including WNT and cancer signaling pathways. The WNT1, WNT3a, WNT7b, WNT11 and APC2, which are highly up regulated, are involved in both signaling pathway. CHIP analysis shows these four WNT genes are the downstream targets of PRC2-SUZ12, therefore we reasonably detected the tri-methylation level of histone 3 lysine 27 (H3K27Me3) by CHIP assay using anti-H3K27Me3 antibody. Our study shows the fusion protein is significantly decreased the H3K27Me3 level on the promoter region of these target genes (compare with wild type SUZ12). In summary, we confirmed fusion protein of JAZF1-SUZ12 causes the WNT signaling activation via decreasing the H3K27Me3 level on target promoter regions in ESS tumorigenesis. A numbers of small molecule inhibitors of WNT members and RNA interference technique are being used to confirm if inactivating the highly activated WNT signaling pathway can reverse the proliferation ability and stop de-differentiation process of HESC/JAZF1- SUZ12 cells and primary ESS tumor cells.

Biography :

Xianyong Ma received his PhD degree with honors from Central South University in P. R. China, and finished his Post-doctoral studies from Yale University. At present, as a Research Scientist he is working on the mechanism of Human Endometrial Carcinogenesis at Molecular Level in Yale Medical School. He has published more than 40 papers in reputed journals, two book chapters regarding micro-array chips and molecular carcinogenesis, and has been serving as an Editorial Board Member of two reputed journals. He is a Founding Member of Epigeno-max Company for development of new treatment strategy of cancers and cardiologic diseases.

Email: xian-yong.ma@yale.edu