[대학원 생명과학과 세미나 안내]
연사 : 신근유 교수(포항공대 생명과학과)
연제 : Stem cells in regeneration and malignancy: role of Hedgehog signaling
일시 : 2017년 12월 8일 (금) 오후 5시
장소 : 하나과학관 A동 B131호
초청교수 : 안지훈 교수
Abstract
Our research is focused on the signaling networks that operate in stem cell regulation during tissue regeneration and in cancer. We began this research with earlier work that identified epithelial stem cells in bladder. This work focused on the identification of stem cells in bladder and on the characterization of signaling pathways that play a crucial role in the bladder regeneration. This work laid a foundation for our study of the cell of origin for bladder cancer. The core of this work is an examination of the cell of origin of bladder carcinoma using an unbiased carcinogenesis model that mimics human carcinogenesis, addressing long-standing issues concerning the cell of origin in cancer and the natural history of cells as they progress through a pre-cancerous state in invasive carcinoma. Most recent work in my laboratory showed the unexpected role of Hedgehog signaling activity in bladder cancer progression. In this work we showed that, despite its initial presence in the cancer cell of origin, Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma and blockade of stromal response to Shh dramatically accelerates progression. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Furthermore, we showed that the loss of Shh expression during bladder cancer progression results from the hypermethylation of CpG shore of Shh gene, regions that flank promoter CpG islands with less CG density. The expression of Shh is dramatically increased by pharmacological inhibition of DNA methyltransferase activity with low-dose of Azacitidine, thus reducing bladder cancer progression in our BBN-induced urothelial carcinoma model. We also found that the decreased expression of Shh induces aggressive basal-like muscle invasive subtype of urothelial carcinoma whereas the increased expression of Shh induces less aggressive, more differentiated luminal subtype induced by Hh mediated stromal expression of BMP. A favorable effect of BMP pathway activation and the inhibition of DNA methylation with FK506 and Azacitidine, respectively, suggests the potential combinatorial therapy to control the progression in 70-80% patients with noninvasive urothelial carcinoma at initial diagnosis, and to reduce the growth of invasive carcinoma at later stage by differentiating into less aggressive, manageable subtype of bladder cancer.