| To better elaborate my research achievements from the aspects of drug development and gene therapy, my research work was divided into two distinct parts. In the first part,by which mechanism, plumbagin, the Chinese herb monomer, inhibits tumor growth through anti-angiogenesis function was discussed; in the second part, how LGR4/GPR48regulate breast cancer initiation and progression through cancer stem cell was lucubrated.1. Angiogenesis is the multi-process composing of endothelial cell proliferation, migration and interaction as well as corporation with the environments based on the existing vessels. Because angiogenesis is the commonality for all the tumor development, drugs designed to target angiogenesis are of high clinical value.Plumbagin is a crystal compound isolated from some Chinese herbs such as plumbaginaceae, Ebenaceae and Droseraceae. Previous studies showed its antibacterial, antifertility, anticoagulant and anti-cancer properties. And, recent studies reported its antiatherosclerotic and anti-inflammation effects as well. However its function in tumor angiogenesis has not yet been reported. So in the first part, I discovered that plumbagin can specifically inhibit endothelial cell proliferation and VEGF-induced migration. Furthermore, in chick embryo chorioallantoic membrane and mouse corneal assay, plumbagin exhibits strong anti-angiogenesis effect. In the human colon cancer and prostate cancer xenograft assays, plumbagin inhibits angiogenesis in vivo. To explore the underlined molecular mechanism, we found that plumbagin significantly decreased the ability of endothelial cell to from F-actin stress fiber under the VEGF induction. One of the most important signal pathways that cause this phenomenon is Rac-PAK1-LIMK-Cofilin pathway. Besides, plumbagin also regulates the proliferation of endothelial cells, which is controlled by MEK-ERK/JNK pathway. Both of these two pathways have the common upper stream regulator Ras, which is controlled by VEGFR2. Hence, we tested the role of plumbagin in this cascade, and proved that plmbagin can inhibit the phosphorylation of VEGFR2in the endothelial cells and down-regulate the VEGF activation for downstream signals of Ras pathway, then affects endothelial cell migration and proliferation, and ultimately inhibits tumor angiogenesis. Based on our study, plumbagin could be an anti-cancer drug candidate.2. Cancer stem study is a new field for cancer research, and it is believed that the carcinomas originate from so called cancer stem cell population upon the oncogenic hit. This theory also provides new explanation on drug resistance, anti-radioactivity properties of cancer cells. Inevitably, some discussions and questions were raised up coming with the new theory, including whether the cancer treatment should switch from the traditional to the newly merging one. As a result, more research has been done to target on signaling pathways that are unique for cancer stem cell.G coupled protein family consists of proteins that are characterized by a7transmembarane domain, and it function as a signal transducer. The loss of function of these proteins will lead to multiple human diseases, so50%to60%drugs approved by FDA are designed to specifically target this particular family. Numerous studies have found that tumor cell can take advantage GPCR signaling to overcome the obstacles preventing them from grow wild, and invade other organs through circulation by getting the nutrients and oxygen they need to survive. Therefore, it is important to unravel the mechanism under the regulation of GPCR family, and the success to do so will definitely help us get new strategy to diagnose and eventually win the battle against cancer.LGR4/GPR48belongs to GPCR family, and we have found that the deletion of LGR4in mouse model led to severe development defect in bone, eye, renal and reproduction system. Our most recent paper also points out the importance of LGR4mammary gland development. However, the function of LGR4in cancer including breast cancer is barely known. Base on the data we have so far, we can conclude that LGR4must play a role in breast cancer, but the mechanism still not clear. To address this question, we crossed LGR4null/ko mouse with WNT1driven mouse tumor model. Interestingly, the progression of tumor, and the function of cells labeled by CD90+CD24+, the marker for breast cancer stem cell, are significantly suppressed in WNT+LGR4-/-LGR4mice. We also proved that the cancer stem cells population sorted from Wntl+LGR4-/-mice have poorer ability in self-renewal, in ivtro differentiation and in vivo tumor regeneration. Altogether, LGR4could be an essential pathway for cancer stem cell, therefore it has potential to become a promising drug target. |
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