TrkB/BDNF通路对前列腺癌EMT、anoikis和血管生成的影响及分子机制

Epithelial-mesenchymal transition (EMT) and anoikis resistance are both crucial early events for metastasis cascade, while neovascularization is another rate-limiting step for cancer progression and metastasis. It has been demonstrating that the neurotrophic receptor tyrosine kinase TrkB and its ligand brain derived neurophic factor (TrkB/BDNF) signaling plays vital role in induction of EMT and anoikis resistance as well as promotion of neovascularization. It therefore, is feasible to suppress metastasis by blockade of TrkB/BDNF pathway. In the current proposed project, we will elucidate the impact of TrkB/BDNF signaling in EMT and anoikis resistance in prostate cancer (PCa). Moreover, we will investigate the effect of TrkB/BDNF in the promotion and maintenance of tumor angiogenesis by boosting recruitment, proliferation and survival of marrow-derived endothelial progenitor cells, pro-angiogenic hematopoietic progenitor cells and local endothelial cells. Further, we will determine the role of specific TrkB knockdown in PCa metastasis by inhibiting EMT, provoking anoikis and attenuating tumor angiogenesis via tumor- and vascular endothelial cell lineage-specific expression of TrkB-shRNA, and explore the key targeted genes of TrkB signaling that involve such effects. Additionally, we will choose ceiterin pathways which interplay with TrkB/BDNF and also excise pivotal role in EMT, anoikis resistance and tumor angiogenesis for research targets. The ultimate aim of the proposed project is to clarify the cross talk between those pathways and TrkB/BDNF in inhibition of PCa metastasis and to unveil the molecular mechanism underlying TrkB/BDNF induced bio-effects.

细胞上皮基质转化（EMT）和失巢凋亡（anoikis）耐受是肿瘤转移早期重要事件，血管新生是肿瘤进展和转移的限速步骤。TrkB/BDNF通路可在诱导EMT及anoikis耐受、促进血管生成中发挥关键作用，阻断该通路可能抑制肿瘤转移。本研究拟明确TrkB通路在前列腺癌（PCa）细胞EMT和anoikis耐受中的作用；探讨该通路趋化骨髓来源内皮前体细胞、造血祖细胞和局部内皮细胞，并促使其增殖和存活在肿瘤血管形成和维持中的作用；通过肿瘤组织和血管内皮特异性表达小干扰RNA，靶向性敲低TrkB表达，抑制EMT、诱导anoikis并抑制肿瘤血管生成而影响PCa转移，明确TrkB通路关键靶分子在其中的作用。选择与TrkB/BDNF途径存在交互作用且在EMT、anoikis耐受和血管生成中发挥关键作用的信号通路为切入点，研究其在TrkB/BDNF抑制PCa转移中的作用，明确TrkB通路的分子效应机制。

转移性去势抵抗性前列腺癌（mCRPC）预后极差，但其分子机制尚不清楚。本项目旨在探究脑源性神经生长因子/酪氨酸受体激酶B（BDNF/TrkB）通路在前列腺癌进展中的作用。结果显示：人前列腺癌组织BDNF和TrkB表达均升高，而钙黏素E-cadherin表达降低，且具有相关性；体外研究发现，重组人BDNF处理或过表达TrkB后，人前列腺癌细胞迁移、侵袭、失巢凋亡耐受能力明显增强，过表达TrkB还可导致上皮间质转化（EMT），RNA干扰技术抑制TrkB表达则可逆转EMT的发生。进一步研究表明，蛋白激酶B（AKT）在 BDNF/TrkB 信号介导的的迁移和侵袭能力增强、EMT和失巢凋亡耐受过程中发挥关键作用。体内研究亦证实，过表达TrkB可促进肿瘤生长，而下调TrkB表达则抑制肿瘤生长。因此，BDNF/TrkB 信号通路在前列腺癌进展过程中发挥重要作用，有望成为转移性前列腺癌治疗的潜在新靶点。