FOXA1对EPOR在前列腺癌中的调控机制

Although significant progress has been made in our understanding of advanced prostate cancer, the metastatic prostate cancer remains incurable. Pioneer transcription factor FOXA1 has been shown to play both promoting proliferative and tumor-suppressive roles in prostate cancer, but the latter is far from understood. We found that FOXA1 negatively regulates EPO Receptor. FOXA1 binds to potential EPOR enhancer. As EPO-EPOR signaling has been recently correlated with prostate cancer progression, we hypothesize that FOXA1 regulates EPOR transcription by directly binding to its enhancer. Loss of FOXA1 induces EPOR thus promotes prostate cancer progression. To test this hypothesis, three specific aims are proposed. In Aim 1 we will elucidate how FOXA1 transcriptionally regulates EPOR. In Aim 2 we will investigate the functional significance of FOXA1 regulation of EPO-EPOR signaling. In Aim 3 we will characterize the downstream pathways of FOXA1-EPO-EPOR in prostate cancer. This proposed study will greatly extends our knowledge on AR-independent roles of FOXA1, and provides novel therapeutic strategies for treatment of metastatic prostate cancer and cancer associated anemia.

前列腺癌的转移治疗是该领域研究的难点和热点。最近的研究表明转录先锋因子FOXA1不但驱动前列腺癌的发生发展，还有抑制其生长和转移的作用。我们的前期工作发现FOXA1负调控促红细胞生成素受体EPOR。FOXA1与EPOR的增强子特异性结合。考虑到EPO和EPOR的表达量与前列腺癌发生发展的正相关关系，我们提出科学假说“FOXA1转录调控EPOR从而影响前列腺癌细胞生长、侵袭和凋亡，最终促进前列腺癌发展”。我们将从三个方面展开深入的研究：第一部分验证前列腺癌中FOXA1对EPOR在分子水平的转录调控关系；第二部分明确FOXA1调控的EPO-EPOR信号通路在前列腺癌生长发展中的功能作用；第三部分探索FOXA1-EPO-EPOR的下游通路并开发基于此的前列腺癌基因治疗策略。本研究着眼于更深入的揭示FOXA1独立于雄激素受体AR的功能，为开发临床前列腺癌患者及其贫血治疗的优化治疗方案提供理论依据。

转移型前列腺癌因其致命性是研究上的一个热点也是治疗上的一个难点。FOXA1在前列腺癌中到底是致癌基因还是抑癌基因仍存在争议。我们的研究结果表明FOXA1抑制EPOR转录，并且FOXA1与EPOR在转移型去势抵抗性前列腺癌中表达上具有负相关性。功能上明确了在细胞和动物水平中FOXA1促进前列腺癌细胞增殖并抑制其转移。通过机制研究揭示了FOXA1结合在EPOR的增强子上，并初步探索了EPOR通过JAK2/STAT3、GRB2、ERBB2等信号通路促进肿瘤细胞增殖和转移。由此合成并筛选鉴定了抑制前列腺癌细胞增殖的候选小分子药物，为前列腺癌的诊断和分子靶向药物的研发提供线索。