维甲酸受体β2（RARB2）在肿瘤转移中作用及其调控机理的研究

Metastasis, the spread and growth of tumor cells to distant organs,represents the most devastating attribute of cancer, causes the majority ofcancer patient deaths. The molecular mechanisms of how the metastasis progress remains one of the most enigmatic aspectsof the disease. Our previous studies have shown that the transcription level of RARB2 is much lower in metastatic breast cancer samples than that in the primary breast cancer specimens. Furthermore, we have shown that the non-metastatic T47D breast cancer cells became invasive after functionally inactivating RARB2. All these indicate that RARB2 functions as a metastasis suppressor gene. However, the molecular mechanism ofRARB2 protecting against tumor metastasis is still unknown. Based on our preliminary results, we propose to investigate the potential key downstream genes or key signaling pathways of the RARB2 gene, which play central roles to inhibit tumor metastasis. To do these, we will molecularly dissect the cellular and mouse models, as well as human breast and lung cancer samples to define the molecular mechanism of RARB2's metastasis-inhibition effect. We expect that through performing the proposed studies,we may pinpoint the key genes or pathways etiologically involved in metastasis progression. Subsequently, functional inhibition of these target genes or pathwaysmay provide a novel strategy to prevent or treat breast and lung cancer patients.

癌转移不仅是肿瘤恶化的标志，还是治疗失败与死亡的重要原因。目前肿瘤转移机理尚未明确。申请人前期研究发现1）乳腺癌转移组织中维甲酸受体β2（RARB2）低表达；2）非转移性乳腺癌细胞中RARB2高表达； 预实验发现非转移肿瘤细胞内RARB2功能缺失提高该细胞转移力，提示RARB2可抑制肿瘤转移，但作用机制亟待深入探索。在前期研究基础上，本项目以乳腺癌与肺癌考察对象通过分子、细胞、实验动物与临床手术标本分析RARB2基因在肿瘤转移中的临床意义、生物学功能、作用靶点及其分子机制。揭示RARB2基因在肿瘤转移中的抑制功能与机理，因此本研究将为阐明肿瘤转移研究提供新思路，研究的结果将为肿瘤转移治疗与新药筛选提供新手段和靶点。

维甲酸受体β2（RARB2）是维甲酸（ATRA或RA）结合受体之一。维甲酸与其受体结合，参与多种细胞功能，调节肿瘤增殖与转移。此外，研究已证实整合素β1、细胞粘附分子CD44及Bmi1促进肿瘤转移。故项目组在前期研究基础之上，借助肺癌与乳腺癌细胞模型，开展了RARB2在肿瘤转移中作用及其调控机理的研究，通过研究发现：1）RARB2表达具有重要临床意义；2）ATRA（RA）通过RARB2抑制肺癌与乳腺癌细胞转移；3）RARB2通过调节整合素β1与CD44表达与分布主要是内吞发挥抑制转移功能；4）RA不仅抑制DAB2表达，还通过RARB2促进DAB2IP与DAB2相互作用，促进膜蛋白整合素β1与CD44内吞；5）DAB2IP抑制Bmi1入核，抑制肿瘤转移。从而证实了RARB2促进DAB2IP与DAB2相互作用，从而不仅抑制整合素β1与CD44表达，还通过内吞调节膜分布；此外还通过DAB2IP抑制Bmi1入核，抑制癌细胞转移的分子机制。因此，本研究研究分析了RARB2基因在肿瘤转移中的临床意义、生物学功能、作用靶点及其分子机制，从而揭示了RARB2基因在肿瘤转移中的抑制功能与机理，进而为阐明肿瘤转移研究提供了新思路，还为肿瘤转移治疗与新药筛选提供了新手段和靶点。