CD74调控乳腺癌细胞迁移的分子机制

CD74 is a multifaceted protein which overexpresses in multiple cancers including breast cancer. Its expression is associated with the breast cancer metastasis. However, the molecular mechanism underlying its expression and functions remains unclear. According to our preliminary study, we found YB-1 knockdown using RNAi technique decreased the expression level of CD74, suggesting CD74 may be regulated by phospho-YB-1 at either the transcriptional or the post-transcriptional level. Moreover, CD74 knockdown could reduce the levels of Rac1-GTP and phosho-Cofilin which both play critical role in F-actin polymerization and eventually the motility of the breast cancer cells. Based on the preliminary data, we raise a hypothesis: CD74 is regulated by phosphor-YB-1, and CD74 forms a complex together with CD44 to interact TIAM1. As a GEF, TIAM1 promotes Rac1 signaling axis including PAK1, LIMK1/2 and Cofilin, leading to F-actin remodeling. Eventually, the ability of cell migration, invasion and metastasis is affected by this signaling axis. Accordingly, the present project is going to use cell and animal models to elucidate the molecular mechanism underlying the modulation of CD74 expression as well as the functions of CD74 in enhancing F-actin remodeling and migration in breast cancer cells. Hopefully, the study of CD74 can help us understand the metastatic signaling network in breast cancer cells. In addition, it will be helpful for developing the novel anti-metastasis drugs for cancer therapy in the future.

CD74具有多种生物学功能，在多种肿瘤细胞中高表达，并与高转移乳腺癌相关，但其在乳腺癌细胞中表达及调控转移的机制并不清楚。前期实验表明，CD74可能受p-YB-1调控；抑制CD74表达会降低乳腺癌细胞的迁移能力和F-actin 聚合，同时 Rac1-GTP和p-Cofilin水平下降。基于此，提出如下假说：在乳腺癌细胞中， p-YB-1可能在转录或转录后水平调控CD74表达；CD74与CD44形成复合物，通过TIAM1作为GEF活化Rac1，而PAK1作为其下游效应物，进而通过磷酸化LIMK及Cofilin促进F-actin的重构，最终影响乳腺癌细胞的迁移、侵袭和转移能力。本研究拟利用细胞和动物模型，深入探讨CD74在乳腺癌细胞中表达调控的分子机制，以及通过调控微丝组装重构，最终影响肿瘤细胞迁移、侵袭和转移的分子机制。本研究将加深对乳腺癌转移调控网络的了解，以利于将来抗转移药物的研发。

CD74 具有多种生物学功能，在多种肿瘤细胞中高表达，并与高转移乳腺癌相关。我们在临床标本中进行的研究结果表明， BIDC组织中CD74在质膜和细胞质中的表达水平普遍偏高，且CD74的表达水平与淋巴结转移及临床阶段关系密切，CD74表达阳性也可以作为BIDC病人淋巴结转移的生物学标记。.在本研究中我们深入探讨了CD74调控乳腺癌细胞运动迁移过程中的分子机制。发现，在临床标本中，CD74的表达与乳腺癌及淋巴结转移有关；CD74通过RHOA调控CFL1的磷酸化，促进微丝重构而促进细胞表面突出的形成，进而促进乳腺癌细胞的侵袭和迁移；CD74和CD44共同调控乳腺癌细胞的侵袭、迁移，即CD74-CD44 → RHOA → p-CFL1 → 微丝重构 → 乳腺癌细胞侵袭迁移。而CD74的配体MIF抑制CD74与CD44的结合；CD74下调抑制裸鼠移植瘤的生长和转移。.本项目还研究了在多种肿瘤中高表达的YB-1调控CD74水平的分子机制。我们发现YB1调控CD74稳定性进而影响细胞转移；CD74主要有三个乙酰化位点；当细胞中YB1的表达降低时，CD74与去乙酰化酶SIRT1结合减弱，提高了赖氨酸乙酰化水平，促进了CD74的泛素化，在蛋白水平上变得不稳定。.上述发现为乳腺癌的诊断提出了新标记物，为化疗药物的开发提供了新的靶点。