原癌基因AEG-1网络调控肿瘤细胞转移和胁迫抵抗的分子机制

It has been demonstrated that AEG-1 is a multi-functional onco-protein that highly related to tumor metastasis. The precise mechanism underlying its function, however, is still under largely unclear. Our preliminary data showed that AEG-1 could promote both early and latter stage of tumor metastasis. In early stage of metastasis, AEG-1 specifically inhibits TGF-β induced cytostasis and induces EMT signal. Furthermore, we found that, AEG-1 inhibits growth inhibition via direct interaction with SMAD2,but not SMAD3, and downregulated genes transcripted by SMAD2, but it has no effect on the EMT executed by SMAD3. Whereas, in later stage of tumor metastasis, AEG-1 promotes tumor cell survival under multiple stress conditions that strongly strengthen the ability of metastasis establishment in distant tissue. Importantly, we uncovered an AEG-1/RNA binding protein complex via screening of AEG-1 interacting molecules. Moreover, we demonstrated that, through stabilizing protein translation essential for tumor cell survival and attenuate formation of stress induced RNA granules, AEG-1/RNA binding protein complex carries out extensive anti-stress ability. In the current project, we aim to further investigate the mechanism by which AEG-1 governs the two central steps of tumor metastasis that is critical theoretical basis for achieving comprehensive control of tumor metastasis.

AEG-1被证明是肿瘤转移高度相关的多功能癌基因，正受到广泛重视；然而其通过何种分子机制直接参与肿瘤转移则不清楚。我们发现AEG-1能够同时促进肿瘤转移的前期以及后期事件(Cancer Res 2010; Oncogene 2009)。进一步研究发现，在转移前期AEG-1特异去除TGFβ介导的生长抑制，增强TGFβ介导的EMT过程，使TGFβ功能逆转。在分子水平，AEG-1与SMAD2特异结合，抑制转录下游生长抑制基因，而不影响SMAD3介导的EMT。在转移后期的定植过程中，AEG-1促进癌细胞抵抗多种胁迫信号，大大增强其在远处组织的定植。通过筛选AEG-1结合分子，我们发现了全新的AEG-1/RNA结合蛋白复合体，后者通过稳定蛋白翻译，抑制胁迫诱导的RNA颗粒形成，完成广泛的胁迫抑制。本课题将基于已有基础，深入探讨AEG-1参与肿瘤转移的上述两个核心问题，为综合抑制肿瘤转移提供基础。

肿瘤的转移、复发以及放化疗抵抗等是恶性肿瘤重要的生物学特征，这些恶性表型使得恶性肿瘤的成为致死性疾病。探究肿瘤恶性表型调控机制，可为寻找肿瘤治疗新靶点提供理论依据。然而肿瘤的转移、复发以及放化疗抵抗的具体分子机制极端复杂，远未得以阐明。本研究项目主要针对AEG-1和microRNA在肿瘤恶性表型调控中的具体生物学功能、分子机制以及形成的复杂调控网络进行了探究。在研究中，我们发现：(1) AEG-1与p300及c-Jun形成复合体，AEG-1通过促进p300对c-Jun的乙酰化增强c-Jun转录活性，介导了恶性肿瘤的增殖和血管新生，这在肿瘤转移并形成转移灶的过程中至关重要。并且AEG-1在恶性肿瘤中的高表达指示预后不良(Mol Cell Biol. 2016)。(2) 非小细胞肺癌中异常高表达的miR-582抑制Wnt/β-catenin信号通路负性调控因子AXIN2、DKK3和SFRP1的表达，激活Wnt/β-catenin信号通路，从而促进肿瘤成瘤以及放化疗抵抗(Nat Commun. 2015)。(3) miR-374a通过同时下调WNT/β-catenin信号通路的多个靶蛋白(WIF1, WNT5A, PTEN)，持续激活WNT/β-catenin信号通路从而促进乳腺癌细胞发生上皮间质化和远处转移(J Clin Invest. 2013)。(4) 肿瘤的转移与NF-κB信号通路异常激活相关，而URGCP在肿瘤中的异常高表达是NF-κB信号通路激活的重要原因，并且URGCP可作为指示不良预后的预测因子(Oncotarget. 2015)。(5) miR-186在肺腺癌中低表达，且miR-186的表达越低，患者的生存预差。miR-186可通过抑制细胞周期中的重要调控因子CCND1、CDK2和CDK6的表达，抑制细胞周期，从而抑制肺腺癌细胞的增殖(Cancer Res. 2013)。通过以上研究得知AEG1及其可能参与调控的microRNAs在肿瘤恶性表型的调控中具有重要作用，可能成为恶性肿瘤新的治疗靶点。