多胺微环境对肝癌细胞转移性能及AKT功能的影响

Tumor metastasis is one of mainly character of malignancy, and also the capital reason of patient death. Although tumor metastasis is control by gene, the microenvironment is an indispensable “soil”for adaptability of metastatic cells. Polyamine concentration abnormally increase is a mainly microenvironment for tumor cell growth. In recent years, we found that many polyamine conjugates exert potent against tumor growth and metastatic activity via decrease polyamine concentration and inhibition AKT signal pathway. Lately, we also found that high polyamine microenvironment could facilitate blood vessel neogenesis in chick embryo chorioallantoic membrane model, vascular endothelial cell proliferation, and metastasis and invasion of AKT1-overexpression hepatoma HepG2 cell line. However, AKT1 siRNA could prevent these effects. Hepatocellular carcinoma (HCC) is one of the main causes of death in cancer, especially in China. The object of this program is to investigate the relationship between polyamine microenvironment and hepatoma metastasis, the effect of subtype of AKT (AKT1, AKT2, AKT3) and polyamine constituent (putrescine, spermidine, spermine) in hepatoma metastasis. After this investigation, we could understand the significant biological process in hepatoma metastasis and invasion, elucidate the molecular mechanism of polyamine microenvironment and AKT in hepatoma metastasis. Collectively, these observations could gain further insight into the molecular mechanisms of hepatoma metastasis. Importantly, molecular mechanisms elucidation provides clue for the preservation and/or treatment of hepatoma metastasis.

肿瘤转移是恶性肿瘤的主要特征之一，也是导致患者死亡的首要因素。虽然肿瘤转移主要由基因决定，但微环境对其适应性是必不可少的“土壤”。多胺含量异常升高是肿瘤生长的重要微环境之一，我们近几年的研究发现多胺缀合物可干扰多胺稳态，通过降低肿瘤细胞内的多胺含量并抑制 AKT信号通路从而抑制肿瘤的生长及转移；近期又发现高多胺微环境可促进新生血管的形成及 AKT1高表达肝癌细胞的运动及侵袭能力；反之，AKT1 siRNA可逆转该作用。本项目通过在分子水平、细胞水平以及动物模型上探寻不同的肿瘤多胺微环境对肝癌转移性能及AKT亚型功能的调控，研究天然多胺 (腐胺、精脒、精胺)和AKT各亚型 (AKT1、AKT2、AKT3)与肝癌转移的关系，了解肝癌细胞获得迁移和侵袭能力的重要生物学过程，明确它们在肝癌转移中的病理意义。本课题的完成不仅对理解肝癌转移的分子机制具有理论意义，也对肝癌转移的预防和治疗具有实践意义。

肿瘤转移是恶性肿瘤的主要特征之一，也是导致患者死亡的首要因素。虽然肿瘤转移主要由基因决定，但微环境对其适应性是必不可少的“土壤”。本项目通过在分子水平、细胞水平以及动物模型上探寻不同的肿瘤多胺微环境对肝癌转移性能及AKT 亚型功能的调控，研究天然多胺 (腐胺、精脒、精胺)和AKT 各亚型 (AKT1、AKT2、AKT3)与肝癌转移的关系，了解肝癌细胞获得迁移和侵袭能力的重要生物学过程，明确它们在肝癌转移中的病理意义。实验结果表明多胺含量增加促进肝癌的转移，而降低多胺含量则抑制转移，三种多胺 (腐胺、精脒、精胺) 均可促进肝癌转移，精脒作用最强、精胺次之，腐胺最弱。AKT在多胺促进肝癌转移中具有关键的作用，AKT表达增加则转移能力增强，反之则减弱，其中AKT1促转移作用最强，AKT2次之，AKT3最弱。进一步研究表明多胺通过AKT信号促进肝癌细胞的生长、迁移与侵袭。本研究表明多胺含量异常升高是肿瘤转移的重要微环境之一，本课题的完成不仅对理解肝癌转移的分子机制具有理论意义，也提示可针对多胺及AKT为靶点设计药物用于肝癌转移的预防和治疗。