天冬氨酸/天冬酰胺羟化酶调控肝癌细胞失巢凋亡促进肝癌转移及其机制

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high mortality in China. Despite advances in surgical resection, the disease outcome is still far from satisfactory mostly due to a high recurrence rate, up to 70% over 5 years postoperatively．HCC recurrence is mostly caused by hematogenous metastasis. Previous research has pointed that circulation of tumor cells in blood system is a rate-limit step in the process of tumor metastasis,during which most tumor cells died due to cell anoikis. However, the mechanism underlying anoikis resistance of HCC cells is rarely understood. Previous work in our lab has identified aspartate/aspargine beta-hydroxylase (ASPH)is a novel gene that is highly expressed in tumor tissues and predictive for patient survival and tumor recurrence in HCC. However,the exact function of ASPH remains to be illuminated. This study is aimed to investigate whether ASPH regulated cell anoikis during tumor metastasis of HCC cells, mainly focusing on the following issues:1.We will testify the role of ASPH in regulating HCC cell anoikis in in experimental models assaying cell anoikis in vitro;2.We will investigate downstream signaling of ASPH confering tumor cell resistant to anoikis stimulus through cDNA microarray and mass spectral analysis of proteins interacting with ASPH;3.We will establish the animal model of tumor metastasis by injecting tumor cells through tail vein, and use this model for demonstrating the role of ASPH in regulating cell anoikis and tumor metastasis and evaluating the effect of inhibiting ASPH for preventing tumor recurrence.

肝细胞癌是我国高发且致死率较高的恶性肿瘤。尽管肝癌的外科治疗进步迅速，但是接受手术的病人仍有高达70%的复发率，严重影响了肝癌的治疗效果。肝癌的复发主要是由血道转移导致的。相关研究表明，肿瘤细胞在循环系统中大量的死亡是肿瘤转移中的一个重要限速步骤，这主要是通过失巢凋亡来调节的。然而对于肝癌细胞抵御失巢凋亡的机制缺乏了解。本实验室前期工作发现天冬氨酸/天冬酰胺羟化酶（ASPH）是一个在肝癌组织中高表达且与肿瘤复发高度相关的新基因，但其具体机制尚不明。本课题拟探讨ASPH是否参与调节肝癌细胞抵御失巢凋亡及其具体的分子机制，主要通过1.在体外失巢凋亡模型上验证ASPH能否影响肝癌细胞抵御失巢凋亡；2.利用基因表达谱芯片和相互作用蛋白质谱分析研究ASPH调节失巢凋亡的分子机制；3.利用尾静脉注射肿瘤细胞诱导转移的动物模型验证ASPH对失巢凋亡和转移的影响，并评估抑制ASPH对抗转移的作用。