假基因ENO1P1甲基化修饰的失调对肝细胞癌发生的促进作用机制研究

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor clinical outcome. With the study of the mechanism of HCC, scientists have found that some pseudogenes are closely related to cancer progression. They found that the mRNA level of some pseudogenes increased in cancer tissue, and which promoted the proliferation and invasion of tumor. However, there were few studies on the mechanism of pseudogenes in HCC. In our previous study, we have screened a pseudogene ENO1P1 with higher expression in HCC tissue via high-throughput sequencing. The high expression of ENO1P1 in HCC was significantly positive corresponding with the tumor size and distant metastasis in a large sample validation. And we found that overexpression of ENO1P1 was able to promote the proliferation and invasion of liver cancer cell through cell function experiment. We also preliminarily detected the promoter region hypomethylation changes in the ENO1P1 in HCC. Therefore, we assumed that DNA hypomethylation could promote the transcription of ENO1P1, which may be involved in the proliferation and invasion of HCC. In the following study, we will further explore the mechanism for ENO1P1-participated proliferation and invasion of HCC via Methylation Array, gene microarray and cell function experiment. Moreover, this mechanism likely plays an important role in early diagnosis of HCC as a new molecular mechanism.

肝细胞癌（HCC）是严重影响我国国民健康的恶性肿瘤之一，随着对肿瘤发生机制研究的深入，人们发现有些假基因可以促进肿瘤的发生，但在HCC中研究较少。我们在前期工作中利用高通量测序筛选到在HCC组织中高表达的假基因ENO1P1，通过大样本验证和细胞功能实验发现：其高表达与肿瘤大小、远端转移显著正相关；可促进肝癌细胞株的增殖和侵袭；初步检测到ENO1P1启动子区域的低甲基化改变。我们推测，ENO1P1的升高极有可能与其启动子低甲基化有关，并以此对肝癌细胞增殖和侵袭产生促进作用。接下来，我们将利用甲基化芯片深入研究ENO1P1甲基化修饰的改变，利用表达谱芯片筛选ENO1P1调控的下游基因，结合细胞功能实验全面展开ENO1P1启动子区域甲基化修饰的改变对HCC发生发展的作用机制研究。本课题的实施将为探索HCC发生的分子机制开辟新途径，为肝癌早筛早诊提供有效检测指标。

肝细胞癌（HCC）是严重影响我国国民健康的恶性肿瘤之一，随着对肿瘤发生机制研究的深入，人们发现有些假基因可以促进肿瘤的发生，但在HCC中研究较少。本研究利用高通量测序筛选到在HCC组织中高表达的假基因ENO1P1，通过大样本验证和细胞功能实验发现：ENO1P1高表达与肿瘤细胞大小≥5cm（P=0.021），远端转移（P=0.003）及AFP≥200ug/l（P=0.036）显著正相关，并且与预后不良显著正相关；当同时检测ENO1P1和AFP，将提高HCC早期筛查的检出率(同时检测ENO1P1和AFP的检出率为138/179，只检测AFP的检出率为94/179 )；ENO1P1可促进肝癌细胞株的增殖和侵袭及裸鼠成瘤；通过甲基化芯片对ENO1P1表达升高的HCC组织进行检测，发现其某些启动子位点存在低甲基化情况，利用甲基化特异PCR进行大样本验证，我们发现ENO1P1启动子区域一些位点的低甲基化与HCC的不良预后显著正相关(P=0.042)；最后，我们把ENO1P1在HCC细胞株中过表达，通过转录组测序筛选了与ENO1P1表达改变一致的基因，并且通过大样本验证和双基因干扰细胞功能实验，我们筛选到ENO1P1的下游调控基因STC2，ENO1P1可通过促进STC2基因的表达来促进肝细胞癌细胞株增殖，迁移和侵袭。本课题首次在HCC中研究假基因的作用，本研究取得的成果为探索HCC发生的分子机制开辟了新途径，为肝癌早筛早诊提供了新的检测指标。

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