癌基因诱导的细胞衰老对肝母细胞瘤侵袭性的影响及机制研究

Hepatoblastoma (HB) is the most popular liver cancer in children and is highly invasive. In the zebrafish HB model, we found that cell senescence is closely related with the invasion of tumor cells. Enhancing cell senescence via small molecule compounds can inhibit HB invasion significantly. What is the mechanism of cell senescence in inhibiting HB invasion? The pre-experimental data showed that TIMP2 was positively correlated with cell senescence while negatively correlated with HB invasion. Therefore, we hypothesized that senescent cells inhibit HB invasion by secreting TIMP2. To further clarify the role and mechanism of cell senescence in HB, we will further investigate: 1) knock out and over express TIMP2 in HB cells and zebrafish HB model to demonstrate that cell senescence inhibits HB invasion through secreting TIMP2; 2) explore the relationship between cell senescence/TIMP2 and prognosis in clinic. This study will reveal the relationship between cell senescence and HB invasion, and provide novel therapeutic strategies and theoretical basis for screening effective drugs for the treatment of HB.

肝母细胞瘤（HB）是最常见的儿童肝脏恶性肿瘤，侵袭性强。我们前期在斑马鱼HB模型中发现：癌基因诱导的细胞衰老与肿瘤细胞的侵袭密切相关，且通过小分子化合物促进细胞衰老可显著性抑制HB的侵袭。细胞衰老通过何种机制抑制HB的侵袭性？预实验数据显示TIMP2与细胞衰老呈正相关，而与HB的侵袭性呈负相关。因此，我们假设衰老细胞通过分泌TIMP2抑制HB的侵袭。为进一步明确细胞衰老在HB中的作用及机制，本项目拟：1）在HB细胞系及斑马鱼HB模型上敲除及过表达TIMP2，论证衰老细胞分泌TIMP2抑制HB侵袭的作用；2）在临床上检测细胞衰老及其相关基因表达、TIMP2表达与HB侵袭转移及预后的关系。本项目将揭示细胞衰老与HB侵袭的关系，同时为研发治疗HB的有效药物提供新的策略和理论依据。

本项目工作开展是希望通过基础科学研究加深对小儿最常见的肝脏原发性恶性肿瘤-肝母细胞瘤机制的理解，从而对疾病治疗和药物设计提供一定的理论基础。本项目在肝细胞癌的机制以及中国儿童肝母细胞瘤临床方面的数据分析取得了一定进展，达到了预期目标。.在临床方面，我们利用全基因组测序统计了213位中国肝母细胞瘤儿童样本与958位健康对照组，结果显示与成人癌症有极强相关性的LINC00673 rs11655237 C>T，H19（rs2839698, rs3024270 和 rs217727）多态性与中国儿童肝母细胞瘤患者易感性相关，而我们前期比较关注的KRAS、NRAS和MYC基因多态性与中国儿童肝母细胞瘤患者的易感性并无显著性的关系。.在动物模型方面，我们利用斑马鱼模式动物进行体内注射原代癌细胞，构建了斑马鱼体内癌症模型。结果证明，以斑马鱼为模式动物进行早期临床药物筛选是很有潜力的。相对于细胞培养，斑马鱼模式动物能更好模拟肿瘤的生长体内环境。以斑马鱼模式动物作为承载体，不仅可以模拟体内微环境，还能够避免啮齿动物周期长、花费贵等缺点，是非常理想的临床前期动物模型。