HNRNPK在胃癌发生中的作用及调节胃癌细胞恶性表型的分子机制

Heterogeneous nuclear ribonucleoprotein K (HNRNPK) was abnormally expressed in a variety of cancer, and expression level of which was related with tumor formation, development and prognosis. Found in our previous studies that HNRNPK might play a tumor suppressor gene and participate in regulation of malignant phenotype in gastric cancer. Down-expression of HNRNPK by shRNA increased the capacity of cell proliferation, clone formation, migration and chemo-resistance. From profile database of gene expression in gastric cancer, we found that the expression of HNRNPK was positively correlated with overall survival (OS) and progression-free survival (FP) in gastric cancer patients. Therefore, on the basis of previous work, we will confirm the relationship between HNRNPK and malignant phenotype of gastric cancer cells，clinical significance of HNRNPK in gastric cancer tissues. Gastric cancer model in HNRNPK transgenic mice with P53 knockout model will be produced by methylcholanthrene (MC) induction to verify the impact of HNRNPK and P53 to gastric cancer formation and development. Meanwhile, the molecular mechanisms of malignant phenotype regulated by HNRNPK will be discussed. Thus, mouse models and mechanism analysis will provide theoretical support and experimental basis for foundation of candidate prognosis biomarkers and development of drugs targeting HNRNPK.

核不均一性核糖核蛋白K（HNRNPK）在多种肿瘤中异常表达，其表达水平与肿瘤的发生、发展及预后相关。我们前期发现HNRNPK在胃癌的发生发展过程中可能扮演抑癌基因的角色并参与了胃癌细胞的恶性表型调节。靶向敲低HNRNPK的表达可能通过下调P53通路促进胃癌细胞的恶性表型；胃癌组织基因表达谱数据库分析发现HNRNPK的表达与胃癌患者的总生存、无进展生存呈正相关。本项目拟在前期工作基础上，进一步明确HNRNPK与胃癌细胞恶性表型的关系，分析其表达的临床意义；建立HNRNPK转基因小鼠模型及HNRNPK转基因P53敲除小鼠模型，甲基胆蒽诱发小鼠胃癌，探索HNRNPK对胃癌发生发展的影响及其是否依赖于P53，并初步探讨HNRNPK调节胃癌细胞恶性表型的分子机制。HNRNPK转基因小鼠模型的建立和机制研究将为获得潜在的胃癌预后标志物提供一定的理论依据，为研发针对HNRNPK的靶向药物奠定基础。

胃癌是人类最常见的癌症之一。胃癌发生和发展的分子机制尚不完全清楚。在这项研究中，我们发现核不均一性核糖核蛋白K（HNRNPK）是胃癌患者尤其是早期胃癌的一个有效的预后指标。HNRNPK过表达在体外实验中可抑制肿瘤细胞增殖和集落形成，体内实验时可通过p53/p21/CCND1轴抑制肿瘤生长。生物信息学分析表明HNRNPK相关基因在细胞周期和DNA复制过程富集。蛋白质相互作用网络显示HNRNPK与p53、p21等肿瘤相关基因发生物理相互作用。GSEA分析显示HNRNPK的表达与γ辐射应答及DNA修复呈正相关，同时与血管生成、TGF-β及Hedgehog信号通路的激活呈负相关。最后，研究表明包括甘氨酸在内的几种化学物质可能通过上调HNRNPK抑制胃癌进展。我们的研究表明HNRNPK可能在胃癌中起到抑癌作用并可能成为胃癌的潜在治疗靶点。