HNF1A调控EGFR导致“CA19-9低分泌胰腺癌亚群”低度恶性潜能的机制研究

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Identification of PDAC specific subtypes has shown the charisma to improve the therapeutic response. We had uncovered that “CA19-9-Low&Lewis (+) pancreatic cancer” is a unique subtype with long-term survival and lower EGFR expression. Our previous work suggested that HNF1A was overexpressed in this unique subtype according to RNA-Sequencing. Consistent with publishing data, we detected that overexpression of HNF1A was negatively associated with CA19-9 synthesis related genes, which caused a low CA19-9 secreting. We additionally detected that HNF1A expression was negatively correlated with EGFR expression via co-expression analysis. Besides, ChIP-Sequencing data denoted that HNF1A was able to binding to EGFR fragment sequence. Therefore, we propose a hypothesis that HNF1A transcriptionally regulated EGFR and suppressed progression of pancreatic cancer in “CA19-9-Low&Lewis (+)” subtype. In current study, we would investigate the mechanism of the suppression role of HNF1A in pancreatic cancer, which might suggest the new strategy for efficient therapy.

胰腺癌恶性程度极高，针对特殊亚群开展研究是提高其治疗效果的关键。我们报道了“CA19-9低分泌胰腺癌亚群”是一个具有低恶性潜能的特殊群体，又发现肝细胞核因子α（HNF1A）在此群体中表达显著升高。我们前期研究表明HNF1A过表达能够抑制CA19-9分泌；采用RNA-Seq及ChIP-Seq分析发现，胰腺癌细胞中HNF1A可与EGFR基因序列片段相结合并抑制EGFR表达。由此可假设：HNF1A通过转录调控EGFR抑制胰腺癌恶性潜能。本课题拟对HNF1A及EGFR在胰腺癌亚群中影响肿瘤发生发展的机制开展深入研究，此研究成果将解释低恶性潜能亚群的生物学特征，为胰腺癌的有效治疗提供的新靶点。

胰腺癌恶性程度极高，针对特殊亚群开展研究是提高其治疗效果的关键。我们前期研究发现肝细胞核因子α（HNF1A）在 低恶性潜能的特殊群体“CA19-9低分泌胰腺癌亚群”中显著高表达，又发现HNF1A过表达能够抑制CA19-9分泌，而在胰腺癌细胞中HNF1A可与EGFR基因序列片段相结合并抑制EGFR表达。由此提出假设：HNF1A通过转录调控EGFR抑制胰腺癌恶性潜能。研究通过在胰腺癌细胞中过表达HNF1A后发现细胞的侵袭及转移能力，以及细胞干性都显著增加，而通过转录组研究对HNF1A的下游调节基因发现，下游基因主要与信号转导、细胞粘附及免疫反应相关。而对这些通路研究发现，HNF1A能够调控抑制PI3K/AKT，并且影响黏着斑和蛋白聚糖形成。同时我们对不同胰腺癌细胞在不同葡萄糖浓度处理下CA19-9的表达研究发现，高糖处理下CA19-9的表达会增加，而HNF1A的表达水平会降低同时PI3K/AKT信号被激活。通过对100例胰腺癌病例的转录相关基因的转录水平表达差异进行分析，我们发现了四个代谢相关基因RAF1, AKT3, IDH1, 以及 FGFR1能够显著影响胰腺癌患者的预后，其中IDH1分子受到HNF1A表达调控并且与CA19-9的表达的具有强相关性。总结以上研究我们认为HNF1A在胰腺癌中与肿瘤的代谢方式紧密相关，通过增加葡萄糖利用的同时也会刺激肿瘤恶性潜能增加。此研究成果将解释低恶性潜能亚群的生物学特征，为胰腺癌的有效治疗提供的新靶点。