长链非编码RNA-FGD5-AS1作为ceRNA与miR-137/Calpain2/Dicer反馈环路相互作用促进胰腺癌的侵袭转移

Pancreatic cancer is highly invasive, which is still a difficulty for clinical treatment. Recent research found that the lncRNA can be finctions as ceRNA to regulate the expression of miRNA and downstream target genes，miRNAs play a central role in the occurrence, invasion and metastasis of numerous tumors.Our preliminary study suggests that lncRNA FGD5-AS1 was high expression, which regulate the expression of the miR-137, and then affects the expression of specific genes for metastasis of pancreatic cancer. Therefore, we put forward the research hypothesis, FGD5 - AS1 function as ceRNA, competing with miR-137, to promote the expression of target genes Calpain2, which protease solution FAK and Talin promote focal adhesion turnover, ultimately promote the invasion and metastasis of pancreatic cancer.

胰腺癌的高侵袭转移性仍然是临床治疗的难点。研究认为lncRNA可作为ceRNA可调控microRNA及下游靶基因的表达，在众多的肿瘤发生、侵袭和转移中有着重要的作用。我们前期的研究中发现lncRNA-FGD5-AS1在胰腺癌患者中表达上调，并且调控miR-137的表达进而影响着胰腺癌侵袭转移特异基因的表达。因此，我们提出研究假设，FGD5-AS1作为ceRNA与miR-137相互作用，引起下游靶基因Calpain2的表达上调，通过蛋白酶解FAK、Talin促进黏着斑的周转，进而促进胰腺癌的侵袭转移。

炎症分子和外泌体对肿瘤相关巨噬细胞和肿瘤细胞之间的信号转导至关重要。IL-6是M2巨噬细胞极化后分泌的关键炎症分子，可介导胰腺癌的恶性进展。然而，IL-6和肿瘤源性外泌体在肿瘤相关巨噬细胞和PC中的作用和机制尚不清楚。转录组芯片和实时荧光定量PCR实验表明FGD5-AS1诱导IL-6及FGD5-AS1高表达与胰腺癌患者预后不良相关。通过RNA沉降实验、质谱和双荧光报告素酶实验分析来鉴定外泌体FGD5-AS1促进胰腺癌进展和M2巨噬细胞极化的机制。FGD5-AS1与M2巨噬细胞共培养具有促癌作用。胰腺癌源性外泌体FGD5-AS1通过激活STAT3/NF-κB通路刺激M2巨噬细胞极化。FGD5-AS1与p300相互作用，导致STAT3乙酰化，从而促进STAT3/NF-κB的核定位和转录活性。这些实验结果表明胰腺癌细胞产生富含FGD5-AS1的外泌体，导致M2巨噬细胞极化，促进胰腺癌细胞的恶性行为。靶向外泌体FGD5-AS1可能为胰腺癌患者提供潜在的诊断和治疗策略。