Forkhead-box (FOX) Transcription Factors in the Progression of Pancreatic Cancer

在我们的PDAC病例队列中，对胰腺肿瘤中差异表达的FOX基因与患者结局的相关性进行了研究，结果显示FOXM 1和FOXL 1与患者生存率相关。FOXM 1在胰腺癌中的致癌功能已被早期描述，然而，FOXL 1在胰腺癌中的作用尚不清楚。此外，过表达MIF的胰腺癌细胞和原位肿瘤具有降低的FOXL 1水平。这些发现使我们首先研究FOXL 1在胰腺癌进展中的功能作用。我们发现FOXL 1的高表达与人胰腺导管腺癌（PDAC）的良好临床结局显著相关。此外，FOXL 1的低表达与胰腺癌的转移和晚期病理阶段相关。机制分析表明，FOXL 1的过表达诱导胰腺癌细胞凋亡，抑制增殖和侵袭，而FOXL 1的siRNA沉默抑制凋亡，增强肿瘤细胞的生长和侵袭。此外，FOXL 1过表达显著抑制裸鼠中肿瘤异种移植物的生长。FOXL 1部分通过诱导胰腺癌细胞中的肿瘤坏死因子相关凋亡诱导配体（TRAIL）促进凋亡。此外，FOXL 1抑制锌指E-box-binding homeobox 1（ZEB 1）的转录，ZEB 1是上皮间质转化（EMT）的激活剂，ZEB 1的负调控有助于FOXL 1抑制肿瘤细胞侵袭。总之，我们的研究结果表明FOXL 1表达是PDAC切除患者临床结局的候选预测因子，并且在胰腺肿瘤进展中起抑制作用。进一步的研究是必要的，以确定在胰腺癌进展过程中驱动FOXL 1丢失的分子机制，以及如何利用FOXL 1的恢复来获得治疗益处。我们目前正在研究MIF调节FOXL 1的机制。

Investigation of the differentially expressed FOX genes in pancreatic tumors for their association with patient outcome in our cohort of PDAC cases revealed that FOXM1 and FOXL1 are associated with patient survival. FOXM1 has been earlier described for its oncogeneic function in pancreatic cancer, however, the role of FOXL1 in pancreatic cancer is not known. Furthermore, pancreatic cancer cells and orthotopic tumors overexpressing MIF have a reduced level of FOXL1. These findings led us to first investigate the functional role of FOXL1 in pancreatic cancer progression. We found that a higher expression of FOXL1 is significantly associated with better clinical outcome in human pancreatic ductal adenocarcinoma (PDAC). Furthermore, a lower FOXL1 expression is correlated with metastasis and advanced pathological stage of pancreatic cancer. Mechanistic analyses demonstrated that over-expression of FOXL1 induces apoptosis and inhibits proliferation and invasion in pancreatic cancer cells, whereas silencing of FOXL1 by siRNA inhibited apoptosis and enhanced tumor cell growth and invasion. Furthermore, FOXL1 overexpression significantly suppressed the growth of tumor xenografts in nude mice. FOXL1 promoted apoptosis partly through the induction of TNF-related apoptosis-inducing ligand (TRAIL) in pancreatic cancer cells. In addition, FOXL1 suppressed the transcription of zinc finger E-box-binding homeobox 1 (ZEB1), an activator of epithelial mesenchymal transition (EMT), and the negative regulation of ZEB1 contributed to the inhibitory effect of FOXL1 on tumor cell invasion. Taken together, our findings suggest that FOXL1 expression is a candidate predictor of clinical outcome in patients with resected PDAC and it plays an inhibitory role in pancreatic tumor progression. Further studies are warranted to determine the molecular mechanism driving the loss of FOXL1 during pancreatic cancer progression and how the restoration of FOXL1 can be harnessed for therapeutic benefit. We are currently investigating the mechanism by which MIF regulates FOXL1.