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

FOXL1，一种新的候选肿瘤抑制因子，抑制肿瘤侵袭性并预测人类胰腺癌的预后(Zhang et.艾尔，克莱恩。能。结果，2013)在我们的PDAC病例队列中，对胰腺肿瘤中差异表达的Fox基因与患者预后的关系的研究表明，FOXM1和FOXL1与患者的生存相关。FOXM1在胰腺癌中的致癌作用早有报道，然而，FOXL1在胰腺癌中的作用尚不清楚。此外，高表达MIF的胰腺癌细胞和原位肿瘤的FOXL1水平降低。这些发现引导我们首先研究FOXL1在胰腺癌进展中的功能作用。我们发现FOXL1的高表达与人胰腺导管腺癌(PDAC)的临床预后显著相关。此外，FOXL1的低表达与胰腺癌的转移和病理分期有关。机制分析表明，FOXL1过表达可诱导胰腺癌细胞凋亡，抑制细胞增殖和侵袭，而siRNA沉默FOXL1可抑制细胞凋亡，促进肿瘤细胞生长和侵袭。此外，FOXL1过表达显著抑制裸鼠移植瘤的生长。FOXL1通过诱导肿瘤坏死因子相关的凋亡诱导配体(TRAIL)促进胰腺癌细胞的凋亡。此外，FOXL1还抑制上皮间充质转化(EMT)激活剂锌指E盒结合同源盒1(ZEB1)的转录，而ZEB1的负调控参与了FOXL1对肿瘤细胞侵袭的抑制作用。综上所述，我们的研究结果表明，FOXL1的表达是预测切除PDAC患者临床结果的候选指标，并且它在胰腺肿瘤的进展中起着抑制作用。有必要进行进一步的研究，以确定胰腺癌进展过程中FOXL1缺失的分子机制，以及如何利用FOXL1的恢复来获得治疗效益。我们目前正在研究MIF调节FOXL1的机制。

FOXL1, a Novel Candidate Tumor Suppressor, Inhibits Tumor Aggressiveness and Predicts Outcome in Human Pancreatic Cancer (Zhang et. al., Clin. Can. Res., 2013) 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 of FOXL1.