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等，临床。可以。Res., 2013, In Press)在我们的PDAC病例队列中，对胰腺肿瘤中差异表达的FOX基因与患者预后相关性的调查显示，FOXM1和FOXL1与患者生存相关。FOXM1在胰腺癌中的致癌功能已被早期描述，然而，FOXL1在胰腺癌中的作用尚不清楚。这些发现促使我们研究FOXL1在胰腺癌进展中的功能作用。我们发现FOXL1的高表达与人类胰腺导管腺癌（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晚期病理分期相关。机制分析表明，过表达FOXL1可诱导胰腺癌细胞凋亡，抑制增殖和侵袭，而siRNA沉默FOXL1可抑制凋亡，增强肿瘤细胞生长和侵袭。此外，FOXL1过表达可显著抑制裸鼠肿瘤移植物的生长。FOXL1部分通过诱导胰腺癌细胞中tnf相关的凋亡诱导配体（TRAIL）促进细胞凋亡。此外，FOXL1抑制上皮间充质转化（epithelial mesenchymal transition， EMT）激活因子锌指E-box-binding homeobox 1 （ZEB1）的转录，ZEB1的负调控有助于FOXL1抑制肿瘤细胞侵袭。综上所述，我们的研究结果表明FOXL1表达是PDAC切除患者临床预后的候选预测因子，它在胰腺肿瘤进展中起抑制作用。需要进一步的研究来确定在胰腺癌进展过程中驱动FOXL1缺失的分子机制，以及FOXL1的恢复如何被用于治疗益处。

FOXL1, a Novel Candidate Tumor Suppressor, Inhibits Tumor Aggressiveness and Predicts Outcome in Human Pancreatic Cancer (Zhang et. al., Clin. Can. Res., 2013, In Press) 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. These findings led us to 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.