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

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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.