Journal
CANCER RESEARCH
Volume 75, Issue 22, Pages 4778-4789Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-1952
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Funding
- National Cancer Institute, NIH [R01-CA129956, R01-CA148954, R01-CA152309, R01-CA172233]
- National Natural Science Foundation of China [81120108017]
- [81460461]
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Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/beta-catenin signaling downstream genes and the nuclear expression of beta-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/beta-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of beta-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/beta-catenin signaling, suggesting that targeting novel Merlin/FOXM1/beta-catenin signaling is an effective therapeutic strategy for pancreatic cancer. (C) 2015 AACR.
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