TY - JOUR
T1 - Merlin/NF2 suppresses pancreatic tumor growth and metastasis by attenuating the FOXM1-mediated Wnt/β-catenin signaling
AU - Quan, Ming
AU - Cui, Jiujie
AU - Xia, Tian
AU - Jia, Zhiliang
AU - Xie, Dacheng
AU - Wei, Daoyan
AU - Huang, Suyun
AU - Huang, Qian
AU - Zheng, Shaojiang
AU - Xie, Keping
N1 - Funding Information:
The authors thank Don Norwood for editorial assistance and Xuemei Wang, Associate Director of Quantitative Research, for assistance in statistical analyses. This work was supported by grants R01-CA129956, R01-CA148954, R01-CA152309, and R01-CA172233 from the National Cancer Institute, NIH (K. Xie); grant 81460461 (S. Zheng); and grant 81120108017 from the National Natural Science Foundation of China (Q. Huang).
Publisher Copyright:
© 2015 AACR.
PY - 2015/11/15
Y1 - 2015/11/15
N2 - Merlin, the protein encoded by the NF2gene, is a memberof 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/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer.
AB - Merlin, the protein encoded by the NF2gene, is a memberof 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/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer.
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U2 - 10.1158/0008-5472.CAN-14-1952
DO - 10.1158/0008-5472.CAN-14-1952
M3 - Article
C2 - 26483206
AN - SCOPUS:84947503505
SN - 0008-5472
VL - 75
SP - 4778
EP - 4789
JO - Cancer Research
JF - Cancer Research
IS - 22
ER -