Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling.
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/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.
Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.|Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ming
M
Quan
Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.|Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jiujie
J
Cui
Department of Gastroenterology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
Tian
T
Xia
Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Zhiliang
Z
Jia
Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
Dacheng
D
Xie
Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Daoyan
D
Wei
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Suyun
S
Huang
Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
Qian
Q
Huang
Pathology Department of Affiliated Hospital, Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan, People's Republic of China.
Shaojiang
S
Zheng
Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Keping
K
Xie
D000818:Animals; D015153:Blotting, Western; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D025581:Neurofibromin 2 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000502:physiology*
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D025581:Neurofibromin 2