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Nat Commun. 2015 Oct 7;6:8457. doi: 10.1038/ncomms9457.

A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma.

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International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiiary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai 200433, China.
Institute of Biomedical Sciences, Fudan University, 138 Medical College Road, Shanghai 200032, China.
Department of Surgery, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai 200433, China.
Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, China.
Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, 24 Jinghua Road, Luoyang 471003, China.
Shanghai Center for Engineering Cell Therapy Research, 75 Qianyang Road, Shanghai 201805, China.


Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 ((Δ2-4)Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that (Δ2-4)Merlin interferes with the capacity of wild-type Merlin to bind β-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, (Δ2-4)Merlin overexpression increases the expression levels of β-catenin and stemness-related genes, induces the epithelium-mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the (Δ2-4)Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis.

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