A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma

作者：Luo, Zai-Li; Cheng, Shu-Qun; Shi, Jie; Zhang, Hui-Lu; Zhang, Cun-Zhen; Chen, Hai-Yang; Qiu, Bi-Jun; Tang, Liang; Hu, Cong-Li; Wang, Hong-Yang; Li, Zhong^*

来源：Nature Communications, 2015, 6(1): 8457.

DOI：10.1038/ncomms9457

• NF2 TUMOR-SUPPRESSOR
• NEUROFIBROMATOSIS-2 GENE
• CONTACT INHIBITION
• GROWTH SUPPRESSION
• CELL-LINES
• MUTATIONS
• CANCER
• TUMORIGENESIS
• HOMEOSTASIS
• NF2/MERLIN

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 ((Delta 2-4)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 (Delta 2-4)Merlin interferes with the capacity of wild-type Merlin to bind beta-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, (Delta 2-4)Merlin overexpression increases the expression levels of beta-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 (Delta 2-4)Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis.

• 出版日期2015-10
• 单位中国人民解放军第二军医大学; 河南大学; 复旦大学; 上海交通大学