Molecular alterations of the NF2 gene in hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Zhang,Ning; Zhao,Zhang; Long,Jiang; Li,Hai; Zhang,Bei; Chen,Guangyong; Li,Xiaojin; Lv,Tingxia; Zhang,Wei; Ou,Xiaojuan; Xu,Anjian; Huang,Jian

doi:10.3892/or.2017.6055

Molecular alterations of the NF2 gene in hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Authors:
- Ning Zhang
- Zhang Zhao
- Jiang Long
- Hai Li
- Bei Zhang
- Guangyong Chen
- Xiaojin Li
- Tingxia Lv
- Wei Zhang
- Xiaojuan Ou
- Anjian Xu
- Jian Huang
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Affiliations: Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China, Department of Oncology Minimally Invasive Interventional Radiology, Beijing You-an Hospital, Capital Medical University, Beijing 100069, P.R. China, Department of Hepatopancreatobiliary and Splenic Medicine, The Affiliated Hospital of Medical College of Chinese People's Armed Police Force, Tianjin 300192, P.R. China, Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
Published online on: October 24, 2017 https://doi.org/10.3892/or.2017.6055
Pages: 3650-3658

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Abstract

Neurofibromatosis type 2 with mutations in the neurofibromin 2 (NF2) gene, encoding the Merlin protein, is an autosomal dominant disorder characterized by enhanced cancer predisposition, particularly tumors of the central nervous system. Recent animal studies indicate that disruption of NF2/Merlin function in oval cells, which are hepatic progenitor cells, may lead to the development of primary liver cancers including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its role in human primary liver cancer remains unclear. In the present study, we explored the role of NF2/Merlin in human primary liver cancers. Tumor tissues (n=144) were used for the screening of NF2 mutation, while whole blood samples from 219 HCC and 194 healthy control cases were used for analysis of single nucleotide polymorphisms (SNPs) in liver cancer. The expression and amplification of NF2/Merlin and its downstream gene in the Hippo pathway, Yes-associated protein (YAP), were also analyzed. Missense NF2 mutations were identified in 2 of 106 (1.9%) HCCs and 2 of 38 (5.3%) ICCs. Allele frequency of NF2 IVS4-39 A/A was significantly higher in the HCCs than that in the healthy controls. Noteworthy, NF2/Merlin showed a dual role as a tumorigenic gene and tumor-suppressor gene; Merlin was expressed at higher levels in tumors than in adjacent non-tumor tissues of HCC; while the rate of Merlin upregulation was significantly lower in poorly differentiated ICCs. In addition, a significant negative correlation between Merlin and YAP expression was observed in ICC. In conclusion, we provide initial evidence of human primary liver cancers characterized by molecular alterations of NF2/Merlin and the involvement of the Hippo pathway in the pathogenesis of human liver cancer.

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