Fu Zhao1, Zhijun Yang2, Yang Chen3, Qiangyi Zhou4, Jing Zhang4, Jiang Liu5, Bo Wang6, Qiyang He3, Li Zhang5, Yanbing Yu7, Pinan Liu2. 1. Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People's Republic of China; Neural Reconstruction Department, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China; Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People's Republic of China. 2. Neural Reconstruction Department, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China; Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People's Republic of China. 3. Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China. 4. Neural Reconstruction Department, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China. 5. Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People's Republic of China. 6. Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People's Republic of China. 7. Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People's Republic of China. Electronic address: yuyanbing123@126.com.
Abstract
OBJECTIVE: Vestibular schwannomas (VSs) can cause serious neurological defects including hearing loss and facial paralysis. The aim of this study is to identify whether Hippo signaling could be a potential targetable pathway for clinical treatment in VSs. METHODS: Gene expression profiling was performed in 10 sporadic VSs and 4 normal nerves to identify aberrant genes expression of the Hippo pathway. Western blotting and immunohistochemical staining were used to examine the expression of Hippo core components in 20 VS samples. Neurofibromatosis type 2 (NF2) gene sequencing was also performed in all tumors using sanger sequencing. Verteporfin, inhibitor of yes-associated protein (YAP)-TEA domain family member, was used to assess the effect of proliferation inhibition in human primary VS cells and RT4-D6P2T cell line. RESULTS: We found 51 differentially expressed genes of the Hippo pathway between VSs and healthy controls. Unsupervised analysis identified the 2 molecular variants that significantly related with distinct NF2 mutation status. The phosphorylation levels of large tumor suppressor 1 and YAP were significantly decreased in NF2-mutated VSs compared with wild-type VSs and normal nerves. Immunohistochemical staining showed that increased nuclear YAP expression in VSs was positively correlated with high Ki-67 index and low Merlin expression. Verteporfin reduced viability of primary VS cells and RT4-D6P2T cells. CONCLUSIONS: Our findings implicate that deregulation of the Hippo pathway as a molecular mechanism of pathogenesis in human VSs, and suggest inhibition of this pathway as a potential treatment strategy.
OBJECTIVE:Vestibular schwannomas (VSs) can cause serious neurological defects including hearing loss and facial paralysis. The aim of this study is to identify whether Hippo signaling could be a potential targetable pathway for clinical treatment in VSs. METHODS: Gene expression profiling was performed in 10 sporadic VSs and 4 normal nerves to identify aberrant genes expression of the Hippo pathway. Western blotting and immunohistochemical staining were used to examine the expression of Hippo core components in 20 VS samples. Neurofibromatosis type 2 (NF2) gene sequencing was also performed in all tumors using sanger sequencing. Verteporfin, inhibitor of yes-associated protein (YAP)-TEA domain family member, was used to assess the effect of proliferation inhibition in human primary VS cells and RT4-D6P2T cell line. RESULTS: We found 51 differentially expressed genes of the Hippo pathway between VSs and healthy controls. Unsupervised analysis identified the 2 molecular variants that significantly related with distinct NF2 mutation status. The phosphorylation levels of large tumor suppressor 1 and YAP were significantly decreased in NF2-mutated VSs compared with wild-type VSs and normal nerves. Immunohistochemical staining showed that increased nuclear YAP expression in VSs was positively correlated with high Ki-67 index and low Merlin expression. Verteporfin reduced viability of primary VS cells and RT4-D6P2T cells. CONCLUSIONS: Our findings implicate that deregulation of the Hippo pathway as a molecular mechanism of pathogenesis in human VSs, and suggest inhibition of this pathway as a potential treatment strategy.
Authors: Jessica E Sagers; Roberta L Beauchamp; Yanling Zhang; Sasa Vasilijic; Limeng Wu; Patrick DeSouza; Richard Seist; Wenjianlong Zhou; Lei Xu; Vijaya Ramesh; Konstantina M Stankovic Journal: Sci Rep Date: 2020-03-06 Impact factor: 4.379