Int J Med Sci 2021; 18(9):2008-2016. doi:10.7150/ijms.52431

Research Paper

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma

Jia-Liang Liu1,2,3, Yuan-He You1,2,3, Zhuo-Wei Tian1,2,3, Meng Xiao1,2,3, Jia-Wei Zheng1,2,3, Yan-An Wang1,2,3✉, Zhong Du1,2,3✉

1. Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P.R. China.
2. National Clinical Research Center for Oral Diseases, Shanghai 200011, P.R. China.
3. Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, P.R. China.

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Citation:
Liu JL, You YH, Tian ZW, Xiao M, Zheng JW, Wang YA, Du Z. Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma. Int J Med Sci 2021; 18(9):2008-2016. doi:10.7150/ijms.52431. Available from https://www.medsci.org/v18p2008.htm

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Abstract

Plexiform neurofibroma (pNF) in the head and neck is a characteristic feature in patients with neurofibromatosis type 1 (NF1) and is associated with significant disfigurement and psychological distress. Yes-associated protein (YAP), the key molecule involved in the Hippo pathway, is a vital transductor that regulates the proliferation and remyelinating of Schwann cells. The functional status of YAP and its feasibility as a potential target are still unknown in pNF. A total of 17 pNF tumor tissue specimens from the head and neck were collected at the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Histologically, diagnosis of the Schwann cell region in pNF was achieved with hematoxylin-eosin staining, positive reactions for S100, SOX10, ERK and p-ERK, and low identification of Ki67 and SMA. Compared with normal nerve tissue, obviously increased nuclear YAP was detected in the Schwann cell region of pNF, with a mean nuclear staining rate of 67.11%. Based on the shNF1 Schwann cell model (the RSC96 cell line), with upregulated expression of RAS, ERK and p-ERK, p-YAP (Ser127) and p-YAP (Ser397) were significantly decreased and total YAP and nuclear YAP were increased. According to a confocal assay, the interference of shNF1 substantially promoted YAP nuclear translocation. Compared with control Schwann cells, the YAP inhibitor CA3 might have a more sensitive effect (IC50: NC=0.96±0.04, shNF1=0.71±0.02, P<0.05) on the shNF1 Schwann cell model than the classic MEK1/2 inhibitor selumetinib (IC50: NC=14.36±0.95, shNF1=24.83±0.98, P>0.05). For in vivo inhibition, the CA3 group and the selumetinib group displayed a similar inhibition effect with no significant difference. Increased nuclear translation and the functional state of YAP implies that the YAP-Hippo pathway might play an important role in the formation and remyelination of pNF. Compared with selumetinib, the YAP inhibitor can exhibit a similar but more sensitive effect on NF1-/- Schwann cells. These observations imply that YAP as a novel or adjuvant therapy target in the treatment of pNF.

Keywords: Plexiform neurofibroma, head and neck, NF1, YAP, Selumetinib.